IMMUNOPATHOLOGICAL PROCESS. HYPERSENSITIVITY REACTIONS. AUTOIMMUNE DISEASES. IMMUNE DEFICIENCY SYNDROMES. HEALING AND ADAPTATION. REGENERATION. SCLEROSIS
was founded in
According to this idea, Pasteur worked out a vaccine against anthrax which is dangerous both for animals and for people. Thus, immunology was founded.
Later immunology won the victory over smallpox, polyomyelitis, diphtheria, etc. But recently immuno logy turned from special subject and demonstrated new, uninvestigated problems. There are a lot of scientific and medicine problems which are connected with immunopathological processes. They are autoimmune diseases, tumors growth (especially malignant tumors), transplantation and at last — new infection like HIV (human immunodeficiency virus) infection.
Immunopathological processes are pathological states which are associated with disturbances of structure and thnction of lymphoid tissue.
Before studying the morphology of immunogenesis disturbance it is necessary to know the normal immune morphology.
IN THE IMMUNE RESPONSE
Lymphocytes and their products
T-lymphocytes, or T-cells, are the thymusderived lymphocytes that are found mainly in the interfollicular and paracortical areas of lymph nodes as well as in the periarteriolar sheaths of the spleen. T-cells constitute 70% to 80% of circulating peripheral blood lymphocytes. T-cells recognize antigens in their environment through an antigen-specific T-cell receptor (TCR).
About 95% of T-cells have a TCR composed of two disulfide-linked polypeptide chains, and P, which are noncovalently bound to the CD3 molecular complex. Antigen binds the variable region of the TCR. Postrecognition steps leading to T-cell activation appear to be a function of the CD3 complex.
About 5% of T-cells have a TCR composed of two other distinct chains, y and s. These cells do not have either CD4 or CDX on their surface.
Antigenic diversity of the TCR develops through a process of gene rearrangements analogous to those found in immunoglobulin (Ig) synthesis.
T-cell subtypes. Cytotoxic T-cells are capable of antigen-directed killing. They are important in delayed hypersensitivity reactions, rejection of solid organ transplants, immunity to certain bacteria and viruses, and, possibly, tumor immunity. Monoclonal antibodies that react with cell-surface glycoproteins of these cells are designated CD8, and the T-cell subtype is referred to as CD84.
Helper T-cells are regulatory cells that help B-cells and other T-cells to respond appropriately to antigen. Monoclonal antibody markers for these cells are designated CD4, and the T-cell subtype is referred to as CD4.
Suppressor T-cells act to suppress antibody production by B-cells and, thus, partially control the I- and B-cell immune response. These cells are also designated CD8. T-cell products. A variety of substances known as lymphokines are produced and secreted by T-cells and play important roles in cell-mediated immunologic activities. Examples of lymphokines that regulate lymphocyte activities are following.
Interleukin-2 (IL-2) is a T-cell growth factor that s important for long-term proliferation of activated F-cells. Interleukin-3 (IL-3) stimulates differentiation of bone-marrow stem cells. Interleukin 4 (JL-4) acts as a growth factor for activated T-cells, B-cells, and mast cells. IL-4 up-regulates class II major histocompatibility complex (MHC) expression on B-cells. Interleukin 5 (IL-5) aids in differentiation of B-cells mo antibody-producing plasma cells. Interleukin-6 (IL-6) aids in maturation of T-cells and B-cells, stinmlates growth of hematopoietic precursor cells, and inhibits fibroblasts. Gamma interferon (INF-y) is one of a family of interferons that are proteins with diverse functions. INF-y has antiviral activity, activates macrophages, promotes B-cell differentiation, suppresses hematopoietic precursor cells, and induces the expression of class II MHC on many cell types.
B-lymphocytes, or B-cells, constitute up to 15% of circulating peripheral blood lymphocytes and typically are defined by the presence of endogenously produced immunoglobulins.
B-cells are derived from lymphoid progenitor cells, which are believed to differentiate in the fetal liver and spleen and in the adult bone marrow, although the exact origin in humans is unknown. Once formed, B-cells come to reside in the blood, the germinal centers and superficial cortex of lymph nodes, the lymphoid follicles of the white pulp in the spleen, and the bone marrow.
