NON-PROTEIN NITROGENOUS CONTAINING AND NITROGEN NOT CONTAINING ORGANIC COMPONENTS OF BLOOD. RESIDUAL
NITROGEN. LIPOPROTEINS OF BLOOD PLASMA.
BIOCHEMISTRY OF IMMUNE PROCESSES AND BIOCHEMICAL
MECHANISMS OF IMMUNODEFICIT STATES.
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.
Serum Proteins
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After blood is withdrawn from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.
· As
the current flows, the serum proteins move toward the positive electrode.
· The
stronger the negative charge on a protein, the faster it migrates.
· The
separated proteins appear as distinct bands.
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.
o alpha
globulins (e.g., the proteins that transport thyroxine and retinol [vitamin A])
o beta
globulins (e.g., the iron-transporting protein transferrin)
§ Most
antibodies are gamma globulins.
§ Therefore
gamma globulins become more abundant following infections or immunizations.
Subfractions of a1, a2, b and g globulins, their structure and
functions.
Serum
amyloid A is a related acute-phase marker that
responds rapidly in similar circumstances.
C-reactive
protein, pentraxin-related
Reference ranges
for blood tests, showing C-reactive protein in brown-yellow in center.
The place of synthesis of each fraction and subfruction of blood plasma proteins.
Causes
and consequences of protein content changes in blood plasma.
The principle of the measurement of protein fractions by
electrophoresis method.
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 ×
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 in equilibrium 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
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.
A ketogenic 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)
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.
Prerenal Azotemia
Alternate Names : Azotemia - Prerenal,
Renal Underperfusion, Uremia
Kidney Anatomy
Azotemia
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).
Signs and
symptoms (prerenal azotemia)
- Decreased or absent urine
output
- Fatigue
- Decreased alertness
- Confusion
- Pale skin color
- Rapid pulse
- Dry mouth
·
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).
|
|
The lilipoproteins - Any of the series of soluble lipid-protein complexes which are transported in the blood; each aggregate particle consists of a spherical hydrophobic core containing triglycerides and cholesterol esters surrounded by an amphipathic monolayer of phopholipids, cholesterol and apolipoproteins; classes of lipoproteins include chylomicrons, very low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL).
chylomicrons -
The class of largest diameter soluble lipid-protein complexes which the lowest
in density (mass to volume ratio); their composition is ~2% apolipoproteins,
~5% cholesterol, and ~93% triglycerides and phospholipids; their normal role is
to be synthesized by the intestinal mucosal cells to transport dietary
(exogenous) triglycerides and other lipids from the intestines via the lacteals
and lymphatic system to the systemic circulation to the adipose tissue and
liver for storage and use; they are only present in the blood in significant
quantities after the digestion of a meal.
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.
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:
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 |
|
%Protein |
1.5-2.5 |
5-10 |
15-20 |
20-25 |
40-55 |
|
%Phospholipids |
7-9 |
15-20 |
22 |
15-20 |
20-35 |
|
%Free Cholesterol |
1-3 |
5-10 |
8 |
7-10 |
3-4 |
|
%Triacylglycerols |
84-89 |
50-65 |
22 |
7-10 |
3-5 |
|
%Cholesteryl Esters |
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 |
Surface Components
Core Lipids
VLDLy
Found in Egg Yolk
"VLDLy" was coined to signify
specific lipoproteins that selectively deposit triacylglycerol
to yolk follicles.
The average size of a VLDLy particle is 30nm,
whereas a generic VLDL particle is approximately 70 nm.
VLDLy Metabolism
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 as inflammation. 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 the classic 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 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 alternative pathway starts 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 proteinase papain
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
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, individual V/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.
Training the
immune system -- the "J" curve
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.
Stress is cumulative
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.)
Recommendations
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.
The Human
Immune Response System
An overview of the system
An overview of the system
The human immune response system recognizes pathogens and acts to remove,
immobilize, or neutralize them. The immune system is antigen-specific
(responding to specific molecules on a pathogen) and has memory (its defense to
a pathogen is encoded for future activation). The immune system relies on
several components to fight an infecting pathogen. T cells are lymphocytes that
circulate between the blood, lymph, and lymphoid organs to trigger a systemic
immune response with antigen-receptors on the T cell membrane. B cells are
lymphocytes that activate the primary immune response when antigens bind to
their receptors, causing the B cells to proliferate. Daughter cells of B cells
later differentiate into antibody-releasing plasma cells. B cells also comprise
the immune system's memory (see diagram).
Antibodies, also called immunoglobulins, are
divided into five classes by structure and function, enabling them to recognize
a wide spectrum of antigens. Antibody functions include complement fixation
that can lead to antigen-cell lysis (rupture) and can
cause inflammation. Antibodies also generate a neutralization response where
viruses and bacteria are destroyed by phagocytes. Agglutination, or clumping
together, of foreign cells are caused by B cells' promotion of complex
cross-linking of antibodies binding to antigens. These agglutinated cells are phagocytized. B cells are cloned in massive quantities for
a single specific antigen.
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.
As T. cruzi immunizes humans to their
own antigens, human antibodies attack myocardial and neural cells.
Complement in humans does not become activated solely by T. cruzi invasion; antibodies must be present for
complement to bind to a specific T. cruzi
antigen. This allows T. cruzi to have time to
infect human tissue. Parasite strain and an individual's immune competence are
prime factors in determining the T. cruzi's pathology of an individual.
Once infected with T. cruzi, humans
acquire partial immunity or resistance to the severe pathologies of Chagas' disease's acute phase through subsequent infections
of T. cruzi. This guards many individuals who
live in highly endemic areas from the acute symptoms of chagas.
Complete removable of the parasite from these individuals would risk the onset
of acute chagas through future infection, which is
deadly - especially for children.
T. cruzi incorporates certain host cell
membrane proteins onto its surface thereby masking
its antigenic signal to the immune system's lymphocytes. T. cruzi can also cleave antibody molecules on its surface
thereby escaping the immune response's detection. T.
cruzi frequently invade monocytes,
a circulating phagocyte. Intracellular phagocytosis
bring amastigotic T. cruzi
into tissue cells where they can proliferate. Once inside tissue cells, T. cruzi are undetected by immune response. Trypomastigotes remain in the blood stream for a short
period of time so that the T. cruzi-specific immunoglobulins don't have sufficient time to be activated.
T. cruzi employs successful strategies to
escape the remarkably potent immune response system. By masking themselves or
by eluding the response mechanisms, the parasite is able to adapt to survive
and continue the life of the species.
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
Phagocytosis (engulfment)
Activation of Antibodies
