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Chapter 1.
Morphological and Functional Characteristics of the Immune Systems
Immune protection is an extraordinarily important function in an organism's prevention against the deleterious effects of microbes and viruses, parasites and antigens, etc. There are two type of protection: nonspecific and specific.
1.1) Components of the nonspecific immune protection
Non-specific types of protection include humoral, molecular, and cellular components. Humoral components include C-reactive protein, different types of interleukins (IL), as well as digestive enzymes, the high acidy of gastric juice, bile acids, etc. All of these are designed to demolish the useless and toxic substances, that accumulate in an organism. Proteins that mediate apoptosis (or controlling cellular death) are highly important in this process. Nonspecific cellular protection is carried out by cells that are able to perform phagocytosis. They include granulocytes and a group of mononuclear phagocytes, such as macrophages, monocytes, antigen- presenting cells for lymphocytes and other immunocompetent cells, and promonocytes, histiocytes, Kupffer's cells of the liver, osteoclasts, Hofbauer cells in the chorionic villi, the brain microglia, etc. These two types of nonspecific protection have one common characteristic: they act at early stages of the pathological process, before the specific immune response begins. The fertilization membrane provides as an example of nonspecific protection of early preimplantation embryos at stages of the zygote and morula stages against possible deleterious influences of the maternal environment.
1.2) Components of the specific immune protection
One characteristic of specific immune responses is that their protective activity has concrete targets and it is kept in memory cells for a long time, sometimes for the whole life. Upon reinfection with the same disease agent, these cells react more quickly than after the first infection. Cells of the specific immune response recognize their own cells and tolerate them. All types of specific immune responses are produced by different cells located in the lymphoid organs, such as the thymus, spleen, lymph nodes, tonsils, Peyer's nodules, etc. These cells are constantly mobile in the blood and lymph, and this provides common immune reactions and good contact between these cells and antigens.
Specific immune responses can be performed by: i) the common immune system which produces common immune reactions, cellular or humoral; or ii) the secretory immune system (SIS) which produces secretory (mucosal) immune response. The ltter can be performed a) in the epithelium of mucosal membranes and in many organs and tissues that are in contact with the external environment, b) in an unusual form in vitally important organs and cells, and c) in some morphologically formed barrier structures.
1.2.1) Cellular components of the common immune system
Different immune-competent antigen-presenting cells participate in producing the common cellular immune reactions: mononuclear phagocytes appear in primary contact with an antigen, memory T cells are seen in recurrent contact with the same antigen, T lymphocytes (CD3) are responsible for the common response. There are a few types of lymphocytes, and each of them with its own function: T helpers (CD4) mediate the immune response, while cytotoxic and suppressor T lymphocytes (CD8) and natural killer (NK) cells (CD56 and CD8) produce this response.
The cell-specific immune response takes place in reaction to the appearance of foreign tissues containing MHC class 1. This can be seen, for example, in the incompatible transplantation of tissues or organs, the primary reaction of which occurs in two phases. The first, sensitization, is carried out for 7 to 11 days, from the first contact with the antigens. At this time, a large amount of specific cytotoxic T lymphocytes and NK cells is produced (1). During the second phase, T lymphocytes and phagocytes penetrate the graft tissue and infiltrate its vessels. The tissue is necrotized and torn. Different types of IL and cytokines have been described as major components of the T-cell immune response (2-4).
Human leukocyte antigens (HLA) play a crucial protective role in the process of implantation (5). During implantation, the uterine decidua is invaded by extravillous trophoblast cells whose function is to destroy the walls of the uterine spiral arteries in order to provide an adequate blood flow to the fetus. These cells express an unusual combination of HLA class I molecules, such as HLA-D, HLA-E and HLA-G (6,7), but not HLA-A or HLA-B which have not been found in the trophoblast (8). Recognition of HLA-G stimulates cytokine production (9) and regulates the development, growth and differentiation of the placenta (10).
1.2.2) Humoral components of the common immune system
The humoral immune reaction is trigged by the appearance of foreign antigens of MHC class II (HLA-DP, HLA-DQ, HLA-DR, HLA-G) or other incompatible antigens, such as rhesus-antigens causing the RhD-hemolytic disease of fetuses and newborns (11). After their first contact with foreign antigens, the mononuclear phagocytes transfer information to B lymphocytes which begin to multiply in the presence of T helpers and cytokines (period of sensitization). After about 7 days, a small amount of antigen-specific IgM appears in the blood, and after 2 weeks, a high amount of specific IgG antibodies are already present. The synthesis of antibodies takes place in the lymphoid tissue of many organs, such as the spleen, lymph nodes, tonsils, lymph nodules in the intestine and other organs. Immunoglobulins (Igs) are spread with the blood, lymph and intercellular fluids through all organs and tissue, where they come into contact with specific antigens and destroy them. Upon repeated contacts with the same antigens, this response takes only 3 to 4 days to develop.
