Biochemistry and pathobiochemistry of blood.
Respiratory function of erythrocytes. Pathological forms of hemoglobin.
Acid-base state of blood. Non-protein nitrogenous containing and nitrogen not containing organic
components of blood. Residual nitrogen. Lipoproteins of blood
plasma. Biochemistry of
immune processes.
Blood is a
liquid tissue. Suspended in the watery plasma are seven
types of cells and cell fragments.
· red blood cells (RBCs)
or erythrocytes
· platelets or thrombocytes
· five kinds of white blood cells (WBCs) or leukocytes
o Three kinds of granulocytes
§ neutrophils
§ eosinophils
§ basophils
o Two kinds of
leukocytes without granules in their cytoplasm
§
lymphocytes
monocytes
§
If one takes a sample of blood,
treats it with an agent to prevent clotting, and spins it in a centrifuge,
· the red cells
settle to the bottom
· the white
cells settle on top of them forming the "buffy coat".
The
fraction occupied by the red cells is called the hematocrit. Normally it is
approximately 45%. Values much lower than this are a sign of anemia.
Biological
functions of the blood
The blood is
the most specialized fluid tissue which circulates in vascular system and
together with lymph and intercellular space compounds an internal environment
of an organism.
The blood executes such functions:
1.
Transport of gases – oxygen from lungs is carried to tissues and carbon dioxide
from tissues to lungs.
2.
Transport of nutrients to all cells of organism (glucose, amino acids, fatty
acids, vitamins, ketone bodies, trace substances and others). Substances such
as urea, uric acid, bilirubin and creatinine are taken away from the different
organs for ultimate excretion.
3.
Regulatory or hormonal function – hormones are secreted in to blood and they
are transported by blood to their target cells.
4.
Thermoregulation function - an exchange of heat between tissues and blood.
5.
Osmotic function- sustains osmotic pressure in vessels.
6.
Protective function- by the phagocytic action of leucocytes and by the actions
of antibodies, the blood provides the most important defense mechanism.
7.
Detoxification function - neutralization of toxic substances which is connected
with their decomposition by the help of blood enzymes.
Blood
performs two major functions:
· transport through the body of
o oxygen and carbon dioxide
o food
molecules (glucose, lipids, amino acids)
o ions (e.g., Na+, Ca2+,
HCO3−)
o wastes (e.g., urea)
o hormones
o heat
· defense of
the body against infections and other foreign materials. All the WBCs participate in these
defenses.
The formation of blood cells (cell types and
acronyms are defined below)
All the various types of blood cells
· are produced
in the bone marrow (some 1011 of them each day in an adult human!).
· arise from a
single type of cell called a hematopoietic
stem cell — an
"adult" multipotent stem cell.
These stem cells
· are very rare
(only about one in 10,000 bone marrow cells);
· are attached
(probably by adherens junctions)
to osteoblasts lining the
inner surface of bone cavities;
· express a
cell-surface protein designated CD34;
· produce, by
mitosis, two kinds of progeny:
o more stem cells
(A mouse that has had all its blood stem cells killed by a lethal dose of
radiation can be saved by the injection of a single living stem cell!).
o cells that
begin to differentiate along the paths leading to the various kinds of blood
cells.
Which path is taken is regulated by
· the need for
more of that type of blood cell which is, in turn, controlled by appropriate cytokines and/or
hormones.
Examples:
· Interleukin-7 (IL-7)
is the major cytokine in stimulating bone marrow stem cells to start down the
path leading to the various lymphocytes (mostly B cells andT
cells
).
· Erythropoietin (EPO), produced by the
kidneys, enhances the production of red
blood cells (RBCs).
· Thrombopoietin (TPO), assisted by Interleukin-11 (IL-11),
stimulates the production of megakaryocytes. Their fragmentation produces platelets.
· Granulocyte-macrophage
colony-stimulating factor (GM-CSF),
as its name suggests, sends cells down the path leading to both those cell
types. In due course, one path or the other is taken.
o Under the influence of granulocyte colony-stimulating
factor (G-CSF), they
differentiate into neutrophils.
o Further stimulated by
interleukin-5 (IL-5) they develop into eosinophils.
o Interleukin-3 (IL-3)
participates in the differentiation of most of the white blood cells but plays
a particularly prominent role in the formation of basophils(responsible
for some allergies).
o Stimulated by macrophage colony-stimulating
factor (M-CSF) the
granulocyte/macrophage progenitor cells differentiate into monocytes, macrophages, and dendritic cells (DCs).
Two types of blood cells can be
distinguished - white and red blood cells. White blood cells are called leucocytes.
Their quantity in adult is 4-9
x 109/L. Red
blood cells are called erythrocytes. Their
quantity in peripheral blood is 4,5-5 x 1012/L.
Besides that, there are also thrombocytes or platelets in blood.
Leucocytes
(white blood cells) protect an
organism from microorganisms, viruses and foreign substances, that provides the
immune status of an organism.
· are much less numerous than red
(the ratio between the two is around 1:700),
· have nuclei,
· participate in protecting the
body from infection,
· consist of lymphocytes and monocytes with relatively clear cytoplasm, and
three types of granulocytes,
whose cytoplasm is filled with granules.
Leucocytes
are divided into two groups: Granulocytes and agranulocytes. Granulocytes
consist of neutrophils, eosinophils and basophils. Agranulocytes consist of
monocytes and lymphocytes.
http://www.youtube.com/watch?v=8ytkFqAMoa8
http://www.youtube.com/watch?v=ce0Xndms1bc
Neutrophils
comprise of 60-70 % from all leucocytes. Their main function is to protect
organisms from microorganisms and viruses. Neutrophils have segmented nucleus,
endoplasmic reticulum (underdeveloped) which does not contain ribosomes,
insufficient amount of mitochondria, well-developed Golgi apparatus and
hundreds of different vesicles which contain peroxidases and hydrolases.
Optimum condition for their activity is acidic pH. There are also small
vesicles which contain alkaline phosphatases, lysozymes, lactopherins and proteins of cationic origin.
Glucose
is the main source of energy for neutrophils. It is directly utilized or
converted into glycogen. 90 % of energy is formed in glycolysis, a small amount
of glucose is converted in pentosophosphate pathway. Activation of proteolysis
during phagocytosis as well as reduction of phosphatidic acid and
phosphoglycerols are also observed. The englobement is accompanied by
intensifying of a glycolysis and pentosophosphate pathway. But especially
intensity of absorption of oxygen for neutrophils - so-called flashout of
respiration grows. Absorbed oxygen is spent for formation of its fissile forms
that is carried out with participation enzymes:
1. NADP*Н -OXYDASE catalyzes formation of super
oxide anion
2.
An enzyme NADH- OXYDASE is responsible for formation
of hydrogen peroxide
3. Мyeloperoxydase catalyzes formation of hypochloric acid from
chloride and hydrogen peroxide
Neutrophils
are motile phagocyte cells that play a key role in acute inflammation. When
bacteria enter tissues, a number of phenomena occur that are collectively known
as acute inflammatory response. When neutrophils and other phagocyte cells
engulf bacteria, they exhibit a rapid increase in oxygen consumption known as
the respiratory burst. This phenomenon reflects the rapid utilization of oxygen
(following a lag of 15-60 seconds) and production from it of large amounts of
reactive derivates, such as O2-, H2O2,
OH. and OCl- (hypochlorite ion). Some of these
products are potent microbicidal agents. The electron transport chain system
responsible for the respiratory burst contains several components, including a
flavoprotein NADPH:O2-oxidoreductase (often called NADPH-oxidase)
and a b-type cytochrome.
The
most abundant of the WBCs. This photomicrograph shows a single neutrophil
surrounded by red blood cells.
Neutrophils
squeeze through the capillary walls and into infected tissue where they kill
the invaders (e.g., bacteria) and then engulf the remnants by phagocytosis.
This
is a never-ending task, even in healthy people: Our throat, nasal passages, and
colon harbor vast numbers of bacteria. Most of these are commensals, and
do us no harm. But that is because neutrophils keep them in check.
However,
· heavy doses of radiation
· chemotherapy
· and many other forms of stress
can
reduce the numbers of neutrophils so that formerly harmless bacteria begin to
proliferate. The resulting opportunistic
infection can be
life-threatening.
http://www.youtube.com/watch?v=EpC6G_DGqkI&feature=related
Some
important enzymes and proteins of neutrophilis.
Myeloperoxidase (MPO). Catalyzed following reaction:
H2O2 + X-(halide) + H+® HOX
+ H2O (where X- =
Cl-, Br-, I- or
SCN-; HOX=hypochlorous acid)
HOCl,
the active ingredient of household liquid bleach, is a powerful oxidant and is
highly microbicidial. When applied to normal tissues, its potential for causing
damage is diminished because it reacts with primary or secondary amines present
in neutrophils and tissues to produce various nitrogen-chlorine (N-Cl)
derivates; these chloramines are also oxidants, although less powerful than
HOCl, and act as microbicidial agents (eg, in sterilizing wounds) without
causing tissue damage. Responsible for the green color of pus.
NADPH-oxidase.
2O2 + NADPH ® 2O2- + NADP + H+
Key
component of the respiratory burst. Deficiency may be observed in chronic
granulomatous disease.
Lysozyme.
Hydrolyzes
link between N-acetylmuramic acid and N-acetyl-D-glucosamine found in certain
bacterial cell walls. Abundant in macrophages.
Defensins.
Basic
antibiotic peptides of 29-33 amino acids. Apparently kill bacteria by causing
membrane damage.
Lactoferrin.
Iron-binding
protein. May inhibit growth of certain bacteria by binding iron and may be
involved in regulation of proliferation of myeloid cells.
Neutrophils
contain a number of proteinases (elastase, collagenase, gelatinase, cathepsin
G, plasminogen activator) that can hydrolyze elastin, various types of
collagens, and other proteins present in the extracellular matrix. Such
enzymatic action, if allowed to proceed unopposed, can result in serious damage
to tissues. Most of these proteinases are lysosomal enzymes and exist mainly as
inactive precursors in normal neutrophils. Small amounts of these enzymes are
released into normal tissues, with the amounts increasing markedly during
inflammation. The activities of elastase and other proteinases are normally
kept in check by a number of antiproteinases (a1-Antiproteinase, a2-Macroglobulin,
Secretory leukoproteinase inhibitor, a1-Antichymotrypsin, Plasminogen
activator inhibitor-1, Tissue inhibitor of metalloproteinase) present in plasma
and the extracellular fluid.
Basophiles
Basophiles
make up 1-5% of all blood leukocytes. They are actively formed in the
bone marrow during allergy.
Basophiles take part in the
allergic reactions, in the blood coagulation and intravascular lipolysis. They
have the protein synthesis mechanism, which works due to the biological
oxidation energy . They synthesize the mediators of allergic reactions –
histamine and serotonin, which during allergy cause local inflammation.
Heparin, which is formed in the basophiles, prevents the blood coagulation and
activates intravascular lipoprotein lipase, which splits triacylglycerin.
The
number of basophils also increases during infection. Basophils leave the blood
and accumulate at the site of infection or other inflammation. There they
discharge the contents of their granules, releasing a variety of mediators such
as:
· histamine
· serotonin
· prostaglandins
and leukotrienes
which
increase the blood flow to the area and in other ways add to the inflammatory
process. The mediators released by basophils also play an important part in
some allergic responses such as
· hay fever and
· an anaphylactic response to insect stings.
Eosinophiles
They
make up 3-6% of all leukocytes. Eosinophiles as well as neutrophiles defend the
cells from microorganisms, they contain myeloperoxidase, lysosomal hydrolases.
About the relations of eosinophiles with testifies the growth of their amount
during the sensitization of organism, i.e. during bronchial asthma,
helminthiasis. They are able to pile and splits histamine, “to dissolve”
thrombus with the participation of plasminogen and bradykinin-kininase.
Monocytes
They
are formed in the bone marrow.
They make up 4-8% of all leukocytes. According to the function they are called
macrophages. Tissue macrophages derive from blood monocytes. Depending on their
position they are called: in the liver – reticuloendotheliocytes, in the lungs
- alveolar macrophages, in the intermediate substance of connective tissue –
histocytes etc. Monocytes are characterized by a wide set of lysosomal enzymes with the optimum activity in
the acidic condition. The major functions of monocytes and macrophages are
endocytosis and phagocytosis.
The
amount – 20-25%, are formed in the lymphoid tissue or thymus, play important
role in the formation of humoral and cellular immunity. Lymphocytes have
powerful system of synthesis of antibody proteins, energy is majorily pertained
due to glycolysis, rarely – by aerobic way.
http://www.youtube.com/watch?v=cD_uAGPBfQQ&feature=related
There
are several kinds of lymphocytes (although they all look alike under the
microscope), each with different functions to perform . The most common types
of lymphocytes are
· B lymphocytes ("B cells"). These
are responsible for making antibodies.
· T lymphocytes ("T cells"). There
are several subsets of these:
o inflammatory T cells that recruit macrophages and
neutrophils to the site of infection or other tissue damage
o cytotoxic T lymphocytes (CTLs) that kill virus-infected
and, perhaps, tumor cells
o helper T cells that enhance the production of
antibodies by B cells
Although
bone marrow is the ultimate source of lymphocytes, the lymphocytes that will
become T cells migrate from the bone marrow to the thymus where they mature. Both B cells and T
cells also take up residence in lymph nodes, the spleen and other tissues where
they
· encounter antigens;
· continue to divide by mitosis;
· mature into fully functional
cells.
Monocytes
leave the blood and become macrophages and dendritic cells.
This
scanning electron micrograph (courtesy of Drs. Jan M. Orenstein and Emma
Shelton) shows a single macrophage surrounded by several lymphocytes.
Macrophages
are large, phagocytic cells that engulf
· foreign material (antigens) that
enter the body
· dead and dying cells of the
body.
Thrombocytes
(blood platelets)
Platelets
are cell fragments produced from megakaryocytes.
Blood
normally contains 150,000–350,000 per microliter (µl) or cubic millimeter (mm3).
This number is normally maintained by a homeostatic (negative-feedback)
mechanism .
The
amount – less than 1%, they play the main role in the process of hemostasis.
They are formed as a result of disintegration of megakaryocytes in the
bone marrow. Their
–life-time is 7-9 days. In spite of the fact that thrombocytes have no nucleus,
they are able to perform practically all functions of the cell, besides DNA
synthesis.
If
this value should drop much below 50,000/µl, there is a danger of uncontrolled
bleeding because of the essential role that platelets have in blood clotting.
Some
causes:
· certain drugs and herbal
remedies;
· autoimmunity.
When
blood vessels are cut or damaged, the loss of blood from the system must be
stopped before shock and possible death occur. This is
accomplished by solidification of the blood, a process called coagulation or clotting.
A
blood clot consists of
· a plug of platelets enmeshed in a
· network of insoluble fibrin molecules.
The
most numerous type in the blood.
· Women average about 4.8 million
of these cells per cubic millimeter (mm3; which is the same as a
microliter [µl]) of blood.
· Men average about 5.4 x 106 per µl.
· These values can vary over
quite a range depending on such factors as health and altitude. (Peruvians
living at 18,000 feet may have as many as 8.3 x 106 RBCs per µl.)
RBC
precursors mature in the bone marrow closely attached to a macrophage.
· They manufacture hemoglobin until
it accounts for some 90% of the dry weight of the cell.
· The nucleus is squeezed out of
the cell and is ingested by the macrophage.
· No-longer-needed proteins are
expelled from the cell in vesicles called exosomes.
Human
blood contains 25 trillion of erythrocytes. Their main function –
transportation of O2 and
CO2 – they perform due
to the fact that they contain 34% of hemoglobin, and per dry cells mass – 95%.
The total amount of
hemoglobin in the blood equals 130-160 g/l. In the process of erythropoesis the
preceding cells decrease their size. Their nuclei at the end of the process are
ruined and pushed out of the cells. 90% of glucose in the erythrocytes is
decomposed in the process of glycolysis and 10% - by pentose-phosphate way.
There are noted congenital defects of enzymes of these metabolic ways of
erythrocytes. During this are usually observed hemolytic anemia and other
structural and functional erythrocytes’ affections.
