I

Lecture

ORGANS of IMMUNE SYSTEM and HAEMOPOESIS

Immune system unites organs and tissues, which provide defense from genetically foreign cells or matters, that got from out or are generated inside the organism, providing constancy of internal organism environment. Organs of immune system may be divided into central and peripheral part.

To central organs of immune system belong thymus gland and red marrow.

To peripheral organs of immune system unite organs are not enveloped in capsule (tonsils, lymphoid follicles, that are situated in walls of hollow organs of digestive and respiratory systems and lymphocytes, which are situated in blood, lymph, connective and epithelial tissue) and capsulated organs (lymphatic nodes and spleen).

 

Thymus

 

Thymus is placed in front part of superior mediastinum and consists of lobes, more frequent two. Outside this gland is tunicate by fibrous capsule that gives off septa, which split up lobes on lobules. They comprise reticular cells with lymphocytes between them (called as thymocytes). The lobules of gland have a cortex and medulla thymi. Can be accessories lobules of thymus. Basic function of thymus maturation and supporting of effector cells (killer) and regulatory cells (helper and supressor) -lymphocytes populations. Also thymus takes part into regulation of neuro-muscular transmission, phosphoric-calcium metabolism, carbohydrate and peptide metabolism, interaction with other endocrine glands (that's why one can be consider thymus gland as a endocrine organ).

Red marrow is sole haemopoetic organ in adult and central organ of immune system. Stem cells are generated in it, they are like lymphocytes because their morphology and during cell-fission give beginning to all formal blood elements, also including cells providing immunity - to leukocytes and lymphocytes. Red marrow in adult is situated in cells of spongy matter of flat and short bones, in epiphysis of long tubular bones. Yellow marrow is situated in diaphysis of long tubular bones. Largest amount of red marrow is situated into epiphysis of femoral and tibiae bones.

The immune system is a set of mechanisms that protect an organism from infection by identifying and killing pathogens. This task is extremely difficult, since pathogens range from viruses to parasitic worms and these diverse threats must be detected with absolute specificity amongst normal cells and tissues. Pathogens are also constantly evolving new ways to avoid detection by the immune system and successfully infect their hosts.

 

Components of the immune system

Innate immune system

Adaptive immune system

Response is non-specific

Pathogen and antigen specific response

Exposure leads to immediate maximal response

Lag time between exposure and maximal response

Cell-mediated and humoral components

Cell-mediated and humoral components

No immunological memory

Exposure leads to immunological memory

Found in nearly all forms of life

Found only in jawed vertebrates

 

To meet this challenge, multiple mechanisms have evolved to recognize and neutralize pathogens. Even simple unicellular organisms such as bacteria possess enzyme systems that protect against viral infections. Other basic immune mechanisms evolved in ancient eukaryotes and remain in their modern descendants, such as plants, fish, reptiles, and insects. These mechanisms include antimicrobial peptides called defensins, pattern recognition receptors, and the complement system. More sophisticated mechanisms, however, developed relatively recently, with the evolution of vertebrates. The immune systems of vertebrates such as humans consist of many types of proteins, cells, organs, and tissues, which interact in an elaborate and dynamic network. As part of this more complex immune response, the vertebrate system adapts over time to recognize particular pathogens more efficiently. The adaptation process creates immunological memories and allows even more effective protection during future encounters with these pathogens. This process of acquired immunity is the basis of vaccination.

Disorders in the immune system can cause disease. Immunodeficiency diseases occur when the immune system is less active than normal, resulting in recurring and life-threatening infections. Immunodeficiency can either be the result of a genetic disease, such as severe combined immunodeficiency, or be produced by pharmaceuticals or an infection, such as the acquired immune deficiency syndrome (AIDS) that is caused by the retrovirus HIV. In contrast, autoimmune diseases result from a hyperactive immune system attacking normal tissues as if they were foreign organisms. Common autoimmune diseases include rheumatoid arthritis, diabetes mellitus type 1 and lupus erythematosus. These critical roles of immunology in human health and disease are areas of intense scientific study.