B-cells normally pass through a maturation sequence characterized by gene rearrangements that produce distinct phenotypes and enormous diversity in the B-cell repertoire. Pre-B-cells contain cytoplasmic ja heavy chain but no surface immunoglobulin. Immature B-cells have surface immunoglobulin M (1gM). With further gene rearrangement, B-cells acquire surface IgD and then proceed to <<switch>> heavy-chain isotypes to express IgG, IgA, or IgE.
Competent B-cells recognize antigen through their surface immunoglobulin receptors. B-cell responses are expanded with the help of T-cells and macrophages. If antigen stimulation persists, B-cells differenti4te into their final stage- the antibody- synthesizing plasma cell. If not, the activated B-cells return to a resting, or <<memory>>, stage.
Immunoglobulins are globular proteins produced by B-cells or plasma cells in response to exposure to a particular antigen. The immunoglobulins react specifically to that antigen. Five isotypes of immunoglobulins IgG, IgA, 1gM, IgD, and IgE are identified by structural differences. The basic structure and functional properties of immunoglobulins are the same• for all isotypes. The basic structural unit of immunoglobulins consists of two identical heavy polypeptide chains and two identical light polypeptide chains covalently linked by disulfide bonds. Each heavy and light chain of the immunoglobulin molecule is divided into two regions.
The variable regions of immunoglobulins are highly heterogeneous and are the sites responsible for binding antigen. These regions are contained within the Fab fragments that are produced following pepsin degradation of the molecule.
The constant regions of immunoglobulins control other functions, such as the binding of complement and cytotropic reactions. The constant regions of the heavy chains are found in the Fc-fragment that is produced following papain degradation of the molecule individual regions into continuous sequence.
Null cells are a population of cytotoxic lymphocytes that are large, possess cytoplasmic granules, and are negative for TCRs and surface immunoglobulin. Their name reflects this lack of traditional T- or B-cell markers.
Natural killer-cells (NK-cells) represent the majority of null cells. NK-cells possess cytolytic activity against a variety of targets in the absence of purposeful immunization. Their cytotoxic activity does not seem to be restricted by the MHC. NK-cells require ccll-cell contact for killing, which is enhanced by interferon and IL-2. Killer-cells (K-cells) are a related population of null cells, which possess Fc-receptors and mediate killing through antibody-dependent mechanisms.
Mononuclear phagocytes are widely distributed in the body; they are given different names depending on their location. In connective tissue, they are called histiocytes; in blood, monocytes; in bone marrow, macrophages; in the liver, Kupffer cells; and in the lung, alveolar macrophages. Mononuclear phagocytes in all of these sites show common properties that make them critical components of inflammatory and immune reactions.
Mast cells and basophils are granulocytes whose electron-dense cytoplasmic granules contain many of the chemical mediators of inflammation, including histamine, heparin. Secretion of these products is mediated through type I hypersensitivity mechanisms.
The complement system is a plasma-based system of proteins that play a major role in host defense (both specific and nonspecific), in the inflammatory response, and in the mediation of tissue injury. Activated complement components regulate a variety of biologic activities, including chemotaxis, opsonization, phagocytosis, and cytolysis. They also promote smooth muscle contraction and vascular permeability.
Complement is activated sequentially in a cascading manner such that a protein is activated only by the protein that directly preceded it in the sequence. Two pathways are possible. 1. Classic pathway. This pathway requires all nine major complement compo-nents. Activation occurs by direct binding of Cl to an antibody (most often IgG or 1gM) in the form of an antigen-antibody complex. Activated Cl cleaves C4 and C2 to form the bimolecular complex C4b.
2. C3 then splits under the influence of C3 convertase to form C3a and C3b. C3a is a small [ragment that, along with other low-molecular-weight peptides generated later in the cascade, causes the release’ofvasoactive amities and lysosomal.