This
scanning electron micrograph (courtesy of Dr. Marion J. Barnhart) shows the
characteristic biconcave shape of red blood cells.
Thus
RBCs are terminally differentiated; that is, they can never divide. They live
about 120 days and then are ingested by phagocytic cells in the liver and
spleen. Most of the iron in their hemoglobin is reclaimed for reuse. The
remainder of the heme portion of the molecule is degraded intobile pigments and excreted
by the liver. Some 3 million RBCs die and are scavenged by the liver each
second.
Red
blood cells are responsible for the transport of oxygen and carbon
dioxide.
In
adult humans the hemoglobin (Hb) molecule
· consists of four polypeptides:
o two alpha (α) chains of 141 amino acids and
o two beta (β) chains of 146 amino acids
· Each of these
is attached the prosthetic group heme.
· There is one atom of iron at
the center of each heme.
· One molecule of oxygen can bind
to each heme.
http://www.youtube.com/watch?v=WXOBJEXxNEo&feature=related
The
reaction is reversible.
· Under the
conditions of lower temperature, higher pH, and increased oxygen pressure in
the capillaries of the lungs, the reaction proceeds to the right. The
purple-red deoxygenated hemoglobin of the venous blood becomes the bright-red oxyhemoglobin of the arterial blood.
· Under the conditions of higher
temperature, lower pH, and lower oxygen pressure in the tissues, the reverse reaction
is promoted and oxyhemoglobin gives up its oxygen.
Carbon
dioxide (CO2) combines with water forming carbonic acid, which
dissociates into a hydrogen ion (H+) and a bicarbonate ions
:
CO2 + H2O ↔ H2CO3 ↔ H+ + HCO3−
95%
of the CO2 generated
in the tissues is carried in the red blood cells:
· It
probably enters (and leaves) the cell by diffusing through transmembrane
channels in the plasma membrane. (One of the proteins that forms the channel is
theD antigen that is the
most important factor in the Rh
system of blood groups.)
· Once
inside, about one-half of the CO2 is
directly bound to hemoglobin (at a site different from the one that binds
oxygen).
· The
rest is converted — following the equation above — by the enzyme carbonic anhydrase into
o bicarbonate
ions that diffuse back out into the plasma and
o hydrogen
ions (H+) that bind to the protein portion of the hemoglobin (thus
having no effect on pH).
Only
about 5% of the CO2 generated
in the tissues dissolves directly in the plasma. (A good thing, too: if all the
CO2 we make were
carried this way, the pH of the blood would drop from its normal 7.4 to an
instantly-fatal 4.5!)
When
the red cells reach the lungs, these reactions are reversed and CO2 is released to the air of the alveoli.
Anemia
is a shortage of
· RBCs
and/or
· the
amount of hemoglobin in them.
Blood Groups
Red
blood cells have surface antigens that differ between people and that create
the so-called blood groups such as the ABO system and the Rh system.
An
Essay on Hemoglobin Structure and Function:
Figure 1 is a model of human deoxyhemoglobin.
It was created in RasMol version 2.6 by Roger Sayle using the pdb coordinates
from the pdb file 4hhb. The 3D coordinates were determed from x-ray crystallography
by Fermi, G., Perutz, M. F., Shaanan, B., Fourme, R.: The crystal structure of
human deoxyhaemoglobin at 1.74 A resolution. J Mol Biol 175 pp. 159 (1984)
Hemoglobin
is the protein that carries oxygen from the lungs to the tissues and carries
carbon dioxide from the tissues back to the lungs. In order to function most
efficiently, hemoglobin needs to bind to oxygen tightly in the oxygen-rich
atmosphere of the lungs and be able to release oxygen rapidly in the relatively
oxygen-poor environment of the tissues. It does this in a most elegant and
intricately coordinated way. The story of hemoglobin is the prototype example
of the relationship between structure and function of a protein molecule.
Hemoglobin Structure
A
hemoglobin molecule consists of four polypeptide chains: two alpha chains, each
with 141 amino acids and two beta chains, each with 146 amino acids. The
protein portion of each of these chains is called "globin". The a and
b globin chains are very similar in structure. In this case, a and b refer to
the two types of globin. Students often confuse this with the concept of a
helix and b sheet secondary structures. But, in fact, both the a and b globin
chains contain primarily a helix secondary structure with no b sheets.
Figure 2 is a close up view of one of the heme
groups of the human a chain from dexoyhemoglobin. In this view, the iron
is coordinated by a histidine side chain from amino acid 87 (shown in green.)
Each
a or b globin chain folds into 8 a helical segments (A-H) which, in turn, fold
to form globular tertiary structures that look roughly like sub-microscopic
kidney beans. The folded helices form a pocket that holds the working part of
each chain, the heme.
http://www.youtube.com/watch?v=eor6EK_JP40
A
heme group is a flat ring molecule containing carbon, nitrogen and hydrogen
atoms, with a single Fe2+ ion
at the center. Without the iron, the ring is called a porphyrin. In a heme
molecule, the iron is held within the flat plane by four nitrogen ligands from
the porphyrin ring. The iron ion makes a fifth bond to a histidine side chain
from one of the helices that form the heme pocket. This fifth coordination bond
is to histidine 87 in the human a chain and histidine 92 in the human b chain.
Both histidine residues are part of the F helix in each globin chain. t
The
Bohr Effect
The
ability of hemoglobin to release oxygen, is affected by pH, CO2 and by the differences in the
oxygen-rich environment of the lungs and the oxygen-poor environment of the tissues.
The pH in the tissues is considerably lower (more acidic) than in the lungs.
Protons are generated from the reaction between carbon dioxide and water to
form bicarbonate:
CO2 + H20 ----------------->
HCO3- + H+
This
increased acidity serves a twofold purpose. First, protons lower the affinity
of hemoglobin for oxygen, allowing easier release into the tissues. As all four
oxygens are released, hemoglobin binds to two protons. This helps to maintain
equilibrium towards the right side of the equation. This is known as the Bohr effect, and is vital in
the removal of carbon dioxide as waste because CO2 is insoluble in the bloodstream. The
bicarbonate ion is much more soluble, and can thereby be transported back to
the lungs after being bound to hemoglobin. If hemoglobin couldn’t absorb the
excess protons, the equilibrium would shift to the left, and carbon dioxide
couldn’t be removed.
In
the lungs, this effect works in the reverse direction. In the presence of the
high oxygen concentration in the lungs, the proton affinity decreases. As
protons are shed, the reaction is driven to the left, and CO2 forms as an insoluble gas to be
expelled from the lungs. The proton poor hemoglobin now has a greater affinity
for oxygen, and the cycle continues.
Haemoglobin or hemoglobin (frequently abbreviated as Hb or Hgb) is the iron-containing oxygen-transport metalloprotein in the red blood cells of the blood in vertebratesand
other animals; in mammals the protein makes up about 97% of the
red cell’s dry content, and around 35% of the total content including water.
Hemoglobin transports oxygen from the lungs or gills to the rest of the body, such as to
the muscles, where it releases
the oxygen load. Hemoglobin also has a variety of other gas-transport and
effect-modulation duties, which vary from species to species, and which in
invertebrates may be quite diverse.
The
name hemoglobin is the
concatenation of heme and globin, reflecting the fact that each subunit of hemoglobin is a globular protein with an embedded heme (or
haem) group; each heme group contains an iron atom, and this is responsible for the binding
of oxygen. The most common type of hemoglobin in mammals contains four such
subunits, each with one heme group.
Mutations
in the genes for the hemoglobin protein in humans result
in a group of hereditary diseases termed the hemoglobinopathies,
the most common members of which are sickle-cell
disease and thalassemia. Historically in human
medicine, the hemoglobinopathy of sickle-cell
disease was the first disease to
be understood in its mechanism of dysfunction, completely down to the molecular
level. However, not all of such mutations produce disease states, and are
formally recognized as hemoglobin
variants (not diseases).
Hemoglobin
(Hb) is synthesized in a complex series of steps. The heme portion
is sythesized in both the the mitochondria and cytosol of the immature red blood cell, while
the globin protein portions of the molecule are
sythesized by ribosomes in the cytosol [3]. Production of Hb continues in the
cell throughout its early development from theproerythroblast to the reticulocyte in the bone marrow. At this point, the
nucleus is lost in mammals, but not in birds and many other species. Even after
the loss of the nucleus in mammals, however, residual ribosomal RNA allows
further synthesis of Hb until the reticulocyte loses its RNA soon after
entering the vasculature (this hemoglobin-synthetic RNA in fact gives the reticulocyte its reticulated appearance and name).
The
empirical chemical formula of the most common human hemoglobin is C2952H4664N812O832S8Fe4, but as noted above, hemoglobins vary
widely across species, and even (through common mutations) slightly among
subgroups of humans.
In
humans, the hemoglobin molecule is an assembly of four globular protein subunits. Each subunit is composed of a protein chain tightly associated with a
non-proteinheme group. Each
protein chain arranges into a set of alpha-helix structural segments connected together
in a globin fold arrangement, so called because this
arrangement is the same folding motif used in other heme/globin proteins such
as myoglobin. This folding pattern contains a pocket
which strongly binds the heme group.
A
heme group consists of an iron (Fe) atom held in a heterocyclic ring, known as a porphyrin. The iron atom, which is the
site of oxygen binding, bonds with the fournitrogens in the center of the ring, which all
lie in one plane. The iron is also bound strongly to the globular protein via
the imidazole ring of a histidine residue below the porphyrin ring. A sixth
position can reversibly bind oxygen, completing the octahedral group of six
ligands. Oxygen binds in an "end-on bent" geometry where one oxygen
atom binds Fe and the other protrudes at an angle. When oxygen is not bound, a
very weakly bonded water molecule fills the site, forming a distorted octahedron.
The
iron atom may either be in the Fe2+ or Fe3+ state, but ferrihemoglobin
(methemoglobin) (Fe3+) cannot bind oxygen. In binding, oxygen
temporarily oxidizes Fe to (Fe3+), so iron must exist in the +2
oxidation state in order to bind oxygen. The body reactivates hemoglobin found
in the inactive (Fe3+) state by reducing the iron center.
In
adult humans, the most common hemoglobin type is a tetramer (which contains 4 subunit proteins)
called hemoglobin A,
consisting of two α and two β subunits non-covalently bound, each
made of 141 and 146 amino acid residues, respectively. This is denoted as
α2β2. The subunits are structurally similar and
about the same size. Each subunit has a molecular weight of about
17,000 daltons, for a total molecular
weight of the tetramer of about
68,000 daltons. Hemoglobin A is the most intensively studied of the
hemoglobin molecules.
The
four polypeptide chains are bound to each other by salt bridges, hydrogen bonds, and hydrophobic interactions. There are
two kinds of contacts between the α and β chains: α1β1 and α1β2.
Oxyhemoglobin is formed during respiration when oxygen binds to the heme component
of the protein hemoglobin in red blood cells. This process occurs in the
pulmonary capillaries adjacent to the alveoli of the lungs. The oxygen then travels through
the blood stream to be dropped off at cells where it is utilized in aerobic glycolysis and in the production of ATP by
the process of oxidative
phosphorylation. It doesn't however help to counteract a decrease in blood pH. Ventilation, or breathing, may reverse
this condition by removal of carbon dioxide, thus causing a shift up in pH.
Deoxyhemoglobin is the form of hemoglobin without the bound
oxygen. The absorption spectra of oxyhemoglobin and deoxyhemoglobin
differ. The oxyhemoglobine has significantly lower absorption of the
660 nm wavelength than deoxyhemoglobin, while at
940 nm its absorption is slightly higher. This difference is used for
measurement of the amount of oxygen in patient's blood by an instrument called pulse oximeter.
The
oxidation state of iron in hemoglobin is always +2. It does not change when
oxygen binds to the deoxy- form.
Assigning
oxygenated hemoglobin's oxidation state is difficult because oxyhemoglobin is
diamagnetic (no net unpaired electrons), but the low-energy electron
configurations in both oxygen and iron are paramagnetic. Triplet oxygen, the
lowest energy oxygen species, has two unpaired electrons in antibonding π*
molecular orbitals. Iron(II) tends to be in a high-spin configuration where
unpaired electrons exist in eg antibonding orbitals. Iron(III) has an
odd number of electrons and necessarily has unpaired electrons. All of these
molecules are paramagnetic (have unpaired electrons), not diamagnetic, so an
unintuitive distribution of electrons must exist to induce diamagnetism.
The
three logical possibilities are:
1)
Low-spin Fe2+ binds to
high-energy singlet oxygen. Both low-spin iron and singlet oxygen are
diamagnetic.
2)
High-spin Fe3+ binds
to .O2- (the superoxide ion) and antiferromagnetism oppositely
aligns the two unpaired electrons, giving diamagnetic properties.
3)
Low-spin Fe4+ binds to
O22-. Both are diamagnetic.
X-ray
photoelectron spectroscopy suggests
that iron has an oxidation state of approximately 3.2 and infrared stretching frequencies of the O-O bond suggests a bond length
fitting with superoxide. The correct oxidation state of iron is thus the +3
state with oxygen in the -1 state. The diamagnetism in this configuration
arises from the unpaired electron on superoxide aligning antiferromagnetically
in the opposite direction from the unpaired electron on iron. The second choice
being correct is not surprising because singlet oxygen and large separations of
charge are both unfavorably high-energy states. Iron's shift to a higher
oxidation state decreases the atom's size and allows it into the plane of the
porphyrin ring, pulling on the coordinated histidine residue and initiating the
allosteric changes seen in the globulins. The assignment of oxidation state,
however, is only a formalism so all three models may contribute to some small
degree.
Early
postulates by bioinorganic chemists claimed that possibility (1) (above) was
correct and that iron should exist in oxidation state II (indeed iron oxidation
state III as methemoglobin, when not accompanied by superoxide .O2- to "hold" the oxidation
electron, is incapable of binding O2). The iron chemistry in this
model was elegant, but the presence of singlet oxygen was never explained. It
was argued that the binding of an oxygen molecule placed high-spin iron(II) in
an octahedral field of strong-field ligands; this change in field would
increase the crystal field
splitting energy, causing iron's electrons to pair into the diamagnetic
low-spin configuration.
Binding
and release of ligands induces a conformational (structural) change in
hemoglobin. Here, the binding and release of oxygen illustrates the structural
differences between oxy- and deoxyhemoglobin, respectively. Only one of the
four heme groups is shown.
As
discussed above, when oxygen binds to the iron center it causes contraction of
the iron atom, and causes it to move back into the center of the porphyrin ring
plane (see moving diagram). At the same time, the porphyrin ring plane itself is
pushed away from the oxygen and toward the imidizole side chain of the
histidine residue interacting at the other pole of the iron. The interaction
here forces the ring plane sideways toward the outside of the tetramer, and
also induces a strain on the protein helix containing the histidine, as it
moves nearer the iron. This causes a tug on this peptide strand which tends to
open up heme units in the remainder of the molecule, so that there is more room
for oxygen to bind at their heme sites.
In
the tetrameric form of normal adult hemoglobin, the binding of oxygen is thus a cooperative process. The binding affinity of
hemoglobin for oxygen is increased by the oxygen saturation of the molecule,
with the first oxygens bound influencing the shape of the binding sites for the
next oxygens, in a way favorable for binding. This positive cooperative binding
is achieved through steric conformational changes of the
hemoglobin protein complex as discussed above, i.e. when one subunit protein in
hemoglobin becomes oxygenated, this induces a conformational or structural
change in the whole complex, causing the other subunits to gain an increased
affinity for oxygen. As a consequence, the oxygen binding curve of hemoglobin
is sigmoidal, or S-shaped,
as opposed to the normal hyperbolic curve associated with noncooperative
binding.
Hemoglobin's
oxygen-binding capacity is decreased in the presence of carbon monoxide because both gases compete for the
same binding sites on hemoglobin, carbon monoxide binding preferentially in
place of oxygen. Carbon dioxide occupies a different binding
site on the hemoglobin. Through the enzyme carbonic
anhydrase, carbon dioxide reacts with water to give carbonic acid, which decomposes into bicarbonate and protons:
CO2 + H2O → H2CO3 → HCO3- + H+
The
sigmoidal shape of hemoglobin's oxygen-dissociation curve results from cooperative binding of oxygen to hemoglobin.