The immune system protects organisms from infection with layered defenses of increasing specificity. Most simply, physical barriers prevent pathogens such as bacteria and viruses from entering the body. If a pathogen breaches these barriers, the innate immune system provides an immediate, but non-specific response. Innate immune systems are found in all plants and animals. However, if pathogens successfully evade the innate response, vertebrates possess a third layer of protection, the adaptive immune system. Here, the immune system adapts its response during an infection to improve its recognition of the pathogen. This improved response is then retained after the pathogen has been eliminated, in the form of an immunological memory, and allows the adaptive immune system to mount faster and stronger attacks each time this pathogen is encountered.

Both innate and adaptive immunity depend on the ability of the immune system to distinguish between self and non-self molecules. In immunology, self molecules are those components of an organism's body that can be distinguished from foreign substances by the immune system. Conversely, non-self molecules are those recognized as foreign molecules. One class of non-self molecules are called antigens (short for antibody generators) and are defined as substances that bind to specific immune receptors and elicit an immune response.

Surface barriers

Several types of barriers protect organisms from infection, including mechanical, chemical and biological barriers. The waxy cuticle of a leaf, the exoskeleton of an insect, the shell of an egg, and the skin are examples of the mechanical barriers that are the first line of defence against infection. However, as organisms cannot be completely sealed, other systems act to protect body openings such as the lungs and the genitourinary tract. In the lungs, coughing and sneezing mechanically eject pathogens and other irritants from the respiratory tract. The flushing action of tears and urine also mechanically expels pathogens, while mucus secreted by the respiratory and gastrointestinal tract serves to trap microorganisms.[6]

Chemical barriers also protect against infection. The skin and respiratory tract secrete antimicrobial peptides such as the β-defensins.[7] Enzymes such as lysozyme and phospholipase A in saliva, tears, and breast milk are also antibacterials.[8][9] Vaginal secretions serve as a chemical barrier following menarche, when they become slightly acidic, while semen contains defensins and zinc to kill pathogens.[10][11] In the stomach, gastric acid, and proteases serve as powerful chemical defenses against ingested pathogens.

Within the genitourinary and gastrointestinal tracts, commensal flora serve as biological barriers by competing with pathogenic bacteria for food and space and, in some cases, by changing the conditions in their environment, such as pH.[12] This reduces the probability that pathogens will be able to reach sufficient numbers to cause illness. However, since antibiotics do not discriminate between pathogenic bacteria and the normal flora, oral antibiotics can sometimes lead to an overgrowth of fungus (fungus is not affected by antibiotics), such as a vaginal yeast infection.[13] Re-introduction of probiotic flora, such as lactobacilli found in yoghurt, can help to restore a healthy balance of microbial populations.[14]

Innate immunity

For more details on this topic, see Innate immune system.

Microorganisms that successfully enter an organism will encounter the cells and mechanisms of the innate immune system. Innate immune defenses are non-specific, meaning these systems recognize and respond to pathogens in a generic way.[5] This system does not confer long-lasting immunity against a pathogen. The innate immune system is the dominant system of host defense in most organisms.[2]

Humoral and chemical barriers

For more details on this topic, see Inflammation.

Inflammation is one of the first responses of the immune system to infection.[15] The symptoms of inflammation are redness and swelling, which are caused by increased blood flow into a tissue. Inflammation is produced by eicosanoids and cytokines, which are released by injured or infected cells. Eicosanoids include prostaglandins that produce fever and the dilation of blood vessels associated with inflammation, and leukotrienes that attract certain leukocytes.[16][17] Common cytokines include interleukins that are responsible for communication between white blood cells; chemokines that promote chemotaxis; and interferons that have anti-viral effects, such as shutting down protein synthesis in the host cell.[18] Growth factors and cytotoxic factors may also be released. These cytokines and other chemicals recruit immune cells to the site of infection and promote healing of any damaged tissue following the removal of pathogens.[19]

Complement system

The complement system is a biochemical cascade that attacks the surfaces of foreign cells. It contains over 20 different proteins and is named for its ability to complement the killing of pathogens by antibodies. Complement is the major humoral component of the innate immune response.[20][21] Many species have complement systems, including non-mammals like plants, fish, and some invertebrates.