Central organs of immune system producing immunecompetent cells are bone marrow and thymus. The bone marrow contains progenitor cells fbr the other lymphoid organs. The progenitor cells produced in the bone marrow circulate to the thymus or peripheral organs of immune system, where they develop into more mature lymphoid cells. Populations of bone marrow cells that may have recirculated back to the bone marrow can respond to antigens and are called B-lymphocytes.
The thymus produces and differentiates small lymphocytes (T-lymphocytes).
Main peripheral organs of immune system are spleen, lymphatic nodes and gastrointestinal associated lymphoid tissue (GALT) and bronchus associated lymphoid tissue (BALT). The main immunocompetent cells are T-lymphocytes, B-lymphocytes, macrophages. There are T- and B-zones in the peripheral organs of the immune system. Thus, in the spleen, periarterial zone of the follicle is T-zone, marginal zone is inhibited by B-lymphocytes. There are T-, B-lymphocytes and macrophages in the red pulp of the spleen. In the lymphatic nodes, paracortical zone and peripheral zone of the follicle is T-zone, cortical layer, light centers of the follicles are B-zone. There are T-, B-lymphocytes and macrophages in the medullar substance. Gastrointestinal associated lymphoid tissue (GAiT) and bronchus associated lymphoid tissue (BALT) have different immunocompetent cells, i.e. T-lymphocytes, B-lymphocytes, macrophages without any zones.
For identification of immunocompetent cells we use monoclonal antibodies to different immune cells (Cluster of differentiation).
ilistocompatibility antigens. In humans, the major histocompatibility genes are located on the short arm of chromosome 6. These genes code for the histocompatibility antigens termed human leukocyte antigens (HLAs). HLAs are products of genes of the MFIC, which is a highly polymorphous set of membrane-associated glycoproteins that are critical for the recognition of self during cell—cell immunologic reactions. Two broad categories of MHC antigens are described.
Class I MFIC antigens are composed of two noncovalently linked polypeptide chains. The smaller chain is a superficial protein termed 32—microglobulin. The heavy chain is a trans-membrane protein that bears the antigenic determinants for the alleles of the three major, class I loci, which are designated HLA-A, HLAH, and HLA-C. The alleles of this antigen system are codominant.
Class II MHC antigens are composed of two I ioncovalently linked glycoproteins; however, both are transmembrane proteins. Class II antigens are encoded by the HLA-D gene, which is divided into three major cci designated HLA-DP, HLA-DQ, and HLA-DR.
Class II antigens are located mostly in macrophages, B-cells, activated T-cells, endothelial cells and (lendritic cells).
Rheumatic heart disease
Thymus is the organ regulating the whole immune system. At immunogenesis disturbances we usually see the following processes and pathology.
I. Accidental thymus transformation (involution), that is reduction in the size and mass due to thymocyte migration to the peripheral immune organs and blood as well as due to their partial decomposition and absorption by macrophages (this is called apoptoses).
According to T. Ivanovskaya (1976), accidental involution consists of 5 stages.
Stage 1 <<holey clearing>> — accumulation of lymphocytes around the macrophages. It occurs in the cortex. Stage 2 — transition of the lymphocytes from the cortex to the medullar substance. The boundary between the layers is either poorly seen or not seen at all.
Stage 3 <<layer inversion>>, when the cortex layer looks light, and medullar layer looks dark as a result of transition of lymphocytes from the cortex to the medullar substance.
Stage 4 Reduction in the lymphocyte amount in the both layers, reticular stroma growth.
Stage 5 — collapse of the lobe of the thymus and sclerosis and lobe atrophy.
Accidental transformation more often occurs in the newborn suffering from stress factors. The more powerful is the stimulus, the more pronounced is the degree of involution. Accidental involution occurs in infections, intoxications, in the children born from sick mothers. The process is reversible. Elimination of pathological agent results in thymus normalization.
2. Thymus hyperplasia (thymolymphatic state, thymomegaly) The weight and the size of thymus are considerably increased. Microscopic examination reveals a large number of immature lobules (zones are not distinct). The density of the thymocytes is high. If this condition is accompanied by hypoplasia of adrenal and sexual glands as well as narrow aorta anà arteries, this pathological process is called <<thymo-lymphatic state>>.