Hence
blood with high carbon dioxide levels is also lower in pH (more acidic). Hemoglobin can bind protons and carbon dioxide which causes a
conformational change in the protein and facilitates the release of oxygen.
Protons bind at various places along the protein, and carbon dioxide binds at
the alpha-amino group forming carbamate. Conversely, when the carbon
dioxide levels in the blood decrease (i.e., in the lung capillaries), carbon
dioxide and protons are released from hemoglobin, increasing the oxygen affinity
of the protein. This control of hemoglobin's affinity for oxygen by the binding
and release of carbon dioxide and acid, is known as the Bohr effect.
The
binding of oxygen is affected by molecules such as carbon monoxide (CO) (for example from tobacco smoking, cars and furnaces).
CO competes with oxygen at the heme binding site. Hemoglobin binding affinity
for CO is 200 times greater than its affinity for oxygen, meaning that small
amounts of CO dramatically reduces hemoglobin's ability to transport oxygen.
When hemoglobin combines with CO, it forms a very bright red compound called carboxyhemoglobin. When inspired air
contains CO levels as low as 0.02%, headache and nausea occur; if the CO
concentration is increased to 0.1%, unconsciousness will follow. In heavy
smokers, up to 20% of the oxygen-active sites can be blocked by CO.
In
similar fashion, hemoglobin also has competitive binding affinity for cyanide (CN-), sulfur monoxide (SO), nitrogen dioxide (NO2), and sulfide (S2-),
including hydrogen sulfide (H2S). All of these bind to
iron in heme without changing its oxidation state, but they nevertheless
inhibit oxygen-binding, causing grave toxicity.
The
iron atom in the heme group must be in the Fe2+ oxidation state to support oxygen and
other gases' binding and transport. Oxidation to Fe3+ state converts hemoglobin into hemiglobin or methemoglobin (pronounced
"MET-hemoglobin"), which cannot bind oxygen. Hemoglobin in normal red
blood cells is protected by a reduction system to keep this from happening. Nitrogen
dioxide and nitrous oxide are capable of converting a small
fraction of hemoglobin to methemoglobin, however this is not usually of medical
importance (nitrogen dioxide is poisonous by other mechanisms, and nitrous
oxide is routinely used in surgical anesthesia in most people without undue
methemoglobin buildup).
In
people acclimated to high altitudes, the concentration of 2,3-bisphosphoglycerate (2,3-BPG) in the blood is increased,
which allows these individuals to deliver a larger amount of oxygen to tissues
under conditions of lower oxygen tension. This phenomenon, where molecule Y
affects the binding of molecule X to a transport molecule Z, is called a heterotropic allosteric effect.
A
variant hemoglobin, called fetal
hemoglobin (HbF, α2γ2),
is found in the developing fetus,
and binds oxygen with greater affinity than adult hemoglobin. This means that
the oxygen binding curve for fetal hemoglobin is left-shifted (i.e., a higher
percentage of hemoglobin has oxygen bound to it at lower oxygen tension), in comparison
to that of adult hemoglobin. As a result, fetal blood in the placenta is able to take oxygen from maternal
blood.
Hemoglobin
also carries nitric oxide in the globin part of the molecule.
This improves oxygen delivery in the periphery and contributes to the control
of respiration. NO binds reversibly to a specific cystein residue in globin;
the binding depends on the state (R or T) of the hemoglobin. The resulting
S-nitrosylated hemoglobin influences various NO-related activities such as the
control of vascular resistance, blood pressure and respiration. NO is released
not in the cytoplasm of erythrocytes but is transported by an anion exchanger
called AE1 out of them.[]
When red cells reach the end of their life due to
aging or defects, they are broken down, the hemoglobin molecule is broken up
and the iron gets recycled. When the porphyrin ring is broken up, the fragments
are normally secreted in the bile by the liver. This process also produces one
molecule of carbon monoxide for every molecule of heme degraded
[4]; this is one of the few natural sources of carbon monoxide production in the human body, and is
responsible for the normal blood levels of carbon monoxide even in people
breathing pure air. The other major final product of heme degradation is bilirubin. Increased levels of this
chemical are detected in the blood if red cells are being destroyed more
rapidly than usual. Improperly degraded hemoglobin protein or hemoglobin that
has been released from the blood cells too rapidly can clog small blood
vessels, especially the delicate blood filtering vessels of the kidneys, causing kidney damage
Decrease of hemoglobin, with or
without an absolute decrease of red
blood cells, leads to symptoms of anemia.
Anemia has many different causes, although iron
deficiencyand its resultant iron
deficiency anemia are the most
common causes in the Western world. As absence of iron decreases heme synthesis,
red blood cells in iron deficiency anemia are hypochromic (lacking the red
hemoglobin pigment) and microcytic (smaller than normal). Other anemias are rarer.
In hemolysis (accelerated breakdown of red blood
cells), associated jaundice is caused by the hemoglobin metabolite bilirubin, and the circulating
hemoglobin can cause renal
failure.
Some mutations in the globin chain
are associated with the hemoglobinopathies,
such as sickle-cell disease and thalassemia.
Other mutations, as discussed at the beginning of the article, are benign and
are referred to merely as hemoglobin
variants.
There is a group of genetic
disorders, known as the porphyrias that are characterized by errors in
metabolic pathways of heme synthesis. King George
III of the United Kingdom was
probably the most famous porphyria sufferer.
To a small extent, hemoglobin A
slowly combines with glucose at a certain location in the molecule.
The resulting molecule is often referred to as Hb A1c. As theconcentration of glucose in the blood increases, the
percentage of Hb A that turns into Hb A1c increases. In diabetics whose glucose usually runs high, the
percent Hb A1c also runs high. Because of the slow rate of Hb A combination
with glucose, the Hb A1c percentage is representative of glucose level in the
blood averaged over a longer time (the half-life of red blood cells, which is
typically 50-55 days).
Hemoglobin levels are amongst the
most commonly performed blood
tests, usually as part of a full blood count or complete blood count. Results are
reported in g/L, g/dLor mol/L. For conversion, 1 g/dL is 0.621
mmol/L. If the total hemoglobin concentration in the blood falls below a set
point, this is called anemia.
Normal values for hemoglobin levels are:
· Women:
12.1 to 15.1 g/dl
· Men:
13.8 to 17.2 g/dl
· Children:
11 to 16 g/dl
· Pregnant
women: 11 to 12 g/dl
Anemias
are further subclassified by the size of the red blood cells, which are the
cells which contain hemoglobin in vertebrates. They can be classified as
microcytic (small sized red blood cells), normocytic (normal sized red blood
cells), or macrocytic (large sized red blood cells). The hemaglobin is the
typical test used for blood
donation. A comparison with the hematocrit can be made by multiplying the
hemaglobin by three. For example, if the hemaglobin is measured at 17, that
compares with a hematocrit of .51
Glucose levels in blood can vary widely each
hour, so one or only a few samples from a patient analyzed for glucose may not
be representative of glucose control in the long run. For this reason a blood
sample may be analyzed for Hb A1c level,
which is more representative of glucose control averaged over a longer time
period (determined by the half-life of the individual's red blood cells, which
is typically 50-55 days). People whose Hb A1c runs 6.0% or less show good
longer-term glucose control. Hb A1c values which are more than 7.0% are
elevated. This test is especially useful for diabetics.[8]
BIOLOGICAL
BUFFERS OF
BLOOD
Acid–base
homeostasis is the part of human homeostasis concerning the proper balance
between acids and bases, also called body pH. The body is very sensitive to its
pH level, so strong mechanisms exist to maintain it. Outside the acceptable
range of pH, proteins are denatured and digested, enzymes lose their ability to
function, and death may occur.
A
buffer solution is an aqueous solution consisting of a mixture of a weak acid
and its conjugate base or a weak base and its conjugate acid. Its pH changes
very little when a small amount of strong acid or base is added to it. Buffer
solutions are used as a means of keeping pH at a nearly constant value in a
wide variety of chemical applications.
Many
life forms thrive only in a relatively small pH range so they utilize a buffer
solution to maintain a constant pH. One example of a buffer solution found in
nature is blood. The body's acid–base balance is normally tightly regulated,
keeping the arterial blood pH between 7.38 and 7.42. Several buffering agents
that reversibly bind hydrogen ions and impede any change in pH exist.
Extracellular buffers include bicarbonate and ammonia, whereas proteins and
phosphate act as intracellular buffers. The bicarbonate buffering system is
especially key, as carbon dioxide (CO2) can be shifted through
carbonic acid (H2CO3) to hydrogen ions and bicarbonate
(HCO3-):
Acid–base
imbalances that overcome the buffer system can be compensated in the short term
by changing the rate of ventilation. This alters the concentration of carbon
dioxide in the blood, shifting the above reaction according to Le Chatelier's
principle, which in turn alters the pH.
The
kidneys are slower to compensate, but renal physiology has several powerful
mechanisms to control pH by the excretion of excess acid or base. In response
to acidosis, tubular cells reabsorb more bicarbonate from the tubular fluid,
collecting duct cells secrete more hydrogen and generate more bicarbonate, and
ammoniagenesis leads to increased formation of the NH3 buffer. In responses to alkalosis, the
kidneys may excrete more bicarbonate by decreasing hydrogen ion secretion from
the tubular epithelial cells, and lowering rates of glutamine metabolism and
ammonium excretion.
This
huge buffer capacity has another not immediately obvious implication for how we
think about the severity of an acid-base disorder. You would think that the magnitude
of an acid-base disturbance could be quantified merely by looking at the change
in [H+] - BUT this is not so.
Because
of the large buffering capacity, the actual change in [H+] is so
small it can be ignored in any quantitative assessment, and instead, the
magnitude of a disorder has to be estimated indirectly from the decrease in the
total concentration of the anions involved in the buffering. The buffer anions,
represented as A-, decrease because they combine stoichiometrically
with H+ to produce HA.
A decrease in A- by 1
mmol/l represents a 1,000,000 nano-mol/l amount of H+ that is hidden from view and this is
several orders of magnitude higher than the visible few nanomoles/l change in
[H+] that is visible.) - As noted above in the comments about the
Swan & Pitts experiment, 13,999,994 out of 14,000,000 nano-moles/l of H+ were hidden on buffers and just to count
the 36 that were on view would give a false impression of the magnitude of the
disorder.
The
major buffer system in the ECF is the CO2-bicarbonate buffer system.
This is responsible for about 80% of extracellular buffering. It is the most
important ECF buffer for metabolic acids but it cannot buffer respiratory
acid-base disorders.
The
components are easily measured and are related to each other by the
Henderson-Hasselbalch equation.
Henderson-Hasselbalch Equation
pH = pK’a + log10 (
[HCO3] / 0.03 x pCO2)
The
pK’a value is dependent on the temperature, [H+] and the ionic
concentration of the solution. It has a value of 6.099 at a temperature of 37C
and a plasma pH of 7.4. At a temperature of 30C and pH of 7.0, it has a value
of 6.148. For practical purposes, a value of 6.1 is generally assumed and
corrections for temperature, pH of plasma and ionic strength are not used
except in precise experimental work.
The
pK'a is derived from the Ka value of the following reaction:
CO2 + H2O <=> H2CO3 <=> H+ + HCO3-
(where
CO2 refers to
dissolved CO2)
The
concentration of carbonic acid is very low compared to the other components so
the above equation is usually simplified to:
CO2 + H2O <=> H+ + HCO3-
By
the Law of Mass Action:
Ka
= [H+] . [HCO3-] / [CO2] . [H20]
The
concentration of H2O is so large (55.5M) compared to the other
components, the small loss of water due to this reaction changes its
concentration by only an extremely small amount. This means that [H2O]
is effectively constant. This allows further simplification as the two
constants (Ka and [H2O] ) can be combined into a new constant K’a.
K’a
= Ka x [H2O] = [H+] . [HCO3-] / [CO2]
Substituting:
K'a
= 800 nmol/l (value for plasma at 37C)
[CO2]
= 0.03 x pCO2 (by
Henry’s Law) [where 0.03 is the solubility coefficient]
into
the equation yields the Henderson Equation:
[H+]
= (800 x 0.03) x pCO2 /
[HCO3-] = 24 x pCO2 /
[HCO3-] nmol/l
Taking
the logs (to base 10) of both sides yields the Henderson-Hasselbalch equation:
pH
= log10(800) - log (0.03 pCO2 /
[HCO3-] )
pH
= 6.1 + log ( [HCO3] / 0.03 pCO2 )
On
chemical grounds, a substance with a pKa of 6.1 should not be a good buffer at
a pH of 7.4 if it were a simple buffer. The system is more complex as it is
‘open at both ends’ (meaning both [HCO3] and pCO2 can be adjusted) and this greatly
increases the buffering effectiveness of this system. The excretion of CO2 via the lungs is particularly
important because of the rapidity of the response. The adjustment of pCO2 by
change in alveolar ventilation has been referred to as physiological buffering.
The
other buffer systems in the blood are the protein and phosphate buffer systems.
These
are the only blood buffer systems capable of buffering respiratory acid-base
disturbances as the bicarbonate system is ineffective in buffering changes in H+ produced by itself.
The
concentration of phosphate in the blood is so low that it is quantitatively
unimportant. Phosphates are important buffers intracellularly and in urine
where their concentration is higher.
Phosphoric
acid is triprotic weak acid and has a pKa value for each of the three
dissociations:
The
three pKa values are sufficiently different so that at any one pH only the
members of a single conjugate pair are present in significant concentrations.
At
the prevailing pH values in most biological systems, monohydrogen phosphate
(HPO4-2) and dihydrogen phosphate (H2PO4-)
are the two species present. The pKa2 is 6.8 and this makes the closed
phosphate buffer system a good buffer intracellularly and in urine. The pH of
glomerular ultrafiltrate is 7.4 and this means that phosphate will initially be
predominantly in the monohydrogen form and so can combine with more H+ in the renal tubules. This makes the
phosphate buffer more effective in buffering against a drop in pH than a rise
in pH.
Note:
The ‘true’ pKa2 value is actually 7.2 if measured at zero ionic strength but at
the typical ionic strength found in the body its apparent value is 6.8. The
other factor which makes phosphate a more effective buffer intracellularly and
in urine is that its concentration is much higher here than in extracellular
fluid.
Protein
buffers in blood include haemoglobin (150g/l) and plasma proteins (70g/l).
Buffering is by the imidazole group of the histidine residues which has a pKa
of about 6.8. This is suitable for effective buffering at physiological pH.
Haemoglobin is quantitatively about 6 times more important then the plasma
proteins as it is present in about twice the concentration and contains about
three times the number of histidine residues per molecule. For example if blood
pH changed from 7.5 to 6.5, haemoglobin would buffer 27.5 mmol/l of H+ and total plasma protein buffering
would account for only 4.2 mmol/l of H+.
Deoxyhaemoglobin
is a more effective buffer than oxyhaemoglobin and this change in buffer
capacity contributes about 30% of the Haldane effect. The major factor
accounting for the Haldane effect in CO2 transport is the much greater ability
of deoxyhaemoglobin to form carbamino compounds.
This
buffer functions in exactly the same way as the phosphate buffer. Additional H+ is consumed by HCO3- and additional OH- is consumed by H2CO3.
The value of Ka for this equilibrium is 7.9 Ч 10-7,
and the pKa is 6.1 at body temperature. In blood
plasma, the concentration of hydrogen carbonate ion is about twenty times the
concentration of carbonic acid. The pH of arterial blood plasma is 7.40. If the
pH falls below this normal value, a condition called acidosis is produced. If the pH rises above the
normal value, the condition is called alkalosis.
The
concentrations of hydrogen carbonate ions and of carbonic acid are controlled
by two independent physiological systems. Carbonic acid concentration is
controlled by respiration, that is through the lungs. Carbonic acid is in
equilibrium with dissolved carbon dioxide gas.
H2CO3(aq) CO2(aq)
+ H2O(l)
An
enzyme called carbonic anhydrase catalyzes the conversion of carbonic acid to
dissolved carbon dioxide. In the lungs, excess dissolved carbon dioxide is
exhaled as carbon dioxide gas.