1.2.3) The secretory (mucosal) immune system
The secretory (mucosal) immune system (SIS) participates in the induction and regulation of immune responses in both the mucosal and systemic compartments of an organism after antigen exposure. The significance of this system for the organism comes to light when one considers that the total internal surface of all organs which are in the permanent contact with the external environment amounts to many hundreds of square meters. The most important known function of the SIS is the immune protection of organs which are in close contact with this environment and therefore with "symbiotic" microbes and foreign antigens, such as the mucous membranes of the digestive, respiratory and urogenital tracts, and the eyes (12,13). The SIS consists of an integrated cross-communication pathway of lymphoid tissues made up of inductive and effector sites for the host protection against foreign antigens (14).
The SIS contains several protein components, such as Igs (IgG, IgA, IgM), polymeric Ig receptor (pIgR) also called transmembrane secretory component (SC), joining (J) chain, and antigen-presenting and immunocompetent cells, such as mononuclear phagocytes, B lymphocytes and plasma cells secreting Igs, particularly IgA (12,13,15). The simultaneous presence of SC, J chain and Igs in the same structure is recognized as morphological evidence of the functional SIS activity (15,16).
Despite its similarity to the common immune system, the SIS functions independently already at the stage of Ig synthesis. This was described at first by Dr. A. Besredka (1919), who found that, after introducing pathogens with food, antibodies appear at first in the intestine and only later in the blood (cited after ref.12). Production of Ig polymers in the mucosa-associated lymph-epithelial structures, particularly in the Peyer's patches in the small intestine, in the lymph nodes, and the tonsils, and in lymph follicles in other organs, is performed by B lymphocytes (17,18). The location of antigen-presenting cells allow them to begin synthesizing anti-pathogenic Igs very quickly. B cells migrate from these inductive sites as the memory cells to exocrine tissues all over the body.
Mucous membranes are thus furnished with secretory antibodies in an integrated way, ensuring a variety of specificities at every secretory effector site. Then the second stage in the SIS function begins: proteins ensure immunoglobulin transport through the mucous epithelium and secretion into intercellular spaces and then into the lumen of space-containing organs.
The trans-cellular transport of Igs through the epithelium of mucous membranes occurs in three phases: i) trapping of Igs on the basal-lateral surface of the epithelial cells (endocytosis or internalization), ii) transport of Igs throughout the cell cytoplasm (transcytosis), and iii) secretion of Igs on the apical surface of the epithelium (exocytosis). In the organ lumens, Igs come into contact with specific pathogenic antigens and destroy them. Ig transport is effected by two receptors: pIgR/SC and J chain. The third component of this transport is Igs themselves, represented mainly by IgA and, to a lesser extent, IgG and IgM in adults (19,20).
SC, which has been characterized as a glycoprotein, is the most important receptor of the SIS because it is responsible for the external transport of locally produced polymeric IgA and IgM (17,18). SC is expressed as a transmembrane protein in the secretory mucosal epithelial cells (21), and plays a significant role in immunity by mediating the translocation of IgA and IgM (22). SC represents the soluble ectodomain of pIgR, a membrane protein that transfers mucosal antibodies across epithelial cells. In the protease-rich environment of the intestine, SC is thought to stabilize the associated IgA by as yet unestablished molecular mechanisms (23). In the mucosal immune protection, SC exerts its protective role in the soluble IgA by delaying cleavage in the hinge/Fc region of the alpha-chain, and by not holding together degraded fragments.
At the week 4 of gestation and during all subsequent human intrauterine development, SC and J chain are detected in the ectoderm- and endoderm-derived structures even when Ig-producing lymphocytes and lymphoid organs are absent (24,25). It appears that in embryos the whole SC is located inside the cells. This suggestion was proven by the finding that in the stroma of trophoblastic villi SC is not found during the excretion of Igs (26). The early presence of SC in normally and pathologically developed human embryos (fetus amorphous, anencephaly, etc.) suggests that SC is one of the earliest appearing proteins in the ectoderm- and endoderm-derived structures. In the evolution of life forms, SC has been described in vertebrates, mammalian species in particular (27).
J chain, a small (15 kDa) polypeptide, was first found outside of the SIS: in the bone marrow lymphocytes, thymocytes and in B lymphocyte-synthesized IgG and IgD (17). J chain was also discovered in IgA and IgM in some subclasses of B lymphocytes and in plasma cells (19). In the epithelium of the human intestinal mucosa and bile ducts, J chain is located together with Igs on the basolateral membrane and in the cytoplasmic villi, indicating its heterogenic origin and transport paths. In adult epithelial and other cells (except lymphoid cells), J chain presents exclusively in association with polymeric Igs (28). In secreted fluid, the J chain has been described as a part of the secretory Igs, in the form of sIgA and sIgM (29). J chain has not been found in non-lymphoid cells (30), but it has been detected in mucous cells of invertebrates which have neither Igs nor the lymphoid system (31).