Sudden death syndrome (crib death) may occur in thymomegaly, it results from insufficiency of F-lymphocytes of the cortex and medullar substance of the adrenal glands.
3. Thymus hypoplasia is characterized by absence of lobule division into cortical and medullar substance, poor development of reticuloepithelial component, responsible for hormonal fUnction, as well as lymphocyte component. As a rule thymus hypoplasia is typical for congenital immune deficiency.
CHANGES OF LYMPHOID TISSUE AT ANTiGEN STIMULATION
In the thymus, different stages of accidental transformation are observed.
In the bone marrow the first hyperplasia of B-lymphocytes are observed, when it becomes empty, as a result of increased transition of lymphocytes.
The reaction in peripheral lymphoid organs is similar. First, T-zones and B-zone hyperplasia occurs. [viacrophages and plasmatic cells appear as well as their blasts producing immunoglobulins. Vascular endothelium is swollen, there are lymphocytes in the lumen. After that both T- and B-zones become empty. T-zone is characterized by holeyn appearance. In B-zone density of the cells decreases. The lymphocytes either die or circulate in the blood.
Reticuloepithelium hyperplasia and lymphoplasmocyte infiltration occur in the interstitial tissue oF the kidneys, pancreas, intestines, liver, muscles.
A state of balance in the immune responses (humoral or cell-mediated) is essential for protection against endogenous and exogenous antigens. Hypersensitivity is defined as a state of exaggerated immune response to an antigen. The lesions of hypersensitivity (immunologic tissue injury) are produced due to interaction between antigen and product of the immune response.
Depending upon the rapidity and duration the immune response, four distinct foms of hypersensitivity reactions are recognized:
Type I reaction: Immediate type in which on administration of antigen, the reaction occurs immediately (within seconds to minutes). Immune response in this type is mediated largely by humoral antibodies. Immediate type of hypersensitivity is ffirther of three types — type I, II and III.
Immediate hypersensitivity rcaction morphologically manifests by the picture of acute immune inflammation which develops rapidly, alteration and exudation stages prevail, proliferation increases slowly. The vessels and connective tissues are involved first. Alteration manifests by mucoid, fibrinoid swelling and fibrinoid necrosis. The exudate is either fibrinous or fibrino-hemorrhagic. Acute immune inflammations are observed in tuberculosis, syphilis. It is responsible for vascular reaction in lupus crythematosus, glomerulonephritis, nodular periarteritis.
Type II reaction: antibody-mediated cytotoxicity. In this type, antibody reacts with a normal or altered cell-surface component, leading to subsequent destruction or inactivation of the target cell.
Type III reaction: immune complex disease. In this type of reaction, circulating antigen—antibody (immune) complexes (which normally are removed by the reticuloendothelial system) are deposited in tissues, leading to complement activation and further tissue injury. Immune complexes may also develop in situ (i.e., antibodies are directed against antigens that are endogenous to the tissues or have been planted there), thus triggering localized tissue damage.
Type IV reaction: cell-mediated hypersensitivity. Cell-mediated hypersensitivity reactions do not require the presence of antibody and, characteristically, are delayed anywhere from about 24 hours to 2 weeks. Three interrelated mechanisms are recognized, all of which involve activated T-cells.
Two types of cells take part in this reaction. They are sensibilized lymphocytes and macrophages. Morphologically it manifests by chronic immune inflammation characterized by lymphocyte-macrophage infiltration. When we see lymphocyte-macrophage infiltration accompanied by vascular plasmorrhagic and degenerative processes we can conclude about immune inflammation. The condition occurs in autoimmune diseases, tuberculosis, brucellosis, dermatitis.
Granulomatosis is morphological manifestation of slow hypersensitivity reaction.
Reaction of transplant rejection resembles slow hypersensitivity reaction. Transplant antigens induce the production of antibodies and sensibilized lymphocytes which infiltrate the transplant.
Microscopically, lymphohistiocyte infiltration is observed in the transplant. Cellular infiltration causes the disturbance of blood circulation and edema, as a result degenerations and necrosis of transplant develop. The neutrophils and macrophages appear in the transplant. Enzyme destruction of the transplant begins which is followed by its rejection.