CO2(aq) CO2(g)
The
concentration of hydrogen carbonate ions is controlled through the kidneys.
Excess hydrogen carbonate ions are excreted in the urine.
The
much higher concentration of hydrogen carbonate ion over that of carbonic acid
in blood plasma allows the buffer to respond effectively to the most common
materials that are released into the blood. Normal metabolism releases mainly
acidic materials: carboxylic acids such as lactic acid (HLac). These acids
react with hydrogen carbonate ion and form carbonic acid.
HLac(aq)
+ HCO3-(aq) Lac-(aq)
+ H2CO3(aq)
The
carbonic acid is converted through the action of the enzyme carbonic anhydrase
into aqueous carbon dioxide.
H2CO3(aq) CO2(aq)
+ H2O(l)
An
increase in CO2(aq) concentration stimulates increased breathing,
and the excess carbon dioxide is released into the air in the lungs.
The
condition called respiratory acidosis occurs when blood pH falls as a result
of decreased respiration. When respiration is restricted, the concentration of
dissolved carbon dioxide in the blood increases, making the blood too acidic.
Such a condition can be produced by asthma, pneumonia, emphysema, or inhaling
smoke.
Metabolic acidosis is the decrease in blood pH that
results when excessive amounts of acidic substances are released into the
blood. This can happen through prolonged physical exertion, by diabetes, or
restricted food intake. The normal body response to this condition is increases
breathing to reduce the amount of dissolved carbon dioxide in the blood. This
is why we breathe more heavily after climbing several flights of stairs.
Respiratory alkalosis results from excessive breathing that
produces an increase in blood pH. Hyperventilation causes too much dissolved
carbon dioxide to be removed from the blood, which decreases the carbonic acid
concentration, which raises the blood pH. Often, the body of a hyperventilating
person will react by fainting, which slows the breathing.
Metabolic alkalosis is an increase in blood pH resulting
from the release of alkaline materials into the blood. This can result from the
ingestion of alkaline materials, and through overuse of diuretics. Again, the
body usually responds to this condition by slowing breathing, possibly through
fainting.
The
carbonic acid-hydrogen carbonate ion buffer works throughout the body to
maintain the pH of blood plasma close to 7.40. The body maintains the buffer by
eliminating either the acid (carbonic acid) or the base (hydrogen carbonate
ions). Changes in carbonic acid concentration can be effected within seconds
through increased or decreased respiration. Changes in hydrogen carbonate ion
concentration, however, require hours through the relatively slow elimination
through the kidneys
Plasma is the straw-colored liquid in which the blood cells
are suspended.
Plasma
transports materials needed by cells and materials that must be removed from
cells:
· various
ions (Na+, Ca2+, HCO3−, etc.
· glucose
and traces of other sugars
· amino
acids
· other
organic acids
· cholesterol
and other lipids
· hormones
· urea
and other wastes
Most
of these materials are in transit from a place where they are added to the
blood (a "source")
· exchange
organs like the intestine
· depots
of materials like the liver
to
places ("sinks") where they will be removed from the blood.
· every
cell
· exchange organs like the kidney, and
skin.
Proteins
make up 6–8% of the blood. They are about equally divided between serum albumin and a great variety of serum globulins.
After
blood is withdrawn from a vein and allowed to clot, the clot slowly shrinks. As
it does so, a clear fluid called serum is squeezed out. Thus:
Serum is blood
plasma without fibrinogen and other clotting factors.
The
serum proteins can be separated by electrophoresis.
· A
drop of serum is applied in a band to a thin sheet of supporting material, like
paper, that has been soaked in a slightly-alkaline salt solution.
· At
pH 8.6, which is commonly used, all the proteins are negatively charged, but
some more strongly than others.
· A
direct current can flow through the paper because of the conductivity of the
buffer with which it is moistened.
· As
the current flows, the serum proteins move toward the positive electrode.
· The
stronger the negative charge on a protein, the faster it migrates.
· After
a time (typically 20 min), the current is turned off and the proteins stained
to make them visible (most are otherwise colorless).
· The
separated proteins appear as distinct bands.
· The
most prominent of these and the one that moves closest to the positive
electrode is serum albumin.
· Serum
albumin
o is
made in the liver
o binds
many small molecules for transport through the blood
o helps
maintain the osmotic pressure of the blood
· The
other proteins are the various serum globulins.
· They
migrate in the order
o alpha
globulins (e.g.,
the proteins that transport thyroxine and retinol [vitamin A])
o beta
globulins (e.g.,
the iron-transporting protein transferrin)
o gamma
globulins.
§ Gamma
globulins are the least negatively-charged serum proteins. (They are so weakly
charged, in fact, that some are swept in the flow of buffer back toward the
negative electrode.)
§ Most
antibodies are gamma globulins.
§ Therefore
gamma globulins become more abundant following infections or immunizations.
Albumins –
multidispersed fraction of blood plasma which are characterized by the high electrophoretic mobility and mild dissolubility in water and
saline solutions. Molecular weight of albumins is about 60000. Due to high hydrophilic properties albumins bind a significant
amount of water, and the volume of their molecule under hydratation is doubled. Hydrative layer formed around the serum albumins provides to
70-80 % of oncotic pressure of blood plasma proteins, that can be applied in
clinical practice at albumins transfusion to patients with tissue edemas. The
decreasing of albumins concentration in blood plasma, for example under
disturbance of their synthesis in hepatocytes at liverfailure, can cause the water
transition from a vessels into the tissues and development of oncotic edemas.
Albumins
execute also important physiological function as transporters of a lot of
metabolites and diverse low molecular weight structures. The molecules of
albumins have several sites with centers of linkage for molecules of
organic ligands, which are
affixed by the electrostatic and hydrophobic bonds. Serum albumins can affix and
convey fatty acids, cholesterol, cholic pigments (bilirubin and that similar),
vitamins, hormones, some amino
acids, toxins and
medicines.
Albumins
also execute the buffer function. Due to the availability in their structure
amino and carboxylic groups albumins can react both as acids and as alkaline.
Albumins
can bound different toxins in blood plasma (bilirubin, foreign substances et
c.). This is the desintoxicative function
of albumins.
Albumins
also play role of amino acids depot in the organism. They can supply amino
acids for the building of another proteins, for example enzymes.
Globulins -
heterogeneous fraction of blood proteins which execute transport (a1-globulins –
transport of lipids, thyroxin, corticosteroid
hormones; a2-globulins -
transport of lipids, copper ions; b-globulins - transport of lipids,
iron) and protective (participation of b-globulins in immune reactions as
antitoxins; g-globulins as immunoglobulins)
functions. They also support the blood oncotic pressure and acid-alkaline
balance, provide amino acids for the organism requirements. The molecular
weight of globulins is approximately 150000-300000.
The
globulin level in blood plasma is 20-40 g/l. A ratio between concentrations of
albumins and globulins (so called “protein coefficient”) in blood plasma is
often determined in clinical practice. In healthy people this coefficient is
1,5-2,0.
Fibrinogen – important protein of blood plasma, precursor of
fibrin, the structural element of blood clots. Fibrinogen participates in blood
clotting and thus prevents the loss of blood from the vascular system of
vertebrates. The approximate molecular weight of fibrinogen is 340000. It is
the complex protein, it contains the carbohydrate as prosthetic group. The
content of firinogen in blood is 3-4 g/l.
Subfractions of a1, a2, b and g globulins, their structure and functions.
Immunoglobulins (Ig A,
Ig G, Ig E, Ig M) - proteins of g-globulin fraction of blood plasma
executing the functions of antibodies which are the main effectors of humoral
immunity. They appear in the blood serum and certain cells of a vertebrate in
response to the introduction of a protein or some other macromolecule foreign
to that species.
Immunoglobulin
molecules have bindind sites that are specific for and complementary to the
structural features of the antigen that induced their formation. Antibodies are
highly specific for the foreign proteins that evoke their formation.
Molecules
of immunoglobulins are
glycoproteins. The protein part of immunoglobulins contain four polipeptide chains: two
heavy H-chains and two light L-chains.
The acute
phase response develops in a wide range of acute and chronic inflammatory
conditions like bacterial, viral, or fungal infections; rheumatic and other
inflammatory diseases; malignancy; and tissue injury or necrosis. These
conditions cause release of interleukin-6 and other cytokines that trigger the
synthesis of CRP and fibrinogen by the liver. During the acute phase response,
levels of CRP rapidly increase within 2 hours of acute insult, reaching a peak
at 48 hours. With resolution of the acute phase response, CRP declines with a
relatively short half-life of 18 hours. Measuring CRP level is a screen for
infectious and inflammatory diseases. Rapid, marked increases in CRP occur with
inflammation, infection, trauma and tissue necrosis, malignancies, and
autoimmune disorders. Because there are a large number of disparate conditions
that can increase CRP production, an elevated CRP level does not diagnose a
specific disease. An elevated CRP level can provide support for the presence of
an inflammatory disease, such as rheumatoid arthritis, polymyalgia rheumatica
or giant-cell arteritis.
The physiological role of CRP is to
bind to phosphocholine expressed on the surface of dead or dying cells (and
some types of bacteria) in order to activate the complement system. CRP binds
to phosphocholine on microbes and damaged cells and enhances phagocytosis by
macrophages. Thus, CRP participates in the clearance of necrotic and apoptotic
cells.
CRP is a member of the class of
acute-phase reactants, as its levels rise dramatically during inflammatory processes occurring in the body. This
increment is due to a rise in the plasma concentration of IL-6, which is produced predominantly
by macrophages[2] as well asadipocytes. CRP binds to phosphocholine on microbes. It is thought to assist
in complement binding to foreign and damaged cells
and enhances phagocytosis by macrophages (opsonin mediated phagocytosis), which
express a receptor for CRP. It is also believed to play another important role
in innate immunity, as an early
defense system against infections.
CRP rises up to 50,000-fold in acute
inflammation, such as infection. It rises above normal limits within 6 hours,
and peaks at 48 hours. Its half-life is constant, and therefore its level is
mainly determined by the rate of production (and hence the severity of the
precipitating cause).
Serum amyloid A is a related acute-phase marker that
responds rapidly in similar circumstances.
C-reactive protein (g-fraction). This protein received the
title owing to its capacity to react with C-polysaccharide of a pneumococcus
forming precipitates. According to its chemical nature C-reactive protein is
glycoprotein.
C-reactive protein,
pentraxin-related
CRP is used mainly as a marker of
inflammation. Apart from liver
failure, there are few known factors that interfere with CRP production.[2]
Measuring and charting CRP values can
prove useful in determining disease progress or the effectiveness of
treatments. Blood, usually collected
in a serum-separating tube, is
analysed in amedical laboratory or
at the point of care. Various analytical methods are available for CRP
determination, such as ELISA, immunoturbidimetry, rapid immunodiffusion, and visual agglutination.
Reference ranges for blood tests, showing
C-reactive protein in brown-yellow in center.
A high-sensitivity CRP (hs-CRP) test
measures low levels of CRP using laser nephelometry.
The test gives results in 25 minutes with a sensitivity down to 0.04 mg/L.
Normal concentration in healthy human
serum is usually lower than 10 mg/L, slightly increasing with aging. Higher levels are found in late pregnant women, mild inflammation and viral
infections (10–40 mg/L),
active inflammation, bacterial infection (40–200 mg/L), severe bacterial infections and burns (>200 mg/L).[26]
CRP is a more sensitive and accurate
reflection of the acute phase response than the ESR (Erythrocyte Sedimentation
Rate). The half-life of CRP is constant. Therefore, CRP level is mainly
determined by the rate of production (and hence the severity of the
precipitating cause). In the first 24 h, ESR may be normal and CRP elevated.
CRP returns to normal more quickly than ESR in response to therapy.
Arterial damage results from white blood cell invasion and inflammation within the wall. CRP is a general
marker for inflammation and infection, so it can be used as a very rough proxy
for heart disease risk. Since many things can cause elevated CRP, this is not a
very specific prognostic indicator.[27] Nevertheless, a level above
2.4 mg/L has been associated with a doubled risk of a coronary event
compared to levels below 1 mg/L;[2] however, the study group in this case
consisted of patients who had been diagnosed with unstable angina pectoris;
whether elevated CRP has any predictive value of acute coronary events in the
general population of all age ranges remains unclear.
Crioglobulin - the protein
of the g-globulin fraction. Like to the C-reactive protein
crioglobulin absent in blood plasma of the healthy people and occurs at
leukoses, rheumatic disease, liver cirrhosis, nephroses. The characteristic
physico-chemical feature of crioglobulin is its dissolubility at standard body
temperature (37 oC)
and capacity to form the sediment at cooling of a blood plasma up to 4 oC.
a2-macroglobulin - protein of a2-globulin fraction, universal serum
proteinase inhibitor. Its contents (2,5 g/l) in blood plasma is highest
comparing to another proteinase inhibitors.
The
biological role of a2-macroglobulin
consists in regulation of the
tissue proteolysis systems which
are very important in such physiological and pathological processes as blood
clotting, fibrinolysis, processes
of immunodefence, functionality of a complement system, inflammation, regulation of vascular tone (kinine and renin-angiothensine system).
a1-antitrypsin (a1-globulin) – glycoprotein with a molecular weight 55 kDa. Its
concentration in blood plasma is 2-3 г/л.
The main biological property of this inhibitor is its capacity to form
complexes with proteinases oppressing proteolitic activity of such enzymes as trypsin, chemotrypsin, plasmin, trombin. The
content of a1-antitrypsin
is markedly increased in inflammatory processes. The inhibitory activity of a1-antitrypsin is very important in
pancreas necrosis and acute pancreatitis because in these conditions the
proteinase level in blood and tissues is sharply increased. The congenital
deficiency of a1-antitrypsin
results in the lung emphysema.
Fibronectin –
glycoprotein of blood plasma that is synthesized and secreted in intercellular space by different
cells. Fibronectin present on a surface of cells, on the basalmembranes, in connective tissue and in blood. Fibronectin has properties of a «sticking» protein and contacts with the carbohydrate groups
of gangliosides on a surface of plasma membranes
executing the integrative function in intercellular interplay. Fibronectin also plays important role in the
formation of the pericellular matrix.
Haptoglobin - protein of a2-globulin fraction of blood plasma. Haptoglobin has capacity to bind a free
haemoglobin forming a complex that refer to b-globulins electrophoretic fraction.
Normal concentration in blood plasma - 0,10-0,35 g/l.
Haptoglobin-hemoglobin
complexes are absorbed by the
cells of reticulo-endothelial system, in particular in a liver, and oxidized to
cholic pigments. Such haptoglobinfunction promotes the preservation of iron
ions in an organism under conditions of a physiological and pathological
erythrocytolysis.
Transferrin - glycoprotein belonging to the b-globulin fraction. It binds in a blood plasma iron
ions (Fe3+). The protein has on the surface two centers of linkage
of iron.Transferrin is a
transport form of iron delivering its to places of accumulation and usage.
Ceruloplasmin - glycoprotein of the a2-globulin fraction. It can bind the
copper ions in blood plasma. Up to 3 % of all copper contents in an organism
and more than 90 % copper contents in
plasma is included in ceruloplasmin. Ceruloplasmin has properties of ferroxidase oxidizing the iron ions. The decrease of ceruloplasmin in organism (Wilson disease) results in exit of
copper ions from vessels and its accumulation in the connective tissue that
shows by pathological changes in a liver, main brain, cornea.
The place of synthesis of each fraction and
subfruction of blood plasma proteins.
Albumins, a1-globulins, fibrinogen are fully
synthesized in hepatocytes. Immunoglobulins are produced by plasmocytes (immune
cells). In liver cryoglobulins and some other g-globulins are produced too. a2-globulins and b-globulins are partly synthesized in liver and partly
in reticuloendothelial cells.
Causes and consequences of protein content changes
in blood plasma.
Hypoproteinemia - decrease of the total contents of
proteins in blood plasma. This state occurs in old people as well as in
pathological states accompanying with the oppressing of protein synthesis
(liver diseases) and activation of decomposition of tissue proteins
(starvation, hard infectious diseases, state after hard trauma and operations, cancer).
Hypoproteinemia (hypoalbuminemia) also occurs in kidney diseases, when the
increased excretion of proteins via the urine takes place.