In humans, this response is activated by the binding of complement proteins to carbohydrates on the surfaces of microbes or by complement binding to antibodies that have attached to these microbes. This recognition signal triggers a rapid killing response.[23] The speed of the response is a result of signal amplification that occurs following sequential proteolytic activation of complement molecules, which are also proteases. After complement proteins initially bind to the microbe, they activate their protease activity, which in turn activates other complement proteases, and so on. This produces a catalytic cascade that amplifies the initial signal by controlled positive feedback.[24] The cascade results in the production of peptides that attract immune cells, increase vascular permeability, and opsonize (coat) the surface of a pathogen, marking it for destruction. This deposition of complement can also kill cells directly by disrupting their plasma membrane.[20]

Cellular barriers of the innate system

A scanning electron microscope image of normal circulating human blood. One can see red blood cells, several knobby white blood cells including lymphocytes, a monocyte, a neutrophil, and many small disc-shaped platelets.

Leukocytes (white blood cells) act like independent, single-celled organisms and are the second arm of the innate immune system.[5] The innate leukocytes include the phagocytes (macrophages, neutrophils, and dendritic cells), mast cells, eosinophils, basophils, and natural killer cells. These cells identify and eliminate pathogens, either by attacking larger pathogens through contact or by engulfing and then killing microorganisms.[22] Innate cells are also important mediators in the activation of the adaptive immune system.[3]

Phagocytosis is an important feature of cellular innate immunity performed by cells called 'phagocytes' that engulf, or eat, pathogens or particles. Phagocytes generally patrol the body searching for pathogens, but can be called to specific locations by cytokines.[5] Once a pathogen has been engulfed by a phagocyte, it becomes trapped in an intracellular vesicle called a phagosome, which subsequently fuses with another vesicle called a lysosome to form a phagolysosome. The pathogen is killed by the activity of digestive enzymes or following a respiratory burst that releases free radicals into the phagolysosome.[25][26] Phagocytosis evolved as a means of acquiring nutrients, but this role was extended in phagocytes to include engulfment of pathogens as a defense mechanism.[27] Phagocytosis probably represents the oldest form of host defense, as phagocytes have been identified in both vertebrate and invertebrate animals.[28]

Neutrophils and macrophages are phagocytes that travel throughout the body in pursuit of invading pathogens.[29] Neutrophils are normally found in the bloodstream and are the most abundant type of phagocyte, normally representing 50% to 60% of the total circulating leukocytes.[30] During the acute phase of inflammation, particularly as a result of bacterial infection, neutrophils migrate toward the site of inflammation in a process called chemotaxis, and are usually the first cells to arrive at the scene of infection. Macrophages are versatile cells that reside within tissues and produce a wide array of chemicals including enzymes, complement proteins, and regulatory factors such as interleukin-1.[31] Macrophages also act as scavengers, ridding the body of worn-out cells and other debris, and as antigen presenting cells that activate the adaptive immune system.[3]

Dendritic cells (DC) are phagocytes in tissues that are in contact with the external environment; therefore, they are located mainly in the skin, nose, lungs, stomach, and intestines.[32] They are named for their resemblance to neuronal dendrites, as both have many spine-like projections, but dendritic cells are in no way connected to the nervous system. Dendritic cells serve as a link between the innate and adaptive immune systems, as they present antigen to T cells, one of the key cell types of the adaptive immune system.[32]

Mast cells reside in connective tissues and mucous membranes, and regulate the inflammatory response.[33] They are most often associated with allergy and anaphylaxis.[30] Basophils and eosinophils are related to neutrophils. They secrete chemical mediators that are involved in defending against parasites and play a role in allergic reactions, such as asthma.[34] Natural killer or NK cells are leukocytes that attack and destroy tumor cells, or cells that have been infected by viruses.[35]

Adaptive immunity

The adaptive immune system evolved in early vertebrates and allows for a stronger immune response as well as immunological memory, where each pathogen is "remembered" by a signature antigen.[36] The adaptive immune response is antigen-specific and requires the recognition of specific non-self antigens during a process called antigen presentation. Antigen specificity allows for the generation of responses that are tailored to specific pathogens or pathogen-infected cells. The ability to mount these tailored responses is maintained in the body by "memory cells". Should a pathogen infect the body more than once, these specific memory cells are used to quickly eliminate it.

