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Study materials, Course Immunopathology, Module IIA Institute of Immunology, 3rd Medical Faculty, CHU 1. Antibody immune response and regulation Each B lymphocyte is able to produce only antibodies of one specifity. After the activation by relevant epitope, B lymphocyte proliferates and differentiates (clonal selection). Because only a few lymphocytes are specific for a given antigen, T cells and B cells need to migrate throughout the body to increase the probability that they will encounter that particular antigen. (lymphocytes spend only about 30 minutes in the blood during each cycle around the body) . Summary of B cells development: Rearrangement of genes for H chain and surface expression of pre - BCR (µ+ψL) Successful rearrangement of genes for L chain and surface expression of IgM (BCR) Immature B lymphocytes- testing for potential autoreaction Somatic mutation and affinity maturation – only the cells with the highest binding affinity to antigen will survive B1 lymphocytes - the first cells originating during ontogenesis. The most of B1 lymphocytes express membrane marker CD5 on their surface. B1 lymphocytes are source of so called natural antibodies of IgM class (isotype). B2 lymphocytes - majority population. After B2 lymphocytes become memory cells, they usually start expressing IgG, IgA or IgE as their antigen - specific receptor. Epitopes of B lymphocytes – T independent 1 (TI-1) B cell antigens – e.g. bacterial 1lipopolysaccharide causes polyclonal activation of BCRs. TI-2 – polymers or repetitive structures, which react with large number of BCRs. T dependent antigens (TD) – induce primary and secondary immune response resulting in memory cells and antibodies with high binding affinity to antigen. Primary antibody response – stimulation of B lymphocytes through BCR, activation of Th lymphocytes mediated by antigen presenting cells (MHC class II molecule + protein). Activation of B lymphocytes results in antibody formation with low affinity to antigen (IgM isotype). Immunocomplexes IgM and antigen accumulate on the surface of follicular dendritic cells (FDC). Secondary antibody response – recognition of antigens, which are present on the surface of FDC in primary lymphoid follicles; signals from Th lymphocytes, another proliferation and differentiation of B lymphocytes, mutation of V genes for H and L chains (somatic mutation). Clones of B lymphocytes with partially altered biding sites for antigen arise (in comparison with entering cells), only B lymphocytes with the highest affinity for antigen survive. Isotype switch – rearrangement of genes for constant domains of H chain, which locates new CH sequence next to exon V/D/J must be performed to express different isotype as µ or δ. Antibody function: Neutralization Opsonization Complement activation 1 05/05/2017 Study materials, Course Immunopathology, Module IIA Institute of Immunology, 3rd Medical Faculty, CHU 2. Immune reactions of T cells – Th1, Th2 reactions, cytotoxic reactions, regulatory roles of T cells, NK and NKT cells, onco-immunology. T cells are the central population of the immune system. Cytotoxic CD8+ T cells recognize the antigen presented by MHC class I molecules. An example of antigen presented by MHC class I molecules to cytotoxic T cells are viral particles. CD8+ T cells are activated by the recognition of viral antigens and induce apoptotic cascade in infected cells leading to their destruction and to the elimination of viral infection. Apoptotic cascade can be induced by molecular pathways such as Fas-FasL, perforine-granzyme, lymphotoxin etc. Another population of T cells are CD4+ T cells. CD4+ T cells recognize the antigens presented by MHC class II molecules expressed on the professional antigen presenting cells. CD4+ T cells are also called T - helpers for their capacity to actively interact with other cell populations. Originally naïve Th0 cells mature into either Th1 or Th2 profile. Th1 cells produce interferon-gamma and participate in the inflammatory reactions. Th1 cells potentate further maturation of Th0 cells into the Th1 profile, induce proinflammatory functions of macrophages and induce the maturation of dendritic cells by CD40-CD154 pathway. The hallmark of Th2 cells is the production of IL-4 and IL-13. Th2 cells induce the maturation of B cells into plasmatic cells and their production of antibodies by direct cell-to-cell contact (CD40-CD154 interaction) or by cytokines. Regulatory T cells constitute a separate subpopulation of T cells. The group of regulatory