J chain has been described in 3.5-4-week-old human embryos inside and outside the SIS (26), and in 16-week-old fetuses, in lymphoid cells of the spleen, thymus and bone marrow (32). The mature plasma cells, the main site of J chain and Igs synthesis in adults (32) are not formed in fetuses even under severe antigenic attacks, such as the RhD hemolytic disease of fetuses and newborns (11). In mouse, no J-chain expression was detected in embryonic tissues, but an expression of mu-heavy chain was detected in the fetal liver on day 17 (33). J-chain expression has been detected in the spleen on day 9 and in the intestine on day 15 after birth.
In epithelial cells of adults, J chain is involved in creating of the binding site for pIgR/SC in the Ig polymers, by determining the polymeric quaternary structure and interacting directly with the receptor protein (19,20). The main function of J chain is to form pIgA and pIgM by connecting two IgA molecules or five IgM molecules via Fc receptors (34). However, in early fetal development, it appears that J chain functions is not restricted to the formation of polymeric Igs.
Some researches believe that the whole process of Ig transport, including the stages endocytosis " transcytosis " exocytosis, is performed only by the SC. J chain participates in the formation of polymeric Igs, helping with their transport in the form of endocytosis. According to an other opinion, Igs entrance into some epithelial cells is performed only by J chain without SC participation. This latter opinion was proven in studies with pIgR-/-/S-/- mice whose intestinal epithelium does not contain SC but does contain IgA (35). IgA was found in high concentrations in the blood and in low concentrations in the bile, intestinal content and faeces, indicating its low excretion. In healthy people with the normal cellular contents of SC, IgA has been found in high levels in the blood and in all excretions. These data suggest that SC participates in the IgA excretion.
Participation of J chain in Ig transport was confirmed in clinical observations of patients with IgA nephropathies complicated by the high blood levels of IgA. Excretion of IgA with the urine causes disorders in glomerular mesangium of the kidneys. Intestinal IgA concentration was extremely low in some of these patients due to the low content of J chain (36). Participation of SC and J chain in different phases of Ig transport has been proven by their different cellular localization: SC is located in the apical parts of cells while J chain is located in the basal parts (37). These data indicate that J chain participates mainly in endocytosis while SC participates in exocytosis.
It appears that in embryos, the SC is located inside the cells and does not going outside of their borders. This suggestion finds some confirmation in the fact that SC was not found in the stroma of the intestine or inside of its contents, even under an increased Ig secretion (26). Similar observations were made in the choroid plexuses and thyroid. In the thyroid gland, the follicular epithelium and in particular the colloid contain all three types of Igs, but SC and J chain are located only in the epithelium and not in the colloid (25,38). This means that upon Ig exocytosis, SC and J chain remain inside the cells. This conclusion was confirmed by observations of the intracellular localization of these receptors in other cells (39). It should be noted that the precise mechanism and time of the appearance of J chain in human embryos remain unclear: it is not known whether they are transported to the embryo together with maternal Igs or synthesized by cells of the embryo itself as it is described for invertebrates (31).
The described mechanism of Ig exocytosis without SC or J chain is characteristic of the merocrine (eccrine) secretion that takes place in the mucosal membranes, salivary and lachrymal glands and pancreas. In the apocrine secretion, the entire apical portion of the epithelial cells is excreted together with its organelles. SC as well as Igs are situated in the apical compartment and secreted into the lumen (37). Massive release of the free and conjugated SC takes place in holocrine secretion whereby the secretory cells are totally destroyed, and their contents released into the lumen.
Cellular defoliation may be significant under both normal and pathological conditions. The decrease and even disappearance of Igs in the bronchial, gastric, intestinal and pancreatic epithelium in embryos exposed to massive antigenic attacks show that exocytosis of Igs together with SC and J chain is not a universal characteristic (25,38). Igs disappear in the epithelium of the brain ventricles choroids plexuses in meningitis and sepsis. It appears that epithelial-cell excretion of Igs conjugated with SC and J chain is not the only method of exocytosis.