Lymphocytes

The cells of the adaptive immune system are special types of leukocytes, called lymphocytes. B cells and T cells are the major types of lymphocytes and are derived from pluripotential hemopoietic stem cells in the bone marrow.[22] B cells are involved in the humoral immune response, whereas T cells are involved in cell-mediated immune responses.

Association of a T cell with MHC class I or MHC class II, and antigen (in red)

Both B cells and T cells carry receptor molecules that recognize specific targets. T cells recognize a non-self target, such as a pathogen, only after antigens (small fragments of the pathogen) have been processed and presented in combination with a self receptor called a major histocompatibility complex (MHC) molecules. There are two major subtypes of T cells: the killer T cell and the helper T cell. Killer T cells only recognize antigens coupled to Class I MHC molecules, while helper T cells only recognize antigens coupled to Class II MHC molecules. These two mechanisms of antigen presentation reflect the different roles of the two types of T cell. A third, minor subtype are the γδ T cells that recognize intact antigens that are not bound to MHC receptors.[37]

In contrast, the B cell antigen-specific receptor is an antibody molecule on the B cell surface, and recognizes whole pathogens without any need for antigen processing. Each lineage of B cell expresses a different antibody, so the complete set of B cell antigen receptors represent all the antibodies that the body can manufacture.[22]

Killer T cells directly attack other cells carrying foreign or abnormal antigens on their surfaces

Killer T cells are a sub-group of T cells that kill cells infected with viruses (and other pathogens), or are otherwise damaged or dysfunctional.[39] As with B cells, each type of T cell recognises a different antigen. Killer T cells are activated when their T cell receptor (TCR) binds to this specific antigen in a complex with the MHC Class I receptor of another cell. Recognition of this MHC:antigen complex is aided by a co-receptor on the T cell, called CD8. The T cell then travels throughout the body in search of cells where the MHC I receptors bear this antigen. When an activated T cell contacts such cells, it releases cytotoxins that form pores in the target cell's plasma membrane, allowing ions, water and toxins to enter. This causes the target cell to burst, or to undergo apoptosis.[40] T cell killing of host cells is particularly important in preventing the replication of viruses. T cell activation is tightly controlled and generally requires a very strong MHC/antigen activation signal, or additional activation signals provided by "helper" T cells (see below).[40]

[edit] Helper T cells

Helper T cells regulate both the innate and adaptive immune responses and help determine which types of immune responses the body will make to a particular pathogen.[41][42] These cells have no cytotoxic activity and do not kill infected cells or clear pathogens directly. They instead control the immune response by directing other cells to perform these tasks.

Helper T cells express T cell receptors (TCR) that recognize antigen bound to Class II MHC molecules. The MHC:antigen complex is also recognized by the helper cells CD4 co-receptor, which recruits molecules inside the T cell (e.g. Lck) that are responsible for T cell's activation. Helper T cells have a weaker association with the MHC:antigen complex than observed for killer T cells, meaning many receptors (around 200-300) on the helper T cell must be bound by an MHC:antigen in order to activate the helper cell, while killer T cells can be activated by engagement of a single MHC:antigen molecule. Helper T cell activation also requires longer duration of engagement with an antigen presenting cell.[43] The activation of a resting helper T cell causes it to release cytokines that influence the activity of many cell types. Cytokine signals produced by helper T cells enhance the microbicidal function of macrophages and the activity of killer T cells.[5] In addition, helper T cell activation causes an upregulation of molecules expressed on the T cell's surface, such as CD40 ligand (also called CD154), which provide extra stimulatory signals typically required to activate antibody-producing B cells.[44]