T cells involves naturally occurring regulatory T cells - CD4+CD25+ T cells and NKT cells. The other subgroup of regulatory T cells can be induced by the specific conditions of the immune responses. A typical example of induced regulatory T cells are Th3 CD4+ T cells producing regulatory cytokines TGF-beta an IL-10. Th3 CD4+ T cells are induced by the oral antigen administration. NK cells are the cells of the innate immune system. Their activation is antigen non-specific and they do not require the presentation of antigen by MHC molecules. NK cells participate in the elimination of viral infections (mainly herpes viruses) and tumour cells. Morphological and functional failures of T cell populations and their misbalances can induce the development of several diseases. The failures of regulatory T cells are involved in the rupture of self-tolerance and the development of autoimmune diseases. Patients suffering from autoimmune diseases often exhibit decreased numbers of regulatory T cells and decreased function of the residual populations of regulatory T cells. Th1-Th2 balance is impaired in several types of diseases. The Th2 profile dominates in allergic diseases, Th1 profile of the immune response is characteristic for autoimmune diseases such as type 1 diabetes mellitus, multiple sclerosis and others. The immune system can recognize and destroy tumour cells by the action of NK and cytotoxic T cells. The increasing incidence of oncological disorders witnesses the capacity of tumour cells to avoid the attack of immune system – due to the production of suppressive cytokines (TGF-beta), downregulation of MHC molecules on the surface of tumour cells and others. The stimulation of the immune system of oncological patients or even the vaccination with tumour antigens represents the hopes for the treatment of oncological disorders. 2 05/05/2017 Study materials, Course Immunopathology, Module IIA Institute of Immunology, 3rd Medical Faculty, CHU 3. The inflammation, the immune reaction The basic functions of the immune system is the defense against environmental, usually infectious agents, defense against dangerous agents originated in own body such as tumor cells and the regulation of the immune response (the prevention of the reaction of immune system against own tissues). The elimination of infections agents is due to the cooperation of cells and mediators of both innate and adaptive immune system. The innate immune system recognizes evolutionary old, conserved structures on pathogen surface (pathogen associated molecular pattern). These molecules (lipopolysaccharide for example) are expressed by bacteria whereas they are never expressed on the surface of eukaryotes. The recognition of PAMP by the cells and mediators of innate immunity leads to the rapid development of immune reaction and usually to the elimination of infectious agents. The innate immune system involves neutrophils, macrophages, NK cells etc. The typical mediator of innate immunity is complement – a cascade of proteins that generates active mediators by the cleavage of inactive precursors. The active complement mediators have cytotoxic, opsonic and other functions. The hallmark of the adaptive immunity is the specific recognition of antigen determinants by the receptor of T or B cells. The antigen recognition activates T or B cells and induces their clonal expansion – the expansion of cells able to recognize the same antigen. A disadvantage of this reaction is its relative slowness. However, when the adaptive immune system is exposed to the same antigen for the second time, the reaction is much more rapid and very efficient. This hallmark of the adaptive immune system is cold the immunologic memory and it is the base of the vaccines against many infectious diseases. Transplantation immunology, immunology of reproduction and gestation. Transplantation medicine replaces damaged tissues and organs of one patient by the tissues of donors of various immunogenetic matching. The immune system of recipient can perceive the grafts as a foreign and can develop the immune reaction leading to graft rejection. The goal of transplantation medicine/immunology is to suppress the “physiological” immune reaction and to promote the graft acceptation. The basic strategy in this field is to choose the donor-recipient pairs with the highest matching in ABO and HLA system and the use of immunosuppressive drugs. The gametes are the potential target of the immune reaction and the immunity can contribute to the some cases of infertility. The sperms are protected from