Immunologic tolerance and autoimmunity. An immune response generated against self antigens is an aberrancy that implies a loss of immunologic ability to distinguish between self and nonself. The normal status of immunologic nonresponsiveness to self is termed tolerance. Tolerance probably represents an active process involving continuous generation of cellular and .humoral inhibitory regulators. Loss of tolerance to self antigen is referred to as autoimmunity. The mechanisms by which tolerance is generated and lost are poorly understood. Theories of autoimmunity include: 1. Recognition of previously hidden or sequestered antigen.
2. Diminution of suppressor T-cell function.
3. Increase in helper T-cell activity.
4. T-cell-independent polyclonal B-cell activation by complex antigens.
5. Modification of self antigens by drugs or microorganisms.
6. Cross-reactivity between autologous antigens and microbial antigens.
Autoimmune diseases are those occurring as a result of the reaction of autoantibodies and sensibilized lymphocytes against normal antigens of the own tissue. P he causes of autoimmune diseases are not clearly known. Chronic viral infections, radiation and genetic Ihctors may be responsible for them.
Before studying the pathogenesis of autoimmune diseases it is necessary to know thç major histocompatibility complex (MHC), which includes class 1, 2, 3 markers.
Class 2 MHC markers are also called HLA-Dr. ‘Ihere are a lot of autoimmune diseases which are connected with genetic disturbances of HLA-Dr system. That is why HLA genes are included into predisposing factors in the pathogenesis of autoimtriune diseases.
In the pathogenesis of autoimmune diseases the Iollowrng factors are distinguished: • predisposing (HLA genes, hormonal background, genetically dependent features of the target cells);
• initiating (viral and bacterial infections, exposure of immune system and target organs to chemical and physical factors);
• contributing (dysifinction of immune system, T-lymphocyte suppressor activity).
In the pathogenesis, 2 mechanisms can be! distinguished, therefore all the autoimmune diseases. can be divided into 2 groups.
Group 1. Organ specific diseases. They are characterized by disturbance of physiological isolation of the organs and tissues due to absence of immune’ tolerance. Lymphohistiocyte infiltration occurs in the tissues (like at slow hypersensitivity reaction). The main organ specific diseases are:
1. Endocrine glands:
Hashimoto ‘s (autoimmune) thyroiditis.
Insulin-dependent diabetes mellitus.
Idiopathic Addison’s disease.
2. Alimentary tract:
Autoimmune atrophic gastritis in pernicious anemia.
3. Blood cells:
Autoimmune hemolytic anemia.
Autoimmune thrombocytopenia. 4. Others:
Primary biliary cirrhosis.
Chronic active hepatitis.
Autoimmune skin diseases.
Group 2. Organ non-specific diseases. Primary disturbances in the immune system causing the loss lability to distinguish <<own>> and <<foreign>> antigens. [hey are:
Systemic lupus erythematosus.
Scleroderma (Progressive systemic sclerosis).
Polyarteritis nodosa (PAN).
Sj ogren’s syndrome.
Mixed connective tissue disease.
The diseases with autoimmune disturbances.
In these diseases antigenic properties of the tissues change, which causes immune reaction development.
Autoimmunization is responsible not for the beginning but the progress of the disease as autoimmune antibodies appear during the disease. It is observed in glomerulonephritis, hepatitis, chronic gastritis, bum disease, rheumatism, liver cirrhosis. IMMUNE DEFICIENCY SYNDROMES
Immune deficiency syndromes result from immune system insufficiency.
All immune deficiencies are divided into 2 groups: primary, congenital immune deficiencies and secondary, acquired immune deficiencies.
Primary IDS may be understood as primary defects in development of the immune system. Secondary ones results from diseases or drugs that affect immune system.
Primary IDS may be classified into following 4 general groups depending on the stage in development at which the defect occurs:
• T-cell deficiencies;
• B-cell deficiencies;
• Combined (T-, B-cell) deficiencies;
• Deficiency in inflammatory cells (agranulocytosis).