[edit] γδ T cells

γδ T cells possess an alternative T cell receptor (TCR) as opposed to CD4+ and CD8+ (αβ) T cells and share the characteristics of helper T cells, cytotoxic T cells and NK cells. The conditions that produce responses from γδ T cells are not fully understood. Like other 'unconventional' T cell subsets bearing invariant TCRs, such as CD1d-restricted Natural Killer T cells, γδ T cells straddle the border between innate and adaptive immunity.[45] On one hand, γδ T cells are a component of adaptive immunity as they rearrange TCR genes to produce receptor diversity and can also develop a memory phenotype. On the other hand, the various subsets are also part of the innate immune system, as restricted TCR or NK receptors may be used as pattern recognition receptors. For example, large numbers of human Vγ9/Vδ2 T cells respond within hours to common molecules produced by microbes, and highly restricted Vδ1+ T cells in epithelia will respond to stressed epithelial cells.[46]

An antibody is made up of two heavy chains and two light chains. The unique variable region allows an antibody to recognize its matching antigen.[38]

[edit] B lymphocytes and antibodies

A B cell identifies pathogens when antibodies on its surface bind to a specific foreign antigen.[47] This antigen/antibody complex is taken up by the B cell and processed by proteolysis into peptides. The B cell then displays these antigenic peptides on its surface MHC class II molecules. This combination of MHC and antigen attracts a matching helper T cell, which releases lymphokines and activates the B cell.[48] As the activated B cell then begins to divide, its offspring secrete millions of copies of the antibody that recognizes this antigen. These antibodies circulate in blood plasma and lymph, binding to pathogens expressing the antigen and marking them for destruction by complement activation or for uptake and destruction by phagocytes. Antibodies can also neutralize challenges directly, by binding to bacterial toxins or by interfering with the receptors that viruses and bacteria use to infect cells.[49]

[edit] Alternative adaptive immune system

Although the classical molecules of the adaptive immune system (e.g. antibodies and T cell receptors) exist only in jawed vertebrates, a distinct lymphocyte-derived molecule has been discovered in primitive jawless vertebrates, such as the lamprey and hagfish. These animals possess a large array of molecules called variable lymphocyte receptors (VLRs for short) that, like the antigen receptors of jawed vertebrates, are produced from only a small number (one or two) of genes. These molecules are believed to bind pathogenic antigens in a similar way to antibodies, and with the same degree of specificity.[50]

Lymph Nodes (lymphonodeulae).The lymph nodes are small oval or bean-shaped bodies, situated in the course of lymphatic and lacteal vessels so that the lymph and chyle pass through them on their way to the blood. Each generally presents on one side a slight depressionthe hilusthrough which the bloodvessels enter and leave the interior. The efferent lymphatic vessel also emerges from the node at this spot, while the afferent vessels enter the organ at different parts of the periphery. On section a lymph node displays two different structures: an external, of lighter colorthe cortical; and an internal, darkerthe medullary. The cortical structure does not form a complete investment, but is deficient at the hilus, where the medullary portion reaches the surface of the node; so that the efferent vessel is derived directly from the medullary structures, while the afferent vessels empty themselves into the cortical substance.

Structure of Lymph Nodes.A lymph Node consists of (1) a fibrous envelope, or capsule, from which a frame-work of processes (trabeculae) proceeds inward, imperfectly dividing the Node into open spaces freely communicating with each other; (2) a quantity of lymphoid tissue occupying these spaces without completely filling them; (3) a free supply of bloodvessels, which are supported in the trabeculae; and (4) the afferent and efferent vessels communicating through the lymph paths in the substance of the node. The nerves passing into the hilus are few in number and are chiefly distributed to the bloodvessels supplying the node.

  The capsule is composed of connective tissue with some plain muscle fibers, and from its internal surface are given off a number of membranous processes or trabeculae, consisting, in man, of connective tissue, with a small admixture of plain muscle fibers; but in many of the lower animals composed almost entirely of involuntary muscle. They pass inward, radiating toward the center of the node, for a certain distancethat is to say, for about one-third or one-fourth of the space between the circumference and the center of the node. In some animals they are sufficiently well-marked to divide the peripheral or cortical portion of the node into a number of compartments (so-called follicles), but in man this arrangement is not obvious. The larger trabeculae springing from the capsule break up into finer bands, and these interlace to form a mesh-work in the central or medullary portion of the node. In these spaces formed by the interlacing trabeculae is contained the proper node substance or lymphoid tissue. The node pulp does not, however, completely fill the spaces, but leaves, between its outer margin and the enclosing trabeculae, a channel or space of uniform width throughout. This is termed the lymph path or lymph sinus. Running across it are a number of finer trabeculae of retiform connective tissue, the fibers of which are, for the most part, covered by ramifying cells.