the attack of the immune system by the specific structural and immunologic features of testicles such as the specific cytokine milieu, the expression of Fas-L and others. The damage of specific testicular morphological or functional features by inflammation or trauma can lead to the subsequent destruction of sperms and infertility. The sperms can also be destroyed by the immune system of the female during their migration to the ovum in genital female tract. Another example of the participation of the immune system in the gestational complications is the Rh incompatibility. Rh positive fetus can induce the generation of anti Rh IgG antibodies by the Rh negative mother leading very often to the premature interruption of the gestation. 3 05/05/2017 Study materials, Course Immunopathology, Module IIA Institute of Immunology, 3rd Medical Faculty, CHU 4. Mucosal immunity The function of mucosal immunity: defense against infectious pathogens, the barrier against penetration of infectious and immunogenic agent to the circulation, low reactivity against non pathogenic antigens and the maintenance of mucosal immune homeostasis. Characteristics of mucosal immunity: Strong participation of innate immunity Characteristic populations of T cells Tolerance of luminal antigens Homing of mucosal and exocrine tissues Transport of polygenic immunoglobulins through epithelium – secretory immunoglobulins The mucosal immune system contains 80% immune cells. There are 10 14 bacteria on the mucous surfaces and more than 1000 bacterial species. The mucosal immune system contains organized lymphoid tissues – MALT (mucosa associated lymphoid tissues). The mucosal surfaces and mucosal immune system represent a huge surface communicating with environment. A hallmark of the mucosal immune system is to distinguish between non-pathogenic – commensally and pathogenic microbes. The pathogens are identified due to the recognition of their conserved structures - PAMP (pathogen associated molecular pattern) by the PRR (pattern recognition receptors). PRR include mannose receptor, scavenger receptors, CD14 receptor for polysaccharide, complement receptors etc. Toll like receptors – a subgroup of PRR. Originally described in insects, identification of bacterial antigens such as LPS, CpG etc. The recognition by TLR induces the gene replication, transcription etc leading to the development of the immune responses. The colonization of mucosal surfaces by the bacteria is an important factor for the development of adaptive immunity. The antigens are transported from the intestinal lumen by M cells – specialized population of enterocytes. The antigens are then captured and processed by antigen presenting cells and B cells in subepithelial spaces. The antibodies of class A are produced by B cells localized in germinal centers of follicular zones. The secretory IgA and IgM neutralize antigens on mucosal surfaces (immune inclusions). The secretory IgA do not activate, that might damage mucosa. The immunocomplexes of IgA can be captured on APC and induce the immune response (immune elimination). The immune response against orally administrated antigen depends on the genetic background of individuum, the type of commensally bacteria and the type of the immune reaction. The majority of orally administrated antigens induce the suppression of specific immunity (oral tolerance). Many chronic immune-disorders develop due to the failures of mucosal immunity and tolerance. Autoimmunity Autoimmunity develops due to the failure of immune tolerance. The mechanisms of immune tolerance: Thymic tolerance Positive selection in thymus - cells survive by binding to MHC molecules (cells which bind with low affinity to MHC therefore they have a potential to bind to MHC plus foreign protein with high affinity) Negative selection - cells which bind to MHC plus self peptides with high affinity have a potential of induction autoimmunity. These cells are eliminated Limitation of the central tolerance Many self peptides are not expressed in the thymus Thymic tolerance is not induced to many tissue specific proteins (in the brain, muscle, joints, islet of Langerhans) - autoreactive T cells to many tissue-specific proteins can be detected in healthy people Mechanisms of peripheral tolerance Immunological ignorance Many of antigens are invisible to the immune system (intact vitreous humor of the eye). Limited distribution of these molecules (on APC) means that most organ specific molecules will not be presented to CD4+ T cells at levels high enough to induce T-cell activation. Separation