T-cell deficiencies manifests by agenesis, hypoplasia of the thymus and T-dependent zones of the immune system. They are inherited according to autosome dominant type, e.g. MacCusic syndrome. Except for the pathology of thymus and primary lymphatic tissue, defects of development occur.
DiGeorge syndrome is a selective deficiency of T-cells. This lack results from failure of the third and fourth pharyngeal pouches to develop and become thymus and parathyroid glands. DiGeorge syndrome is thought to be the result of an early intrauterine growth defect. It is not genetically linked. Affected infants have total absence of T-cell immunity, in association with iiypocalcemia and tetany. All lymphocytes are B-cells. Plasma cells are present in normal numbers. T-cell areas, such as paracortical areas of lymph nodes and periarteriolar sheaths, are depressed.
Chronic mucocutaneous candidiasis is a
selective defect of T-cell immunity characterized by recurrent candidal infections involving the skin and mucous membranes. The remainder of T-cell functions are intact, as is B-cell immunity. The defect may be inherited as an autosomal recessive gene. Chronic mucocutaneous candidiasis is associated with endocrinopathies. Hypoparathyroidism is most common. Addison’s disease, hypothyroidism, diabetes mellitus, and pernicious anemia are also seen. This association suggests a multiorgan endocrinopathy with selective thymic dysfunction.
B-cell deficiencies. The type of inheritance is connected with X-chromosome, e.g. agammaglohulinemia — Bruton’s syndrome. The thymus is preserved. B-zones in the peripheral lymphatic organs are absent. Immunoglobulins synthesis is absent.
Bruton’s (X-linked) agammaglobulinemia
In 1952, Bruton described an X-linked deficiency in immunoglobulin production. These patients suffered from recurrent bacteria-related bronchitis, otitis, and skin infection. Infections usually began at about age 6 months, as circulating maternal antibodies in the infants subsided. All immunoglobulins were either markedly decreased or absent. Circulating mature B- cells were also absent.
It is now recognized that pre-B-cells are present in patients with Bruton’s agammaglobulinemia, and there seems to be a defect in the B-cell maturation sequence. Morphologically, there are no germinal centers in lymph nodes; the spleen, and the tonsils. Plasma cells are absent.
Transient hypogammaglobulinemia of infancy is characterized by diminished levels of immunoglobulin but the ability to produce certain antibody. The disorder appears to be related to an abnormally long delay in the production of serum immunoglobulin. (Maternal antibodies normally decline in the infant over the first 6 months of life.) Defects in helper T-ceIl function are thought to be responsible.
Common variable immunodeficiency is a somewhat poorly defined entity characterized by hypogammaglobulinemia despite normal numbers of circulating B-cells. Inmost cases, there is no clear-cut genetic predisposition. Patients range in age from very young to elderly, although young adults are most commonly affected.
IgA deficiency is the most common immunodeficiency disorder, occurring in about
Combined syndromes—insufficiency of cellular and humoral immunity (T-, B-cell). This is inherited according to autosome-recessive type, e.g. GlanzmannRiniker syndrome (aganimaglobulinemia of Swiss type, Severe combined immunodeficiency (SCID). Ilypoplasia of thymus and peripheral lymphatic tissue.
Severe combined immunodeficiency (SCifi) is a severe disorder characterized by near total absence of both T-cell and B-cell immunity. Infants present early with recurrent opportunistic infections. SCID ‘nay be transmitted as either an X-linked or autosomal recessive trait.
Morphologically, there is a virtual absence of lymphoid tissue in the form of lymph nodes, spleen, and tonsils. The thymus gland fails to descend from the neck into the mediastinum and lacks lymphoid cells and Hassall’s corpuscles.
patients appear to have a stem-cell defect. A deficiency in the enyzme adenosine deaminase (
Secondary deficiencies occur after full development of the immune system. Some of these are secondary to immunosuppressive therapy, e.g. in tumors, autoimmune diseases, glomerulonephritis, ect. Chronic virus infections and HIV (human immunodeficiency virus) may cause secondary deficiencies.