Hyperproteinemia - increase of
the total contents of proteins in blood plasma. There are two types of hyperproteinemia - absolute and
relative.
Absolute hyperproteinemia – accumulation
of the proteins in blood. It occurs in infection and inflammatory diseases
(hyperproduction of immunoglobulins), rheumatic
diseases (hyperproduction of C-reactive protein), some malignant tumors
(myeloma) and others.
Relative hyperproteinemia – the
increase of the protein concentration but not the absolute amount of proteins.
It occurs when organism loses water (diarrhea, vomiting, fever, intensive
physical activity etc.).
The principle of the measurement of protein
fractions by electrophoresis method.
Electrophoresis
is the separation of proteins on the basis of their electric charge. It depends
ultimately on their base-acid properties, which are largely determined by the
number and types of ionizable R groups in their polipeptide chains. Since
proteins differ in amino acid composition and sequence, each protein has
distinctive acid-base properties. There are a number of different forms of
electroforesis useful for analyzing and separating mixtures of proteins
If
a precursor of an antibody-secreting cell becomes cancerous, it divides
uncontrollably to generate a clone of plasma
cellssecreting a single kind
of antibody molecule. The image (courtesy of Beckman Instruments, Inc.)
shows — from left to right — the electrophoretic separation of:
1. normal human serum
with its diffuse band of gamma globulins;
2. serum
from a patient with multiple
myeloma producing an IgG myeloma protein;
3. serum
from a patient with Waldenström's macroglobulinemia where the cancerous
clone secretes an IgM antibody;
4. serum
with an IgA myeloma protein.
§ Gamma
globulins can be harvested from donated blood (usually pooled from several
thousand donors) and injected into persons exposed to certain diseases such as
chicken pox and hepatitis. Because such preparations of immune globulin contain antibodies against most common
infectious diseases, the patient gains temporary protection against the
disease.
Because
of their relationship to cardiovascular disease, the analysis of serum lipids
has become an important health measure.
The
table shows the range of typical values as well as the values above (or below)
which the subject may be at increased risk of developing atherosclerosis.
· Total
cholesterol is the serum of blood
o HDL
cholesterol
o LDL
cholesterol and
o 20%
of the triglyceride value
· Note
that
o high
LDL values
are bad, but
o high
HDL values
are good.
· Using
the various values, one can calculate a
cardiac risk ratio = total cholesterol divided by HDL cholesterol
A
cardiac risk ratio greater than 7 is considered a warning
A.
Protein fractions which are received by the electrophoresis
Fractions
|
Concentration
|
Relative
contents
|
Albumin
|
38,0
- 50,0 g/l
|
0,50
- 0,60
|
α1 globulins
|
1,4
– 3,0 g/l
|
0,01
- 0,05
|
α-2 globulins
|
5,6
– 9,1 g/l
|
0,07
- 0,13
|
β-
globulins
|
5,4
– 9,1 g/l
|
0,09
– 0,15
|
γ
globulins
|
9,1
– 14,7 g/l
|
0,14
– 0,22
|
Total
protein
|
65,0
– 85, 0 g/l
|
1,00
|
B.
Protein fractions which are
received with the help of imunoelectropheresis on agar
gel.
Protein
|
Concentration
|
|
Acidic
α1 glycoproteid
|
|
0,20
– 0,40 g/l
|
α1Antitrypsyn
|
|
2,00-4,00
g/l
|
Ceruloplasmin
|
|
0,15-0,60
g/l
|
Cu2+
|
16,0-31,0
mkmmol/l
|
|
Haptoglobine
|
|
1,00-4,00
g/l
|
α-2 -
Macroglobulin
|
|
2,50-3,50
g/l
|
Transpheryn
|
|
2,50-4,10
g/l
|
Fe3+
|
11,0-27,0
mkmmol/l
|
|
Fibrinogen
|
|
2,00-4,00
g/l
|
Immunoglobulins
(Ig)
|
|
|
IgG
|
|
8,00-18,00
g/l
|
IgA
|
|
1,00-4,00
g/l
|
IgM
|
|
0,60-2,80
g/l
|
IgD
|
|
0,00-0,15
g/l
|
IgE
|
|
Till
5x10-4
|
|
|
|
|
Residual
nitrogen, its components, ways of their formation, blood content
The
state of protein nutrition can be determined by measuring the dietary intake
and output of nitrogenous compounds from the body. Although nucleic acids also
contain nitrogen, protein is the major dietary source of nitrogen and
measurement of total nitrogen intake gives a good estimate of protein intake
(mg N Ч 6.25
= mg protein, as nitrogen is 16% of most proteins). The output of nitrogen from
the body is mainly in urea and smaller quantities of other compounds in urine
and undigested protein in feces, and significant amounts may also be lost in
sweat and shed skin.
The
difference between intake and output of nitrogenous compounds is known as nitrogen balance. Three states can be defined: In a
healthy adult, nitrogen balance is inequilibrium when intake equals output, and
there is no change in the total body content of protein. In a growing child, a
pregnant woman, or in recovery from protein loss, the excretion of nitrogenous
compounds is less than the dietary intake and there is net retention of
nitrogen in the body as protein, ie, positive
nitrogen balance. In response
to trauma or infection or if the intake of protein is inadequate to meet
requirements there is net loss of protein nitrogen from the body, ie, negative nitrogen balance. The continual catabolism of tissue
proteins creates the requirement for dietary protein even in an adult who is
not growing, though some of the amino acids released can be reutilized.
Nitrogen
balance studies show that the average daily requirement is 0.6 g of protein per kilogram of body weight
(the factor 0.75 should be used to allow for individual variation), or
approximately 50 g/d. Average intakes of protein in developed countries are
about 80–100 g/d, ie, 14–15% of energy intake. Because growing children are
increasing the protein in the body, they have a proportionately greater
requirement than adults and should be in positive nitrogen balance. Even so,
the need is relatively small compared with the requirement for protein
turnover. In some countries, protein intake may be inadequate to meet these
requirements, resulting in stunting of growth.
Residual
nitrogen –
nonprotein nitrogen, that is nitrogen of organic and inorganic compounds that
remain in blood after protein sedimentation.
Organic
and inorganic compounds of residual nitrogen are as follows: urea (50 % of the
residual nitrogen), amino acids (25 %), creatine and creatinine (7,5 %), salts
of ammonia and indicane (0,5 %), other compounds (about 13 %).
Urea
is formed in liver during the degradation of amino acids, pyrimidine
nucleotides and other nitrogen containing compounds. Amino acids are formed as
result of protein decomposition or owing to the conversion of fatty acids or
carbohydrates to amino acids. The pool of amino acids in blood is also
supported by the process of their absorption in intestine. Creatine is produced
in kidneys and liver from amino acids glycine and arginine, creatinine is
formed in muscles as result of creatine phosphate splitting. In result of
ammonia neutralization the ammonia salts can be formed. Indicane is the product
of indol neutralization in the liver.
Creatinine
Urine
The
content of residual nitrogen in blood is 0,2 – 0,4 g/l.
The pathways of convertion of amino acid
nonnitrogen residues.
The
removal of the amino group of an amino acid by transamination or oxidative
deamination produces an α-keto acid that contains the
carbon skeleton from the amino acid (nonnitrogen
residues). These α-keto acids can be used for
the biosynthesis of non-essential amino acids or undergoes a different
degradation process. For alanine and serine, the degradation requires a single
step. For most carbon arrangements, however, multistep reaction sequences are
required. There are only
seven degradation sequences for 20 amino acids. The seven degradation products
are pyruvate, acetyl CoA, acetoacetyl CoA, α-ketoglutarate, succinyl CoA,
fumarate, and oxaloacetate. The last four products are intermediates in the
citric acid cycle. Some amino acids have more than one pathway for degradation.
The
major point of entry into the tricarboxylate cycle is via acetyl-CoA; 10 amino
acids enter by this route. Of these, six (alanine, glycine, serine, threonine, tryptophan and cysteine)
are degraded to acetyl-CoA via pyruvate, five (phenylalanine, tyrosine, leucine, lysine,
and tryptophan) are degraded via acetoacetyl-CoA, and three (isoleucine, leucine and tryptophan) yield acetyl-CoA
directly. Leucine and tryptophan
yield both acetoacetyl-CoA and acetyl-CoA as end products.
The
carbon skeletons of five amino acids (arginine, histidine, glutamate, glutamine
and proline) enter the
tricarboxylic acid cycle via a-ketoglutarate.
The
carbon skeletons of methionine, isoleucine, and valine are ultimately degraded via
propionyl-CoA and methyl-malonyl-CoA to succinyl-CoA; these amino acids are
thus glycogenic.
Fumarate
is formed in catabolism of phenylalanine, aspartate and tyrosine.
Oxaloacetate
is formed in catabolism of aspartate and asparagine. Aspartate is converted to the
oxaloacetate by transamination.
Amino
acids that are degraded to citric acid cycle intermediates can serve as glucose
precursors and are called glucogenic. A glucogenic
amino acid is an amino acid whose carbon-containing
degradation product(s) can be used to produce glucose via gluconeogenesis.
Amino
acids that are degraded to acetyl CoA or acetoacetyl CoA can contribute to the
formation of fatty acids or ketone bodies and are called ketogenic. Aketogenic amino acid is
an amino acid whose carbon-containing degradation product(s) can be used to
produce ketone bodies.
Amino
acids that are degraded to pyruvate can be either glucogenic or ketogenic.
Pyruvate can be metabolized to either oxaloacetate (glucogenic) or acetyl CoA
(ketogenic).
Only
two amino acids are purely ketogenic: leucine and lysine. Nine
amino acids are both glucogenic and ketogenic: those
degraded to pyruvate (alanine, glycine, cysteine, serine, threonine,
tryptophan), as well as tyrosine, phenylalanine, and isoleucine (which have two
degradation products). The remaining nine amino acids are purely glucogenic
(arginine, asparagine, aspartate, glutamine, glutamate, valine, histidine, methionine, proline)
The
regulation of protein metabolism. Protein metabolism is regulated by different
hormones. All hormones according to their action on protein synthesis or
splitting are divided on two groups: anabolic and catabolic. Anabolic hormones
promote to the protein synthesis. Catabolic hormones enhance the decomposition
of proteins.
Somatotropic
hormone (STH, growth hormone):
- stimulates the passing of amino
acids into the cells;
- activates the synthesis of proteins,
DNA, RNA.
Thyroxine
and triiodthyronine:
- in normal concentration
stimulate the synthesis of proteins and nucleic acids;
- in excessive concentration
activate the catabolic processes.
Insulin:
- increases the permeability of
cell membranes for amino acids;
- activates synthesis of proteins
and nucleic acids;
- inhibits the conversion of
amino acids into carbohydrates.
Glucagon:
- stimulates the conversion of amino acids into
carbohydrates.
Epinephrine:
-
activates the protein decomposition.
Glucocorticoids:
- stimulate the catabolic
processes (protein decomposition) in connective, lymphoid and muscle tissues
and activate the processes of protein synthesis in liver;
- stimulate the activity of
aminotransferases;
- activate the synthesis of urea.
Sex
hormones:
- stimulate the processes of
protein, DNA, RNA synthesis;
- cause the positive nitrogenous
balance.
The
role of liver in protein metabolism:
– synthesis of plasma proteins. Most of plasma proteins are
synthesized in liver: all albumins, 75-90 % of α-globulins, 50 % of
β-globulins, all proteins of blood clotting systems (prothrombin,
fibrinogen, proconvertin, proaccelerine). Only γ-globulins are synthesized
in the cells of reticuloendothelial system.
– synthesis of urea and uric acid;
– synthesis of choline and creatine;
– transamination and deamination of amino acids.
Clinical
significance of residual nitrogen measurement in blood. The kinds of azotemia.
Azotemia -
increase of the residual nitrogen content in blood. There are two kinds of
azotemia: absolute and
relative.
Absolute azotemia
– accumulation of the components of residual nitrogen in blood. Relative azotemia occurs
in dehydration of the organism (diarrhea, vomiting).
Absolute
azotemia can be divided on the productive azotemia and retention azotemia. Retention azotemia is caused by the poor excretion
of the nitrogen containing compounds via the kidneys; in this case the entry of
nitrogen containing compounds into the blood is normal.
Retention
azotemia can be
divided on the renal and
extrarenal. Renal retention azotemia occurs in kidney diseases
(glomerulonephritis, pyelonephritis, kidney tuberculosis et c.). Extrarenal retention azotemia is
caused by the violations of kidney hemodynamic and decrease of glomerulus
filtration processes (heart failure, local disorders of kidney hemodynamic).
Productive
azotemia is conditioned by the enhanced entry of nitrogen containing compounds
into the blood. The function of kidneys in this case doesn’t suffer.Productive
azotemia can be observed in cachexia,
leukoses, malignant tumors, treatment by glucocorticoids.
Alternate
Names : Azotemia - Prerenal, Renal Underperfusion, Uremia
Azotemia is a medical condition characterized by abnormal
levels of urea, creatinine, various body waste compounds, and other
nitrogen-rich compounds in the blood as a result of insufficient filtering of the blood
by the kidneys.
Uremia can be used as a synonym, or can be
used to indicate severe azotemia, in which symptoms are produced.
Azotemia
can be classified according to its cause. In prerenal
azotemia the blood supply to
the kidneys is inadequate. In postrenal
azotemia the urinary outflow tract
is obstructed. Other forms of azotemia are caused by diseases of the kidneys
themselves.
Other
causes of azotemia include congestive
heart failure, shock, severe burns, prolonged vomiting or
diarrhea, some antiviral medications, liver failure, or trauma to the kidney(s).
· Thirst, swelling (edema,
anasarca)
· Orthostatic blood pressure
(rises or falls, significantly depending on position)
A urinalysis will typically show a decreased urine sodium
level, a high urine creatinine-to- serum creatinine ratio, a high urine
urea-to-serum urea ratio, and concentrated urine (determined by osmolality and
specific gravity). None of these is particularly useful in diagnosis.
Prompt
treatment of some causes of azotemia can result in restoration of kidney
function; delayed treatment may result in permanent loss of renal function.
Treatment may include hemodialysis or peritoneal dialysis,
medications to increase cardiac output and increase blood pressure, and the
treatment of the condition that caused the azotemia to begin with. NOTE:
Azotemia is not diagnosed with abnormally high levels of Creatinine. Azotemia
simply refers to an elevated level of urea in the blood.
Added
Note: Uremia is not azotemia. Azotemia is one
of many clinical characteristics of uremia, which is a syndome characteristic of
renal disease. Uremia includes Azotemia, as well as acidosis, hyperkalemia,
hypertension, anemia and hypocalcemia along with other findings.
Lipoproteins
and Apoproteins
http://www.youtube.com/watch?v=97uiV4RiSAY
Lipids
are a group of fatty substances that includes triglycerides (fat),
phospholipids and sterols (e.g. cholesterol). They constitute an
important source of energy, serve as precursors for a number of essential
compounds, and are key components of cells and tissues. Cholesterol, for
example, is an indispensable constituent of cellular membranes (1), as well as the precursor for both
steroid hormones and bile acids. On average, the body utilizes
approximately 1000 milligrams of cholesterol per day, 30% of which comes
directly from foods of animal origin, and the rest is synthesized in the liver.
Due to the insolubility of cholesterol and other fatty compounds in the blood,
their redistribution in the body requires specialized carriers capable of solubilzing,
ferrying, and unloading them at specific target sites. Miscarriage of lipids
while in circulation may lead to atherosclerosis; a clinical condition marked
by fatty deposits in the inner walls of arteries, and the leading cause of
death and disability in Western countries.
Most
lipids are transported in the blood as part of soluble complexes called
lipoproteins (LPs). Plasma LPs are spherical particles composed of a
hydrophobic lipid core surrounded by a hydrophilic layer, which renders the
particles soluble. The lipid core contains primarily triglycerides (TG) and
cholesteryl esters (CE), as well as small amounts of other fatty compounds,
such as sphingolipids and fat-soluble vitamins (e.g. vitamins A, D, E, and K).