of autoreactive T cells and autoantigens Naive lymphocytes are kept in circulation between blood and secondary lymphoid tissue. Debris from self tissue breakdown is cleared rapidly by apoptosis, function of complement system and phagocytosis (defects of complement of phagocytes are associated with the development of autoimmunity against intracellular molecules) 4 05/05/2017 Study materials, Course Immunopathology, Module IIA Institute of Immunology, 3rd Medical Faculty, CHU Suppression Active suppression of self reactive T-cells by inhibitory populations of T cells which – Treg cells. The best defined mechanism involved cytokines from Th2 cells specifically inhibiting a Th1 response (IL-4, IL-10) B-cell tolerance At the peripheral level - if newly developed or recently hypermutated B cells bind the appropriate antigen in the absence of T-cell help then the B cell will undergo apoptosis or anergy. Anergy and costimulation Deletion of self-reactive cells by apoptosis Classification of autoimmune reaction Characterization of antigen Detection of autoantibodies or autoreactive T cells The reproduction of the process in vitro The reproduction of the disease on experimental model The autoimmune reaction involves: 1. Humoral immunity – antibodies, usually IgG, cytotoxic effect, development of immunocomplexes, functional changes of cells and proteins, the binding of antibodies on the receptors – stimulation or inhibition of receptors. 2. Cellular immunity – lymphocytes, phagocytes and their cytokines. Mechanism – inflammation, tissue damage, participation of CD8+ T cells, CD4 T cells, macrophages and cytokines. Autoimmune reaction: Physiologic – maintenance of immune – homeostasis (damaged cells). Low concentration, low affinity, polyspecifity, domination of IgM isotype. The concentration increases with age. Pathologic – high concentration, high-affinity IgG, IgA. Questionable participation of IgG in tissue damage. Autoimmune diseases 1. Organ non-specific autoimmune disease Affect multiple organs and is directed against molecule widely distributed through the body, particularly intracellular molecules involved in transcription and translation of the genetic code. 2. Organ specific – target one or few specific tissues/organs (Hashimoto thyroiditis, Type 1 Diabetes Mellitus). Etiology of autoimmunity is unknown 1. Genetic factors of autoimmunity: multiple genes, (MHC-HLA B27, DR3 etc, VNTR) Genes encoding for cytokines, apoptosis, polymorphism of TCR, gene for H chain of Ig etc. 2. Environmental factors: Infection agents – EBV – B cells, Superantigens. Mechanism of molecular mimicry – structural and antigen similarities between self-antigens and epitopes of microorganisms can initiate autoimmune reaction (streptococcal M protein, heart myosin, Coxsackie virus – GAD). Pathologic expression of HLA class II on cells (induced by IFN-, medicaments, UV etc) Laboratory tests Detection of antibodies against autoantigens, test of autoreactivity of T cells. Detection of antibodies is used for the laboratory diagnosis of autoimmune diseases. Detection of autoantibodies against nuclear antigens by indirect fluorescence. Type of fluorescence on Hep-2 cells, antibodies and associated disorders Type of fluorescence Homogenous Peripheral Granulomatous 5 Antinuclear antibodies anti-histon anti-dsDNA anti-dsDNA anti-laminin anti-U1 RNP anti-Sm anti-La anti -Ro anti-PCNA/cyklin anti-KU anti-Scl-70 Disease SLE, RA, DI-SLE, JCA SLE SLE SLE MCTD, SLE SLE SS, SLE, seldom RA SS, SLE, newborn lupus, seldom RA SLE SLE, PSS/DM PSS 05/05/2017 Study materials, Course Immunopathology, Module IIA Nuclear Homogenous Cytoplasmatic 6 antiribozomal RNP anti-PM-Scl anti-U3RNP (fibrilarin) anti-RNA polymerase I anti-centromera anti-tRNA syntetasa (JO-1, PL-7, PL-12 atd.) anti-ribozomal RNP anti-Ro antimitochondrial Institute of Immunology, 3rd Medical Faculty, CHU SLE PSS/DM PSS PSS CREST PM/DM SLE SLE PBC 05/05/2017 Study materials, Course Immunopathology, Module IIA Institute of Immunology, 3rd Medical Faculty, CHU 5. Immunodeficiency – molecular mechanisms of primary ID Causes of impaired immunity Primary missing enzyme missing cell type missing component (no function) (usually in childhood, severe) Secondary caused by other disease – lymphoid malignancy, infection ( HIV) malnutrition, glomerulopathy, protein loss by GIT, burns immunosupresive therapy Types of molecular defect related to primary immunodeficiency Disease/Syndrome Phenotype defect Mutant gene B, T cells receptor Gen defect -complex CD3 AR agamaglobulinemia Selective defect Ig Ig only