  On account of the peculiar arrangement of the frame-work of the organ, the node pulp in the cortical portion is disposed in the form of nodules, and in the medullary part in the form of rounded cords. It consists of ordinary lymphoid tissue, being made up of a delicate net-work of retiform tissue, which is continuous with that in the lymph paths, but marked off from it by a closer reticulation; it is probable, moreover, that the reticular tissue of the node pulp and the lymph paths is continuous with that of the trabeculae, and ultimately with that of the capsule of the node. In its meshes, in the nodules and cords of lymphoid tissue, are closely packed lymph corpuscles. The node pulp is traversed by a dense plexus of capillary bloodvessels. The nodules or follicles in the cortical portion of the node frequently show, in their centers, areas where karyokinetic figures indicate a division of the lymph corpuscles. These areas are termed germ centers. The cells composing them have more abundant protoplasm than the peripheral cells.

  The afferent vessels, as stated above, enter at all parts of the periphery of the node, and after branching and forming a dense plexus in the substance of the capsule, open into the lymph sinuses of the cortical part. In doing this they lose all their coats except their endothelial lining, which is continuous with a layer of similar cells lining the lymph paths. In like manner the efferent vessel commences from the lymph sinuses of the medullary portion. The stream of lymph carried to the node by the afferent vessels thus passes through the plexus in the capsule to the lymph paths of the cortical portion, where it is exposed to the action of the node pulp; flowing through these it enters the paths or sinuses of the medullary portion, and finally emerges from the hilus by means of the efferent vessel. The stream of lymph in its passage through the lymph sinuses is much retarded by the presence of the reticulum, hence morphological elements, either normal or morbid, are easily arrested and deposited in the sinuses. Many lymph corpuscles pass with the efferent lymph stream to join the general blood stream. The arteries of the node enter at the hilus, and either go at once to the node pulp, to break up into a capillary plexus, or else run along the trabeculae, partly to supply them and partly running across the lymph paths, to assist in forming the capillary plexus of the node pulp. This plexus traverses the lymphoid tissue, but does not enter into the lymph sinuses. From it the veins commence and emerge from the organ at the same place as that at which the arteries enter.

  The lymphatic vessels are arranged into a superficial and a deep set. On the surface of the body the superficial lymphatic vessels are placed immediately beneath the integument, accompanying the superficial veins; they join the deep lymphatic vessels in certain situations by perforating the deep fascia. In the interior of the body they lie in the submucous areolar tissue, throughout the whole length of the digestive, respiratory, and genito-urinary tracts; and in the subserous tissue of the thoracic and abdominal walls. Plexiform networks of minute lymphatic vessels are found interspersed among the proper elements and bloodvessels of the several tissues; the vessels composing the net-work, as well as the meshes between them, are much larger than those of the capillary plexus. From these net-works small vessels emerge, which pass, either to a neighboring node, or to join some larger lymphatic trunk. The deep lymphatic vessels, fewer in number, but larger than the superficial, accompany the deep bloodvessels. Their mode of origin is probably similar to that of the superficial vessels. The lymphatic vessels of any part or organ exceed the veins in number, but in size they are much smaller. Their anastomoses also, especially those of the large trunks, are more frequent, and are effected by vessels equal in diameter to those which they connect, the continuous trunks retaining the same diameter.

Lymph.Lymph, found only in the closed lymphatic vessels, is a transparent, colorless, or slightly yellow, watery fluid of specific gravity about 1.015; it closely resembles the blood plasma, but is more dilute. When it is examined under the microscope, leucocytes of the lymphocyte class are found floating in the transparent fluid; they are always increased in number after the passage of the lymph through lymphoid tissue, as in lymph nodes. Lymph should be distinguished from tissue fluid which is found outside the lymphatic vessels in the tissue spaces.