The external layer is made of phospholipids, unesterified cholesterol, and
specialized proteins, called apolipoproteins or apoproteins. These proteins
facilitate lipid solubilization and help to maintain the structural integrity
of LPs. They also serve as ligands for LP receptors and regulate the activity
of LP metabolic enzymes. As depicted in (Figure 1), the
amphipathic molecules that compose the outer layer of LPs are arranged so that
their hydrophobic parts face the central core, and their hydrophilic regions
face the surrounding aqueous environment.
Figure
1: Schematic Illustration of a Lipoprotein Particle
Cholesteryl
esters, which do not contain a free hydroxyl group (-OH) are more hydrophobic
than cholesterol, and better accommodated in the core of LPs. The conversion of
cholesterol to CE is catalyzed by a LP-associated enzyme called
lecithin-cholesterol acyltransferase (LCAT). This enzyme, which promotes packaging
of cholesteryl molecules in LPs, is critical for normal cholesterol metabolism.
Deficiency of LCAT activity leads to accumulation of unesterified cholesterol
in tissues, and is associated with a number of clinical conditions including
corneal opacity, hemolytic anemia, and premature atherosclerosis.
During
ordinary metabolism, plasma LPs lose, acquire, and exchange their lipid and
protein constituents. Normally, fat-rich LPs lose most of their fat within a
few hours of food ingestion, and become smaller and denser particles with
higher relative cholesterol content. The depletion of fat from LPs is catalyzed
by lipoprotein lipase (LPL). This lipolytic enzyme is located on the surface of
endothelial capillaries, and degrades triglycerides to free fatty acids (FFAs)
and glycerol. The released FFAs may stay in circulation bound to albumin, or be
taken-up by muscle and fat cells for usage and storage, respectively.
Lipids
of dietary origin are processed by intestinal epithelial cells, and then
secreted into the bloodstream as part of large, fat-rich LPs called
chylomicrons (chylo = milky, micron= indicates particle size). En route
to the liver, chylomicrons (CM) pass through endothelial capillaries, lose some
fat, and their remnants are taken-up by liver cells. In the liver, the lipids
obtained from CM remnants are re-processed and then secreted back into the
bloodstream as part of very low-density LPs (VLDL). Depletion of fat from VLDL
transforms the particle into an intermediate density lipoprotein (IDL), which
upon further degradation of its fat is converted into a relatively stable
particle, called low density lipoprotein (LDL). Because of its high cholesterol
content, LDL is also called LDL-cholesterol. Of the total blood cholesterol,
60-75% is found in LDL and the rest primarily in high-density lipoprotein (HDL)
particles. The main characteristics of plasma LPs and their associated
apoproteins are summarized in (Tables I
and II), respectively.
All
peripheral cells express the LDL-receptor (LDLR), and recycle it to the cell
surface upon need for cholesterol. Cholesterol is delivered to these cells
through binding of LDL to LDLR, which triggers endocytosis (internalization) of
both species. When the need for cholesterol is satisfied, the recycling of LDLR
is discontinued. Normally, an LDL particle stays in circulation for no
more than a few days before being consumed by a cholesterol needing cell.
However, under conditions of sustained cholesterol excess, the particle stays
in circulation for longer periods of time, and becomes more vulnerable to
undesired modifications (e.g. oxidation). As high levels of oxidized LDL are
commonly found in atherosclerotic plaques, they are thought to be the major
inducer of atherosclerotic lesions. Hence, LDL became known as bad cholesterol.
However, today we know that not all LDL particles are bad, and that some LDL
particles, especially very large ones (with diameter >21.3nm), may even
provide protection against atherosclerosis (2). LDL and HDL particle sizes are largely
determined by a LP-associated protein, called CETP (cholesteryl ester transfer
protein). This protein enhances exchange of non-polar lipids, primarily CE and
TG, and facilitates tight packaging of CE within the core of the particles. The
end result of prolonged and/or efficient CETP action is smaller LDL and HDL
particles. [The LP-anchored CETP can
be envisioned as having a hand that rotates between the interior and exterior
of the particle and capable of holding only one lipid molecule at a time.
Grasping of one molecule releases another and vise versa.]
Genetic
variation at the human CETP gene generates proteins with varying degrees of
activity. For example, a single codon variation, from isoleucine to
valine at position 405, generates a mutant protein, designated I405V, which
manifests significantly reduced CETP activity (3, 4). In a new observational study,
Barzilai, N. et al. (2) found that people with homozygosity for the
I405V allele have larger HDL and LDL particles, and that this genotype is
associated with exceptional longevity and a markedly reduced risk of coronary
artery disease (CAD). Of the 213 centenarians enrolled in the study, 80% had a
high proportion of large LDL particles, compared to just 8% of the subjects in
the control group (256 people in their 60’s and 70’s) (2). Interestingly, HDL and LDL particle
sizes are significantly larger in women than in men, which may account, at
least in part, for the longer life expectancies of women.
Unlike
LDL, HDL is not recognized by LDLR, and cannot deliver cholesterol to tissue
cells. Instead, it has the ability to remove excess peripheral cholesterol and
return it to the liver for recycling and excretion. This process, called
reverse cholesterol transport, is thought to protect against atherosclerosis.
Observational studies over the last 2 decades have consistently shown strong
correlation between elevated HDL levels and low incidents of coronary heart
disease (CHD). Hence HDL has been dubbed “good” cholesterol.
HDL
is synthesized in the liver and intestine as a nascent, discoid-shaped particle
that contains predominantly apoA-I, and some phospholipids. Upon maturation,
HDL assumes a spherical shape, and the composition of its core lipids becomes
very similar to that of LDL. However, the relative higher protein content in
HDL renders the particle denser and more resistant to undesired modifications.
Unlike the case of LDL, the clearance of HDL from circulation is not negatively
affected by excess cholesterol, which may be another reason why HDL, despite
being much smaller particle than LDL (10nm versus 20nm), is not found in
atherosclerotic plaques. It’s worth noting, that the potential of LPs to become
harmful is also influenced by the character of their lipid constituents. For
example, vitamin E and lipids containing omega-3 fatty acid moieties appear to
protect the particles from harmful oxidation and from getting stuck on the
walls of blood vessels.
The
functional difference between LDL and HDL results primarily from the different
character of their major apoproteins, apoB-100 and apoA-I, respectively.
ApoB-100, which is found in VLDL, IDL, and LDL, but not in HDL, serves as a
ligand for LDLR, and provides LDL with the means to deliver cholesterol to
tissue cells. On the other hand, apoA-I, which is found exclusively in HDL, has
a unique ability to capture and solubilze free cholesterol. This apoA-I ability
enables HDL to act as a cholesterol scavenger.
A
mutant apoA-I protein, called apoA-I Milano (apoA-Im), has been identified in a
group of people that live in a small village in northern Italy (5). Carriers of this protein, all
heterozygous for the mutation, had very low levels of HDL (7-14 mg/dl) but
showed no clinical signs of atherosclerosis (5-7). HDL particles in these subjects were
markedly larger than control (12nm versus 9.4nm), which may account for their
immunity against premature atherosclerosis. ApoA-Im differs from natural
apoA-I by having a cysteine residue at position 173 instead of arginine. This
cysteine residue forms disulfide bridges with other apoA-I molecules or with
apoA-II (6, 7), which
apparently lead to larger HDL particles. It also renders apoA-I more
susceptible to catabolism (8), accounting
for the low HDL levels in apoA-Im carriers.
The
therapeutic potential of apoA-I has been recently assessed in patients with
acute coronary syndromes (9). Of
the 47 patients that participated in a randomized controlled trial, 36 received
5 weekly infusions of recombinant apoA-Im/phospholipid complexes, and 11
received only saline infusions. The results showed significant regression in
coronary atherosclerotic volume in the apoA-Im treated group, and virtually no
change in the control group (9). These
results, if reproduced in larger clinical trials, may constitute a
revolutionary breakthrough in the non-invasive treatment of cardiovascular
disease. They should also encourage further exploration into the therapeutic
usefulness of apoA-Im and normal apoA-I in managing atherosclerotic vascular
diseases.
lipoproteins).
low-density
lipoproteins (LDL) -
The class of large diameter soluble lipid-protein complexes which the fourth lowest
in density (mass to volume ratio); their composition is ~25% apolipoproteins,
~45% cholesterol, and ~30% triglycerides and phospholipids; their normal role
is to transport cholesterol and other lipids from the liver and intestines to
the tissues for use; elevated levels of LDL are associated with increased risk
of cardiovascular disease. nickname - bad cholesterol
high-density
lipoproteins (HDL) - The class of
small diameter soluble lipid-protein complexes which the highest in density
(mass to volume ratio); their composition is ~45% apolipoproteins, ~25%
cholesterol, and ~30% triglycerides and phospholipids; their normal role is to
transport cholesterol and other lipids from the tissues to the liver for
disposal; elevated levels of HDL are associated with decreased risk of
cardiovascular disease.
very
low-density lipoproteins (VLDL) -
The class of very large diameter soluble lipid-protein complexes which the
second lowest in density (mass to volume ratio); their composition is ~10%
apolipoproteins, ~40% cholesterol, and ~50% triglycerides and phospholipids;
their normal role is to transport triglycerides and other lipids from the liver
and intestines to the tissues for use; elevated levels of VLDL are associated
with some increased risk of cardiovascular disease.
formation
of lipoproteins
http://www.youtube.com/watch?v=97uiV4RiSAY
What
is Cholesterol?
Cholesterol
is a waxy fat found in the body and, despite what you may have been told, is a
necessary nutrient for the body. Cholesterol is used in the formation of cell
membranes and plays an important role in hormone, bile and vitamin D
production. Cholesterol comes from two sources: the foods that we eat, such as
meat, dairy products and eggs, and our own liver, which produces about eighty
percent of all the cholesterol in the body. That means that only about twenty
percent of our total cholesterol is obtained from food. Since cholesterol is
not water-soluble, the liver packages the cholesterol into tiny spheres called
lipoproteins so that the cholesterol can be transported through the blood. The
lipoproteins can be divided into two different categories: low density and high
density lipoproteins.
http://www.youtube.com/watch?v=-WhADd1GKtA&feature=relmfu
Low
density lipoprotein (LDL): LDL, often dubbed the "bad" cholesterol,
carries most of the cholesterol in the blood and seems to play a role in the
deposition of fat in arteries. These deposits result in blockages called plaque.
In addition to narrowing the arteries and increasing blood pressure, plaque contributes
to the hardening of artery walls, a condition known as atherosclerosis.
High
density lipoprotein (HDL): HDL
is known as the "good" cholesterol. HDL carries cholesterol from the
blood back to the liver for elimination. It is also responsible for removing
the plaque buildup along the artery walls. Elevated levels of HDL are very
desirable because it helps to clear blockages in the arteries, reduces LDL and
decreases blood pressure.
What
are Triglycerides?
Triglycerides
are lipids normally found in increased levels in the blood following the
digestion of fats in the intestine. Consumed calories that are not immediately
used are stored in fat cells in the form of triglycerides and are later
released from fatty tissues when the body needs energy between meals. The major
transporter of triglycerides is a forerunner of LDL, a simpler molecule known
as VLDL (very low density lipoprotein). As the
VLDL loses triglycerides, the VLDL particle is converted into intermediate and
then low density lipoprotein. Over time, elevated triglyceride levels may
result in pancreatitis—a condition that can cause malabsorption of nutrients
and lead to diabetes. As pancreatitis progresses, damage can spread to other
organs, including the heart, lungs and kidneys. High triglyceride levels also
promote the deposition of cholesterol in the arteries and are associated with
known risk factors for heart disease. The exact role that triglycerides play as
an independent risk factor is not yet clear because people with high LDL and
low HDL levels also have high triglyceride levels.
Although
These Researchers Beg to Differ…
One
study by Koren-Morag, Graff and Goldbourt, published in the American Heart
Association journal Circulation, found that individuals with elevated
triglyceride levels have a nearly thirty percent increased probability of
suffering a stroke, even after taking into account other risk factors such as
cholesterol levels. One of the most important aspects of the study is that it
clarifies the independent link of triglyceride levels to stroke, meaning that a
causal relationship is likely.
What
is Plaque?
Excess
LDL cholesterol clings to arterial walls as it is transported through the
system. Macrophages eat
the LDL and become "foam cells." The cells eventually rupture and
begin to form a lipid layer called plaque. Connective fibers form in and around the fatty
layer, causing it to harden. Over time, the fibrous layer thickens, narrowing
the arterial pathway. When calcium deposits form a crust, the plaque becomes
brittle and is more likely to rupture.
The
Problem With Plaque
High
blood cholesterol levels increase the likelihood that the fat will be deposited
as plaque on the inner surface of arterial walls. As these deposits increase,
the channel of the artery narrows, contributing to an increase in blood
pressure. To compensate, the heart must work harder to pump the same volume of
blood through the narrower arteries. When the coronary arteries themselves are
affected by plaque, the harder working heart receives less oxygen, thus
increasing the risk of heart attack. Plaque also contributes to hardening of
the arteries, or atherosclerosis. This loss of flexibility in arterial walls
elevates blood pressure, putting the heart at additional risk. When the plaque
deposits become unstable, they burst, releasing their cholesterol into the
bloodstream all at once. This can trigger clotting in small coronary arteries.
When the artery is completely obstructed, blood flow stops and a heart attack
occurs.
http://www.youtube.com/watch?v=XLLBlBiboJI&feature=related
http://www.youtube.com/watch?v=-WhADd1GKtA&feature=relmfu
What
is a Lipoprotein?
Lipids,
such as triacylglycerols and cholesterol esters, are virtually insoluble in
aqueous solution. Therefore, lipids must be transported by the circulation in
COMPLEX WITH water-soluble PROTEINS.
This
complex LIPOPROTEIN is a globular micelle-like particle that consists of a
nonpolar core of triacylglycerols and cholesterol esters surrounded by an
amphiphilic coating of protein, phospholipid, and cholesterol.
Here
is a diagram of Low-Density Lipoprotein (LDL) which is approximately 25nm in
diameter:
http://www.youtube.com/watch?v=x-4ZQaiZry8
You
need "Quick
Time" Player and Plug-In to view this LDL particle in motion:
video
http://www.youtube.com/watch?v=97uiV4RiSAY
Characteristics
of Lipoproteins in Human Plasma
Characteristic
|
Chylomicrons
|
VLDL
|
IDL
|
LDL
|
HDL
|
Density (g/cm)
|
~0.95
|
~1.006
|
1.006-1.019
|
1.019-1.063
|
1.063-1.210
|
Particle Diameter (nm)
|
75-1200
|
30-80
|
25-35
|
18-25
|
5-12
|
Particle Mass (kD)
|
400,000
|
10,000-80,000
|
5000-10,000
|
2300
|
175-360
|
%Proteina
|
1.5-2.5
|
5-10
|
15-20
|
20-25
|
40-55
|
%Phospholipidsa
|
7-9
|
15-20
|
22
|
15-20
|
20-35
|
%Free Cholesterola
|
1-3
|
5-10
|
8
|
7-10
|
3-4
|
%Triacylglycerolsb
|
84-89
|
50-65
|
22
|
7-10
|
3-5
|
%Cholesteryl Estersb
|
3-5
|
10-15
|
30
|
35-40
|
12
|
Major Apolipoproteins
|
AI,AII,B48,CI,CII,CIII,E
|
B100,CI,CII,CIII,E
|
B100,CIII,E
|
B100
|
AI,AII,CI,CII,CIII,D,E
|
Theoretically,
a 17g egg yolk that contains 2.8g of protein would contain 1.4g of apoB (49%
total yolk protein, MW = 5.5 x 105). Because VLDLy contains
only one apoB protein per particle, this single egg yolk would contain 1.5 x 1018 VLDLy particles. The hen would be
producing VLDLy particles at a rate of 1.5 x 1014 particles per minute for seven days!
Biochemistry of immune processes.
http://www.youtube.com/watch?v=Ys_V6FcYD5I&feature=related
Viruses,
bacteria, fungi, and parasites that enter the body of vertebrates of are
recognized and attacked by the immune
system. Endogenous cells that have undergone alterations— e. g., tumor
cells—are also usually recognized as foreign and destroyed. The immune system
is supported by physiological changes in infected tissue, known asinflammation.