An unusual function of the SIS is characteristic for the protection of different organs and even separate cells that are of vital importance for the intrauterine-developing organism. A list of such organs includes the brain and ganglion neurons, the main endocrine glands, the myocardium, and the gametes (13,42,43). SIS functional activity is already seen in week 4 of gestation (25). A series of morphological and biochemical changes accompany this process. Morphological changes consist of transformation of epithelial layers into cellular clusters, and organs losing their lumens. Biochemically, such organs lose SC, the Ig-secreting receptor, and thus their ability to secret Igs. However, J chain, a receptor that is able to protract Igs into the cellular cytoplasm, remains in the cytoplasm of newly differentiated organs. As a result of these changes, cells in these organs lose some characteristics of the SIS but acquire the ability to store Igs in their cytoplasm and thus to provide the l intracellular protection against pathogens.
These changes, i.e., the loss of SC and preservation of J chain, were not observed in all cells and, of course, not in all differentiated organs. For example, differentiation of neurons is accompanied by preservation of the J chain and intracellular storrage of Igs, but in cells of the neuroglia, originated from the same precursors – neuroblasts, both J chain and Igs are absent. J chain and Igs are not only preserved in the neurons of the brain and spinal ganglions but also in cells of the large endocrine glands, the gametes and in the myocardium (for more details, see Chapter 3). In the myocardium, SC is absent and J chain appears only during this tissue differentiation.
It appears that the intracellular storage of Igs is of great significance to the maintenance of parenchyma cells in specific, strategically important organs: their loss in these organs in even the smallest amount of cells can cause very serious disorders. The described changes are not seen in tissues and organs which are able to intensively regenerate and proliferate. The intracellular storage of Igs may therefore be considered an example of the protection of cells against pathogens. Intracellular neutralization or destruction of many pathogens, such as the Sendai, influenza and hepatitis viruses, may serve as an additional example of such protection.
In vitally important organs or organs located in especially susceptible areas, there is combined functional activity of both known immune systems: common and secretory. Such a situation is seen in the female gametes, surrounded by follicular cells containing SC, in some endocrine glands, and in the brain. And each protective system has its own function. The common immune system protects the whole organism. The SIS protects separate organs and organ systems which are connected to the external environment and affected by massive pathogen attacks.
The above characterization can be useful for better understanding the pathogenesis of disorders caused by long-release viruses, such as human immune deficiency virus (HIV), herpes simplex, herpes zoster, hepatitis viruses B and C, oncogenic viruses of the female genital tract, etc. All of these diseases can be explained by the intracellular neutralization of viruses with the SIS. Aggravation of a disease can result from insufficient or decompensate functional activity in this system.
1.2.4) The secretory immune system in the barrier structures
In addition to the organs with mucous membranes and lumens into which Igs are secreted, there are some organs that do not have these features but nevertheless perform Ig transport by SC and J chain across anatomical barriers. Such barriers include the placental and periovular barriers, serous membranes of the body cavities, the hemato-encephalitic barrier in the ependyma, and the choroid plexuses of the brain ventricles.
At week 3.5 to 4 of gestation and during the second trimester of gestation, both fetal and maternal parts of the human placenta already contain all of the typical components of the SIS (40). In the fetal part of the placenta, SC, J chain, IgA, IgM and IgG are found mainly in the cyto- and syncytiotrophoblast of the chorionic villi and in the epithelium of the amnion. Different subsets of lymphocytes are present in the corresponding stroma. In the maternal part of the placenta, the decidua, proteins of the SIS are found in the decidual cells, whereas macrophages and different subsets of lymphocytes are seen in the decidual stroma (40).
In addition to the mucous membranes and glands of human embryos and fetuses, SC is detected in the trophoblast, amnion, epidermis, mesothelium, thymus, ovary follicular cells, the ependyma of the brain choroid plexuses and some other structures which participate in the formation of the blood-tissue and tissue-tissue barriers (41-43). These data show that the Ig secretion takes place not only in the mucosal membranes and glands but also in the barrier structures via the same mechanism. Thus SIS activity is seen in areas others than the mucous membranes, and this implicates the presence of both mucosal and barrier SIS in the organism.
Functions of the barrier system are very similar to those of the mucosal SIS: they can be considered different types of the same process. Nevertheless, there are a few differences. Mainly IgG and, to a lesser extent, IgA and IgM are secreted in the barrier system, while in the mucosal SIS, IgA is the main secreted component. The mucosal SIS is spread over large areas, for example, in the intestine. The area of the barrier system is not as large, although in the placenta the active area of the chorion of 36- to 40-week-old fetuses can amount to 11.0±1.3 m² (44). The barrier system is usually located in small structures, such as ovarian follicular cells or follicles of the thyroid. Immune-competent cells have not been found in the barrier system, and it seems that this system uses Igs of the common immune system from the blood, lymph and intercellular fluid.
The barrier SIS should be distinguished from the tissue barriers that have no relation to immune reactions. Such tissue barriers are the air-hemolytic barrier in the lungs, the filtrate barrier of the primary urine in the kidneys, the perineural barrier, ovarian membranes as a barrier for sperm penetration, etc.
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