with chains gene for CD3 or chain genes for chain 14q32.3 gene defect for HC 14q 32.3 gene defect for chain 2p11 Defect TCR B cells Absence Ig isotypes absence Deficiency chain Deficiency of chain of cytokine receptor X linked SCID T-B+NK+ SCID Autosomal recesive SCID T-B+NK- SCID Defect of one element of ligand pair X linked Hyper IgM syndrome Deficiency of IgG, gene for chain common. receptor Xq13.1 gene for chain IL-7R 5p13 gene CD154 (CD40 ligand) Xq26.3 IgA, increased IgM Defects of signal molecules X linked agamaglobulinemia Autosom. rec. SCID CD8 lymphopenia X linked lymphoprolif, ZAP-70 deficiency EBV induced lymphoprolif Wiskott-Aldrich syndrome ID, trombocytopenia,ekzema gene for Btk Xq21.3 gene for Jak3 19p13.1 CD45 tyrosin phosphatase RAG1, RAG2 6q21.3 TAP1, TAP2 6q21.3 TAP1, TAP2 6q21.3, gene for transcription factors RFXAP, CIITA, RFXANK gene for ZAP-70 2q12 gene pro SH2D1A adapter protein Xq25 gene for WASP Xp11.23 Metabolic defect SCID AR T-B-NK-adenosine deaminase gene for ADA 20q13.2 MHC class I defect MHC class II defect Absence of B cells T-B+NKT-B+NKT-B-NK+ MHC I A. Antibody deficiency Very low production of Ig isotypes. Infections caused by common bacterial pathogens (Strepto, Pneumococcus, Hemofilus infl.) B. Combined immunodeficiency First weeks, months of life, etiology viral, fungal. Frequent chronic diarrhea, airway infection, soor Failure to thrive C. Complement disorders Decreased activity of C is usually secondary after activation of C cascade – consumption in IC diseases - SLE (consumption of C1, C4, C2) 7 05/05/2017 Study materials, Course Immunopathology, Module IIA Institute of Immunology, 3rd Medical Faculty, CHU Primary, inborn defects: Defect of early components - C1, C2, C4 – deteriorate the capacity of C solubilize IC - immunocomplex disease, similar to lupus (malar rash, arthralgia, GN, chronic vasculitis, rare pyogenic infection. (ANA, anti-dsDNA missing) D,B,P defect recurrent Neisserial infection C3 defect recurrent bacterial infection C1 Inactivator defect Hereditary angioedema D. Defects of phagocytosis - amount or function defect of neutrophils usually involved Infections are recurrent and long-lasting, Clinical symptoms are unusually mild, in comparison with severe infection. Poor response to antibiotics Frequent cause : Staphylococci, Enterobacteria, fungi (Aspergillus, Candida albicans) Skin and mucosa involved, complicated by suppurative lymphadenopathy Types of the defect – enzyme defect - chronic granulomatous disease (low reactive metabolites production - defect NADPH oxidase), no bactericidal function – defects of adhesive molecules - LAD syndrome – deficiency of leukocyte integrins complex CD11b/CD18 on leucocytes (gene for beta 2 subunit) - LAD2 – defect of CD15 – expression of sialyl-LewisX Immunopathologic reactions of hypersenzitivity Tissue damage due to immunopathology reactions Side effect ( necessary) of the defense reactions against dangerous pathogens Exaggerated reactions against harmless exogenous antigens (allergy, hypersensitivity) Aberrant immune reaction against normal autoantigens (autoimmune reactions) Correlates of normal and abnormal immune reactions Immune mechanism Physiological Ab binding Opsonization and activation of C Pathogen lysis IgE production, mast cell activation Th1, macrophages activation Antiparasitic defense Defense against IC pathogens Pathology Opsonization Self cell destruction Allergy inflam. Anaphylaxis Autoimmunity Self-destruction during infection Tissue damage caused by the immune system – Types of immunopathologic reactions Types of immunopathologic reactions Mechanism Disease Immediate (Type I) 1. IgE production, mast cell degranulation Anaphylaxis 2. Late phase of allergic inflammation Atopic diseases - influx of inflammatory cells (Eo) Mediators: Histamine, Leukotrienes Cell bound Ag (Type II) IgG/IgM antibodies cytotoxic Complement lysis Neutrophil activation Opsonization Metabolic stimulation Blocking Ab Immunocomplex reaction (Type III) concentration of IC due to persistent Ag, Ab production, complement activation and inflammation 8 AIHA ABO, Rh incompatibility Goodpasture sy Cold AIHA, ITP Graves’ disease Myasthenia gravis, Pernicious anemia Serum sickness Extrinsic A.Alv (farmers lung) Lepromatous leprosy SLE 05/05/2017 Study materials, Course Immunopathology, Module IIA Institute of Immunology, 3rd Medical Faculty, CHU Cutaneous vasculitis Delayed hypersenzitivity (Type IV) Th1 cytokine production Attraction of Ly, Macrophages by cytokines 9 Graft rejection Tuberculosis, contact dermatitis 05/05/2017