This reaction makes it easier for the immune cells to reach the site of
infection. Two different systems are involved in the immune response. The innate immune system is based on receptors that can
distinguish between bacterial and viral surface structures or foreign proteins
(known as antigens) and those that are endogenous. With the help of these
receptors, phagocytes bind
to the pathogens, absorb them by endocytosis, and break them down. The complement
system (see p. 298) is also part of the innate system. The acquired (adaptive) immune system is based on the ability of the lymphocytes to form highly specific antigen
receptors “on suspicion,” without ever having met the corresponding antigen. In
humans, there are several billion different lymphocytes, each of which carries
a different antigen receptor. If this type of receptor recognizes “its” cognate
antigen, the lymphocyte carrying it is activated and then plays its special
role in the immune response. In addition, a distinction is made between
cellular and humoral immune responses.
The T
lymphocytes (T cells) are
responsible for cellular
immunity. They are named after the thymus, in which the decisive steps in
their differentiation take place. Depending on their function, another
distinction is made between cytotoxic T cells (green) and helper
T cells (blue).
http://www.youtube.com/watch?v=14koX2tbRzU&feature=related
http://www.youtube.com/watch?v=VOD5tuQ5wvo&feature=related
Humoral immunity is
based on the activity of the B lymphocytes (B cells, light brown), which
mature in the bone marrow. After activation by T cells, B cells are able to
release soluble forms of their specific antigen receptors, known as antibodies (see p. 300), into the blood
plasma. The immune system’s “memory” is represented by memory cells. These are
particularly long–lived cells that can arise from any of the lymphocyte types
described. Simplified diagram
of the immune response.
Pathogens
that have entered the body—e. g., viruses (top)—are taken up by antigen-presenting cells (APCs) and proteolytically
degraded (1). The viral fragments produced in this way are then
presented on the surfaces of these cells with the help of special membrane
proteins (MHC proteins; see p. 296) (2). The APCs include B lymphocytes,
macrophages, and dendritic cells such as the skin’s Langerhans cells. The
complexes of MHC proteins and viral fragments displayed on the APCs are
recognized by T cells that carry a receptor that matches the antigen (“T-cell
receptors”) (3). Binding leads to activation of the T cell concerned and
selective replication of it (4, “clonal selection”).
The
proliferation of immune cells is stimulated by interleukins (IL). These are a group of more
than 20 signaling substances belonging to the cytokine family (see p. 392),
with the help of which immune cells communicate with each other. For example,
activated macrophages release IL-1 (5), while T cells stimulate their own
replication and that of other immune cells by releasing IL-2 (6).
Depending on their type, activated T cells have different functions. Cytotoxic T cells (green) are able to recognize and
bind virusinfected body cells or tumor cells (7). They then drive the
infected cells into apoptosis (see p. 396) or kill them with perforin, a protein that perforates the
target cell’s plasma membrane (8). B
lymphocytes, which as APCs present viral fragments on their surfaces, are
recognized by helper T cells (blue) or their T cell receptors (9).
Stimulated by interleukins, selective clonal replication then takes place of B
cells that carry antigen receptors matching those of the pathogen (10).
Thesemature into plasma cells (11) and finally secrete
large amounts of soluble antibodies (12).
• Antigen receptors
Many
antigen receptors belong to the immunoglobulin
superfamily. The common characteristic of these proteins is that they
aremade up from “immunoglobulin domains.” These are characteristically folded
substructures consisting of 70–110 amino acids, which are also found in soluble
immunoglobulins (Ig; see p. 300). The illustration shows schematically a few of
the important proteins in the Ig superfamily. They consist of constant regions
(brown or green) and variable regions (orange). Homologous domains are shown in
the same colors in each case. All of the receptors have transmembrane helices
at the C terminus, which anchor them to the membranes. Intramolecular and
intermolecular disulfide bonds are also usually found in proteins belonging to
the Ig family. Immunoglobulin
M (IgM), a membrane protein
on the surface of B lymphocytes, serves to bind free antigens to the B cells.
By contrast, T cell receptors only bind antigens when they are
presented by another cell as a complex with an MHC protein (see below).
Interaction between MHC-bound antigens and T cell receptors is supported by co-receptors. This group
includes CD8, a membrane
protein that is typical in cytotoxic T cells. T helper cells use CD4 as a co-receptor instead (not
shown). The abbreviation “CD” stands for “cluster of differentiation.” It is
the term for a large group of proteins that are all located on the cell surface
and can therefore be identified by antibodies. In addition to CD4 and CD8,
there are many other co-receptors on immune cells
The MHC proteins are named after the “major
histocompatibility complex”—the DNA segment that codes for them. Human
MHC proteins are also known as HLA antigens (“human leukocyte-associated”
antigens). Their polymorphism is so large that it is unlikely that any two individuals
carry the same set of MHC proteins—except formonozygotic twins. Class I MHC proteins occur in almost all
nucleated cells. They mainly interact with cytotoxic T cells and are the reason
for the rejection of transplanted organs. Class I MHC proteins are heterodimers
(áâ). The â subunit is also known as â2-microglobulin. Class II MHC proteins also consist of two
peptide chains, which are related to each other. MHC II molecules are found on
all antigen- presenting cells in the immune system. They serve for interaction
T-cell activation The
illustration shows an interaction between a virus-infected body cell (bottom)
and a CD8- carrying cytotoxic T lymphocyte (top). The infected cell breaks down
viral proteins in its cytoplasm and
transports the peptide fragments into the endoplasmic reticulum with the help
of a special transporter (TAP)
. Newly synthesized class I MHC proteins on the endoplasmic reticulum are
loaded with one of the peptides and
then transferred to the cell surface by vesicular transport . The viral
peptides are bound on the surface of the á2 domain of the MHC protein in
a depression formed by an insertion as a “floor” and two helices as “walls”
(see smaller illustration). Supported by CD8 and other co-receptors, a T cell
with a matching T cell receptor binds to the MHC peptide complex (5).
This binding activates protein kinases in the interior of the T cell, which
trigger a chain of additional reactions (signal
transduction). Finally, destruction of the virus-infected cell by the
cytotoxic T lymphocytes takes place.
Complement system
The
complement system is part of the innate immune system. It supports nonspecific
defense against
microorganisms. The system consists of some 30 different proteins, the “complement
factors,” which are found
in the blood and represent about 4% of all plasma proteins there. When inflammatory
reactions occur, the complement factors enter the infected tissue and take
effect there. The complement system works in three different ways: Chemotaxis. Various complement factors attract
immune cells that can attack and phagocytose pathogens. Opsonization. Certain complement factors
(“opsonins”) bind to the pathogens and thereby mark them as targets for
phagocytosing cells (e. g., macrophages). Membrane
attack. Other complement
factors are deposited in the bacterial membrane, where they create pores that
lyse the pathogen (see below).
• The
reactions that take place in the complement system can be initiated in several
ways. During the early phase of infection, lipopolysaccharides and other
structures on the surface of the pathogens trigger the alternative
pathway (right). If
antibodies against the pathogens become available later, the antigen– antibody
complexes formed activate theclassic
pathway (left).
Acute-phase proteins are also able to start the complement cascade (lectin pathway). Factors C1 to C4 (for “complement”) belong to the
classic pathway, while factors
B and D form
the reactive components of the alternative pathway. Factors C5 to C9 are responsible for membrane
attack. Other components not shown here regulate the system. As in blood
coagulation (see p. 290), the early components in the complement system are serine
proteinases, which
mutually activate each other through limited proteolysis. They create a
self-reinforcing enzyme
cascade.
Factor C3, the products of which are
involved in several functions, is central to the complement system. The classic pathway is triggered by the formation of factor
C1 at IgG or IgM on the surface of microorganisms (left). C1 is an 18-part
molecular complex with three different components (C1q, C1r, and C1s). C1q is
shaped like a bunch of tulips, the “flowers” of which bind to the Fc region of
antibodies (left). This activates C1r, a serine proteinase that initiates the cascade of
the classic pathway. First, C4 is proteolytically activated into C4b, which in
turn cleaves C2 into C2a and C2b. C4B and C2a together form C3
convertase [1], which
finally catalyzes the cleavage of C3 into C3a and C3b. Small amounts of C3b
also arise from non-enzymatic hydrolysis of C3.
The classic pathway is triggered by the formation of
factor C1 at IgG or IgM on the surface of microorganisms (left). C1 is an 18-part
molecular complex with three different components (C1q, C1r, and C1s). C1q is
shaped like a bunch of tulips, the “flowers” of which bind to the Fc region of
antibodies (left). This activates C1r, a serine proteinase that initiates the cascade of
the classic pathway. First, C4 is proteolytically activated into C4b, which in
turn cleaves C2 into C2a and C2b. C4B and C2a together formC3 convertase [1], which finally catalyzes
the cleavage of C3 into C3a and C3b. Small amounts of C3b also arise from non-enzymatic
hydrolysis of C3. The alternative
pathwaystarts with the binding of factors C3b and B to bacterial
lipopolysaccharides (endotoxins). The formation of this complex allows cleavage
of B by factor D, giving rise to a second form of C3
convertase (C3bBb). Proteolytic
cleavage of factor C3 provides two components with
different effects. The reaction exposes a highly reactive
thioester group in C3b,
which reacts with hydroxyl or amino groups. This allows C3b to bind covalently
to molecules on the bacterial surface (opsonization, right). In addition, C3b
initiates a chain of reactions leading to the formation of the membrane
attack complex Together
with C4a and C5a (see below), the smaller product C3a promotes the inflammatory
reaction and has chemotactic effects. The “late” factors C5 to C9 are
responsible for the development of the membrane
attack complex (bottom). They
create an ion-permeable pore in the bacterial membrane, which leads to lysis of
the pathogen. This reaction is triggered by C5 convertase [2]. Depending on the type of
complement activation, this enzyme has the structure C4b2a3b or C3bBb3b, and it cleaves C5 into C5a and
C5b. The complex of C5b and C6 allows deposition of C7 in the bacterial
membrane. C8 and numerous C9 molecules—which form the actual pore—then bind to
this core. Antibodies
http://www.youtube.com/watch?v=lrYlZJiuf18
http://www.youtube.com/watch?v=Ys_V6FcYD5I&feature=related
• Soluble
antigen receptors, which are formed by activated B cells (plasma cells; see p.
294) and released into the blood, are known as antibodies. They are also
members of the immunoglobulin family (Ig; see p. 296). Antibodies are an
important part of the humoral immune defense system. They have no antimicrobial
properties themselves, but support the cellular immune system in various ways:
1. They bind to antigens on the surface of pathogens and thereby prevent them
from interacting with body cells (neutralization; see p. 404, for example). 2.
They link single-celled pathogens into aggregates (immune complexes), which are
more easily taken up by phagocytes (agglutination).
3. They activate the complement system (see p. 298) and thereby promote the
innate immune defense system (opsonization).
In addition, antibodies have become indispensable aids in medical and
biological diagnosis. Domain
structure of immunoglobulin G _
Type
G immunoglobulins (IgG) are quantitatively the most important antibodies
in the blood,where they form the fraction of ã-globulins (see p. 276).
IgGs (mass 150 kDa) are tetramers with two heavy
chains (H chains; red or
orange) and two light chains (L chains; yellow). Both H chains
are glycosylated (violet; see also p. 43). The proteinasepapain cleaves
IgG into two Fab fragments and one Fc fragment. The Fab (“antigen-binding”) fragments,
which each consist of one L chain and the N-terminal part of an H chain, are
able to bind antigens. The Fc (“crystallizable”) fragment is
made up of the C-terminal halves of the two H chains. This segment serves to
bind IgG to cell surfaces, for interaction with the complement system and
antibody transport. Immunoglobulins are constructed in a modular fashion from
several immunoglobulin domains (shown in the diagram on the right
in Ω form). Classes of
immunoglobulins _
http://www.youtube.com/watch?v=mUXIK5gGD1k
Human immunoglobulins are
divided into five classes. IgA (with two subgroups), IgD, IgE, IgG (with four subgroups), and IgM are defined by their H chains,
which are designated by the Greek letters á, ä, å, ã,
and µ. By contrast, there are only two types of L chain (ê and ë). IgD and IgE
(like IgG) are tetramers with the structure H2L2. By contrast, soluble IgA and
IgM are multimers that are held together by disulfide bonds and additional J peptides (joining peptides). The antibodies
have different tasks. IgMs are the first immunoglobulins
formed after contact with a foreign antigen. Their early forms are located on
the surface of B cells (see p. 296), while the later forms are secreted from
plasma cells as pentamers. Their action targets microorganisms in particular.
Quantitatively, IgGs are the most important
immunoglobulins (see the table showing serum concentrations). They occur in the
blood and interstitial fluid. As they can pass the placenta with the help of
receptors, they can be transferred from mother to fetus. IgAs mainly occur in the intestinal
tract and in body secretions. IgEs are found in low concentrations in
the blood. As they can trigger degranulation of mast cells (see p. 380), they
play an important role in allergic reactions. The function of IgDs is still unexplained. Their plasma
concentration is also very low.
Causes of antibody variety _
There
are three reasons for the extremely wide variability of antibodies: 1. Multiple genes. Various genes are available to
code for the variable protein domains. Only one gene from among these is
selected and expressed. 2. Somatic
recombination. The genes are
divided into several segments, of which there are various versions. Various
(“untidy”) combinations of the segments during lymphocyte maturation give rise
to randomly combined new genes (“mosaic genes”). 3. Somaticmutation. During differentiation of B cells
into plasma cells, the coding genes mutate. In this way, the “primordial” germline
genes can become different somatic
genes in the individual B
cell clones.
Biosynthesis of a light chain _
We
can look at the basic features of the genetic organization and synthesis of
immunoglobulins using the biosynthesis of a mouse ê chain as an example.
The gene segments for this light chain are designated L, V, J, and C. They are
located on chromosome 6 in the germ-line
DNA (on chromosome 2 in humans)
and are separated from one another by introns (see p. 242) of different
lengths. Some 150 identical L
segments code for the signal
peptide (“leader sequence,” 17–20 amino acids) for secretion of the product
The V segments, of which there are
150 different variants, code formost of the variable domains (95 of the 108
amino acids). L and V segments always occur in pairs—in tandem, so to speak. By
contrast, there are only five variants of the J
segments (joining segments)
at most. These code for a peptide with 13 amino acids that links the variable
part of the ê chains to the constant part. A single C segment codes for the constant part of the
light chain (84 amino acids). During the differentiation of B lymphocytes,
individualV/J combinations arise in each B cell. One of
the 150 L/V tandem segments is selected and linked to one of the five J
segments.
The
immune system is a complex, dynamic, and beautifully orchestrated mechanism
with enormous responsibility. It defends against foreign invasion by
microorganisms, screens out cancer cells, adapts as we grow, and modifies how
we interact with our environment. When it malfunctions, disease, cancer or
death can occur. Although it is not necessary to understand all the intimate
details of the immune system, it is wise to have a basic grasp of its
functions. More precisely, we should understand how to stay healthy.
It
appears that the immune system has a training effect, similar to other areas of
physiology (e.g., cardiovascular, muscular). In other words, a balanced
training program of exercise and rest leads to better performance. Studies in
the laboratory and epidemiological observations have shown improved immune
function and fewer URIs in athletes as compared to their couch-potato
counterparts. This is especially true in older athletes and it appears that
regular exercise can help attenuate the age related decline in immune function.
On
the other hand, too much exercise can lead to a dramatically increased risk of
URIs. The stress of strenuous exercise transiently suppresses immune function.
This interruption of otherwise vigorous surveillance can provide an "open
window" for a variety of infectious diseases -- notably viral illnesses --
to take hold. This is especially true following single bouts of excessive
exercise. For example, it has been observed that two-thirds of participants
developed URIs shortly after completing an ultramarathon. Similarly, cumulative
overtraining weakens the athlete's immune system, leading to frequent illness
and injury.
The
best model that accommodates clinical observations and laboratory experiments
is described by the "J"-curve ( Fig. 1). It is important to note that
this curve is individualized. What is moderate training for some is
overtraining for others.
In
addition to strenuous exercise, other forms of stress may also transiently
suppress immune function. Since exercise is not the only stress factor, an
athlete must consider a host of other variables. There are job
responsibilities, family obligations, social interactions, financial concerns
and other components that shape our lives. The sum of all of these affects a
central axis in the body which ultimately influences immune function. Some of
these (e.g., exercise) are under our direct control, and others only partially
or not at all. Recognizing when excess stress occurs is easier if it just comes
from one source. However, all too often it is the sum of many small, difficult
to recognize changes that tips the scales and sends the athlete into the
whirlpool of overtraining and immunosuppression. Alone and in isolation these
small changes would be manageable, but combined they can overwhelm. (Fig.
2.)
Currently,
the best way to stay healthy is to listen to your body. Recognizing the early
warning signs and adapting the training schedule accordingly can help keep you
healthy. In that light, here are some points to ponder and a few
recommendations,
· Keep
a training log. In addition to recording workouts, keep a fatigue score (scale
0-5). It is expected that a hard workout will make you tired, so it is more
important to note the cumulative "feel" during the day. Granted, the
scale is individualized and subjective, but this simple tool is very useful. If
you notice that your fatigue is progressively increasing over days or weeks,
then it is time to add more rest.
· A
properly constructed training program that allows for rest and recovery will
help head off problems before they start. Periodization
is a way to achieve that goal.
· Record
your resting morning heart rate. A progressive increase may tip you off that
you are exceeding your ability to recover.
· Anticipate
added stress in advance (e.g. new job) and adjust the workout schedule
correspondingly. A small amount of rest early will prevent a bigger problem
later.
· To
make sure your anti-oxidant defense system is tuned up, eat five servings of
fruit or vegetables per day. Note: vitamin supplements do not appear to have
the same benefits as fruits and vegetables.
· Heed
your body's early warning signs,
o Disordered
sleep (too much or insomnia)
o Loss
of interest in pleasurable activities
o Moodiness
or depression
o Excessive
muscle soreness
o Poor
concentration. Lack of mental energy.
o Altered
appetite.
o Frequent
injury or illness
o Lack
of physical energy
· Get
an annual influenza vaccine (usually available each year starting in October)
· Because
frequent URIs or unrelenting fatigue may be a sign of an underlying illness, it
is recommended that you consult your physician.
The Anatomy of the Immune System
The
organs of the immune system are stationed throughout the body. They are
generally referred to as lymphoid organs because they are concerned with the
growth, development, and deployment of lymphocytes, the white cells that are
the key operatives of the immune system. Lymphoid organs include the bone
marrow and the thymus, as well as lymph nodes, spleen, tonsils and adenoids,
the appendix, and clumps of lymphoid tissue in the small intestine known as
Peyer's patches. The blood and lymphatic vessels that carry lymphocytes to and
from the other structures can also be considered lymphoid organs.
Cells
destined to become immune cells, like all other blood cells, are produced in
the bone marrow, the soft tissue in the hollow shafts of long bones. The
descendants of some so-called stem cells become lymphocytes, while others
develop into a second major group of immune cells typified by the large,
cell-and particle-devouring white cells known as phagocytes.
The
two major classes of lymphocytes are B cells and T cells. B cells complete
their maturation in the bone marrow. T cells, on the other hand, migrate to the
thymus, a multilobed organ that lies high behind the breastbone. There they
multiply and mature into cells capable of producing immune response-that is,
they become immunocompetent. In a process referred to as T cell
"education," T cells in the thymus learn to distinguish self cells
from nonself cells; T cells that would react against self antigens are
eliminated.
Upon
exiting the bone marrow and thymus, some lymphocytes congregate in immune
organs or lymph nodes. Others-both B and T cells-travel widely and continuously
throughout the body. They use the blood circulation as well as a bodywide
network of lymphatic vessels similar to blood vessels.
Laced
along the lymphatic routes-with clusters in the neck, armpits, abdomen, and
groin-are small, bean-shaped lymph nodes. Each lymph node contains specialized
compartments that house platoons of B lymphocytes, T lymphocytes, and other
cells capable of enmeshing antigen and presenting it to T cells. Thus, the
lymph node brings together the several components needed to spark an immune
response.
The
spleen, too, provides a meeting ground for immune defenses. A fist-sized organ
at the upper left of the abdomen, the spleen contains two main types of tissue:
the red pulp that disposes of worn-out blood cells and the white pulp that
contains lymphoid tissue. Like the lymph nodes, the spleen's lymphoid tissue is
subdivided into compartments that specialize in different kinds of immune
cells. Microorganisms carried by the blood into the red pulp become trapped by
the immune cells known as macrophages. (Although people can live without a
spleen, persons whose spleens have been damaged by trauma or by disease such as
sickle cell anemia, are highly susceptible to infection; surgical removal of
the spleen is especially dangerous for young children and the
immunosuppressed.)
Nonencapsulated
clusters of lymphoid tissue are found in many parts of the body. They are
common around the mucous membranes lining the respiratory and digestive
tracts-areas that serve as gateways to the body. They include the tonsils and
adenoids, the appendix, and Peyer's patches.
The
lymphatic vessels carry lymph, a clear fluid that bathes the body's tissues.
Lymph, along with the many cells and particles it carries-notably lymphocytes,
macrophages, and foreign antigens, drains out of tissues and seeps across the
thin walls of tiny lymphatic vessels. The vessels transport the mix to lymph
nodes, where antigens can be filtered out and presented to immune cells.
Additional
lymphocytes reach the lymph nodes (and other immune tissues) through the
bloodstream. Each node is supplied by an artery and a vein; lymphocytes enter
the node by traversing the walls of the very small specialized veins.
All
lymphocytes exit lymph nodes in lymph via outgoing lymphatic vessels. Much as
small creeks and streams empty into larger rivers, the lymphatics feed into
larger and larger channels. At the base of the neck, large lymphatic vessels
merge into the thoracic duct, which empties its contents into the bloodstream.
Once
in the bloodstream, the lymphocytes and other assorted immune cells are
transported to tissues throughout the body. They patrol everywhere for foreign
antigens, then gradually drift back into the lymphatic vessels, to begin the
cycle all over again
Disorders of the Immune System: Allergy
http://www.youtube.com/watch?v=NFTL51FvX4Q&feature=related
The
most common types of allergic reactions-hay fever, some kinds of asthma, and
hives-are produced when the immune system response to a false alarm. In a
susceptible person, a normally harmless substance-grass pollen or house dust,
for example-is perceived as a threat and is attacked.
Such
allergic reactions are related to the antibody known as immunoglobulin E. Like
other antibodies, each IgE antibody is specific; one reacts against oak pollen,
another against ragweed. The role of IgE in the natural order is not known,
although some scientists suspect that it developed as a defense against
infection by parasitic worms.
The
first time an allergy-prone person is exposed to an allergen, he or she makes
large amounts of the corresponding IgE antibody. These IgE molecules attach to
the surfaces of mast cells (in tissue) or basophils (in the circulation). Mast
cells are plentiful in the lungs, skin, tongue, and linings of the nose and
intestinal tract.
When
an IgE antibody siting on a mast cell or basophil encounters its specific
allergen, the IgE antibody signals the mast cell or basophil to release the
powerful chemicals stored within its granules. These chemicals include
histamine, heparin, and substances that activate blood platelets and attract
secondary cells such as eosinophils and neutrophils. The activated mast cell or
basophil also synthesizes new mediators, including prostaglandins and
leukotrienes, on the spot.
It
is such chemical mediators that cause the symptoms of allergy, including
wheezing, sneezing, runny eyes and itching. They can also produce anaphylactic
shock, a life-threatening allergic reaction characterized by swelling of body
tissues, including the throat, and a sudden fall in blood pressure.
Autoimmune Diseases
Sometimes
the immune system's recognition apparatus breaks down, and the body begins to
manufacture antibodies and T cells directed against the body's own
constituents-cells, cell components, or specific organs. Such antibodies are
known as autoantibodies, and the diseases they produce are called autoimmune
diseases. (Not all autoantibodies are harmful; some types appear to be integral
to the immune system's regulatory scheme.)
Autoimmune
reactions contribute to many enigmatic diseases. For instance, autoantibodies
to red blood cells can cause anemia, autoantibodies to pancreas cells contribute
to juvenile diabetes, and autoantibodies to nerve and muscle cells are found in
patients with the chronic muscle weakness known as myasthenia gravis.
Autoantibody known as rheumatoid factor is common in persons with rheumatoid
arthritis.
Persons
with systemic lupus erythematosus (SLE), whose symptoms encompass many systems,
have antibodies to many types of cells and cellular components. These include
antibodies directed against substances found in the cell's nucleus-DNA, RNA, or
proteins-which are known as antinuclear antibodies, or ANAs. These antibodies
can cause serious damage when they link up with self antigens to form
circulating immune complexes, which become lodged in body tissue and set off
inflammatory reactions (Immune Complex Diseases).
Autoimmune
diseases affect the immune system at several levels. In patients with SLE, for
instance, B cells are hyperactive while suppressor cells are underactive; it is
not clear which defect comes first. Moreover, production of IL-2 is low, while
levels of gamma interferon are high. Patients with rheumatoid arthritis, who
have a defective suppressor T cell system, continue to make antibodies to a
common virus, whereas the response normally shuts down after about a dozen
days.
No
one knows just what causes an autoimmune disease, but several factors are
likely to be involved. These may include viruses and environmental factors such
as exposure to sunlight, certain chemicals, and some drugs, all of which may
damage or alter body cells so that they are no longer recognizable as self. Sex
hormones may be important, too, since most autoimmune diseases are far more
common in women than in men.
Heredity
also appears to play a role. Autoimmune reactions, like many other immune
responses, are influenced by the genes of the MHC. A high proportion of human
patients with autoimmune disease have particular histocompatibility types. For
example, many persons with rheumatoid arthritis display the self marker known
as HLA-DR4.
Many
types of therapies are being used to combat autoimmune diseases. These include
corticosteroids, immunosuppressive drugs developed as anticancer agents,
radiation of the lymph nodes, and plasmapheresis, a sort of "blood
washing" that removes diseased cells and harmful molecules from the
circulation.
Immune Complex Diseases
Immune
complexes are clusters of interlocking antigens and antibodies. Under normal
conditions immune complexes are rapidly removed from the bloodstream by
macrophages in the spleen and Kupffer cells in the liver. In some
circumstances, however, immune complexes continue to circulate. Eventually they
become trapped in the tissues of the kidneys, lung, skin, joints, or blood
vessels. Just where they end up probably depends on the nature of the antigen,
the class of antibody-IgG, for instance, instead of IgM-and the size of the
complex. There they set off reactions that lead to inflammation and tissue
damage.
Immune
complexes work their damage in many diseases. Sometimes, as is the case with
malaria and viral hepatitis, they reflect persistent low-grade infections.
Sometimes they arise in response to environmental antigens such as the moldy
hay that causes the disease known as farmer's lung. Frequently, immune
complexes develop in autoimmune disease, where the continuous production of
autoantibodies overloads the immune complex removal system.
Immunodeficiency Diseases
Lack
of one or more components of the immune system results in immunodeficiency
disorders. These can be inherited, acquired through infection or other illness,
or produced as an inadvertent side effect of certain drug treatments.
People
with advanced cancer may experience immune deficiencies as a result of the
disease process or from extensive anticancer therapy. Transient immune deficiencies
can develop in the wake of common viral infections, including influenza,
infectious mononucleosis, and measles. Immune responsiveness can also be
depressed by blood transfusions, surgery malnutrition, and stress.
Some
children are born with defects in their immune systems. Those with flaws in the
B cell components are unable to produce antibodies (immunoglobulins). These
conditions, known as agammaglobulinemias or hypogammaglobulinemias, leave the
children vulnerable to infectious organisms; such disorders can be combated
with injections of immunoglobulins.
Other
children, whose thymus is either missing or small and abnormal, lack T cells.
The resultant disorders have been treated with thymic transplants.
Very
rarely, infants are born lacking all the major immune defenses; this is known
as severe combined immunodeficiency disease (SCID). Some children with SCID
have lived for years in germ-free rooms and "bubbles." A few SCID
patients have been successfully treated with transplants of bone marrow (Bone
Marrow Transplants).
The
devastating immunodeficiency disorder known as the acquired immunodeficiency
syndrome (AIDS) was first recognized in 1981. Caused by a virus (the human
immunodeficiency virus, or HIV) that destroys T4 cells and that is harbored in
macrophages as well as T4 cells, AIDS is characterized by a variety of unusual
infections and otherwise rare cancers. The AIDS virus also damages tissue of
the brain and spinal cord, producing progressive dementia.
AIDS
infections are known as "opportunistic" because they are produced by
commonplace organisms that do not trouble people whose immune systems are
healthy, but which take advantage of the "opportunity" provided by an
immune defense in disarray. The most common infection is an unusual and
life-threatening form of pneumonia caused by a one-celled organism (a Protozoa)
called Pneumocystis carinii. AIDS patients are also susceptible to unusual
lymphomas and Kaposi's sarcoma, a rare cancer that results from the abnormal
proliferation of endothelial cells in the blood vessels.
Some
persons infected with the AIDS virus develop a condition known as AIDS-related
complex, or ARC, characterized by fatigue, fever, weight loss, diarrhea, and
swollen lymph glands. Yet other persons who are infected with the AIDS virus
apparently remain well; however, even though they develop no symptoms, they can
transmit the virus to others.
AIDS
is a contagious disease, spread by intimate sexual contact, by direct
inoculation of the virus into the bloodstream, or from mother to child during
pregnancy. Most of the AIDS cases in the United States have been found among
homosexual and bisexual men with multiple sex partners, and among intravenous
drug abusers. Others have involved men who received untreated blood products
for hemophilia; persons who received transfusions of inadvertently contaminated
blood-primarily before the AIDS virus was discovered and virtually eliminated
from the nation's blood supply with a screening test; the heterosexual partners
of persons with AIDS; and children born to infected mothers.
There
is presently no cure for AIDS, although the antiviral agent zidovuzine (AZT)
appears to hold the virus in check, at least for a time. Many other
antiretroviral drugs are being tested, as are agents to bolster the immune
system and agents to prevent or treat opportunistic infections. Research on
vaccines to prevent the spread of AIDS is also under way.
Cancers of the Immune System
Cells
of the immune system, like those of other body systems, can proliferate
uncontrollably; the result is cancer. Leukemias are caused by the proliferation
of white blood cells, or leukocytes. The uncontrolled growth of
antibody-producing (plasma) cells can lead to multiple myeloma. Cancers of the
lymphoid organs, known as lymphomas, include Hodgkin's disease. These disorders
can be treated-some of them very successfully-by drugs and/or irradiation.
Immune response to T.
cruzi
The human immune response
to T. cruzi infection
is inadequate; it provides only a partial defense at best. The immune system's response
at its worst causes the defense mechanisms to turn on the body it is intended
to protect, thus often causing more harm to the person than does T.
cruzi.
Immune
response that damages the human body
Unintentional damage is
done to the body's otherwise healthy tissue as the response system attacks what
it recognizes as a trigger for a defensive response but does not recognize that
it is attacking itself. This is what's known as an autoimmune reaction.
Autoimmune
responses are responsible in large part for the destructive symptoms of Chagas
disease. This pathology is referred to as immunopathology. Severe inflammation
occurs around tissue that embody amastigotes as the amastigotes release
themselves from the tissue's dead cells. Among the tissue most often encysted
is myocardial neural plexes. Plexes are networks of nerves that serve a variety
of organs and functions. Digestive system neural plexes are targets as well,
namely in the colon and esophagus. During the acute phase of chagas, B and T
cells are incited to produce antibodies. Since T.
cruzi is able to mask its
presence in the blood, these antibodies do not attack T.
cruzi but instead go after
cell membrane antigenic components called epitopes, that the body's healthy
cells and T. cruzi share.
Research is being done to isolate the epitope and how T.
cruzi uses it to elude
recognition by the immune system.
Scientists
work to find a cure to T. cruzi's infecting the human
species. As research continues into how T. cruzi uses the human body as a host, the
disciplines of parasitology and immunology learn much about how these organisms
adapt and thrive in changing environments. T. cruzi proves to be a formidable opponent in
the fight.
Mediated by Macrophages
Mediated by Lymphocytes and mast
cells
B-Cells
Phagocytosis (engulfment)
Activation of Antibodies
CD8
Cells