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AUTOIMMUNITY AND IMMUNOPATHOLOGY

AUTOIMMUNITY AND IMMUNOPATHOLOGY. INTRODUCTION. Physiological immune reaction is inseparable linked to limited destruction of „self“. Physiological immune reaction itself includes repair mechanisms. Positive outcomes of physiological immune reaction overweight.

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AUTOIMMUNITY AND IMMUNOPATHOLOGY

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  1. AUTOIMMUNITY AND IMMUNOPATHOLOGY

  2. INTRODUCTION Physiological immune reaction is inseparable linked to limited destruction of „self“. Physiological immune reactionitself includes repair mechanisms. Positive outcomes of physiological immune reactionoverweight. Negative outcomes of pathological immune reaction overweight positive outcomes. Harmful immune reaction is designated immunopathological reaction. Immunopathological reactions in association with non-immunological mechanisms are the cause of destructive inflammation. Immunopathological reactionsare induced by numerous stimuli including failure of „self“ tolerance.

  3. IMMUNE RECOGNITION AND ACTIVATION OF T CELL APC APC APC Ag-MHC ligand Ag-MHC ligand Costimulatory receptor Costimulatory receptor Costimulatory receptor TcR TcR TcR Tcell Tcell Tcell signal 1 signal 2 signal 1 signal 2 clonal expansion effector functions anergy apoptosis no effect

  4. Tcells migration Bcells NK T CELLS RECOGNIZE ANTIGEN IN „CONTEXT“ „context“: -costimulatory interactions („danger patterns“) -accessory interactions - cytokine microenvironment = IInd signal cognitive interaction: TcR, HLA-Ag, CD4 (CD8) = Ist signal + activation of T cells clonal expansion effector and regulatory functions

  5. INDUCTION OF SELF TOLERANCE Basic immunological repertoir of TcRs is generated: randomly in advance without presence of Ags in embryonal life in thymus  Basic immunological repertoir of TcRs includes clones with highprobability of self-recognition (autoreactive T cells). Autoreactive clones of T cells have to be eliminated by selection.

  6. SELECTION: POSITIVE: T cell clones are tested for affinity (not recognition) of self HLA I, II molecules no affinity: selection (deletion) NEGATIVE: T cell clones are tested for recognition of self molecules quantitative phenomena effective recognition: selection (deletion) Mature T cell: toleration of self recognition of non-self.

  7. PERIPHERAL MECHANISMS OF TOLERANCE: immune suppression (CD8+ T cells) anergy or apoptosis (absence of IInd signals) administration of antigens via mucosa induces immune tolerance tolerance of food antigens MUCOSAL IMMUNITY AND INDUCTION OF TOLERANCE:

  8. AUTOIMMUNITY: ability to recognize „self“ (self reflection) physiological phenomena, tightly regulated no disease „self“ recognition is followed by inflammation injury disease self-perpetuating process IMMUNOPATHOLOGY:

  9. INDUCTION OF IMMUNOPATHOLOGY: more efficient presentation of autoantigens upregulation of HLA II (I) expression by interferon  efficient costimulation epitope spreading: intra- inter

  10. Structural: Sequential: microb: microb: COOH -Glu-Ser-Arg-Arg-Ala-Leu- NH2 host: -Gln-Arg-Arg-Ala-Ala- host: COOH NH2 MOLECULAR MIMICRY MOLECULAR MIMICRY

  11. intramolecular „spreading“ intermolecular „spreading“ myelin basic protein (MBP) RNA 143 - 173 84 - 106 SSA/Ro 60 kDa SSB/La 47 kDa COOH NH2 SSA/Ro 52 kDa ? calreticulin immunodominant epitopes MECHANISM OF MOLECULAR SPREADING

  12. altered „self“ (xenobiotics, senescence, ...) molecular mimicry (microbial antigens, hsp) autoantigens could be released during infection environmental antigens (allergens) TARGETS OF AUTOREACTIVE T CELLS:

  13. TH2 presentation of microbial. Ag (LPS, CpG, lipoteichoic a.) dendritic c., macrophage, intensive, long term IL-12 presentation of environmental. Ag nonmicrobial origin (allergens) B-cells, weak, short term IL-4 TH1 TH0 INF IL-4 INHIBITION TH1 TH2 TH2 cytotoxic reactivity antibodies production, isotypic switching TH1 IMMUNOREGULATORY SUBSETS OF T CELLS - mature T cells (TH0) differentiate into functionally distinct subsets after antigen stimulation immunopathological reaction IVth type immunopathological reaction Ist type (allergic inflanmation)

  14. IL-4 TH1 IL-5 TH2 INF IL-6 IL-2 TNF G-CSF IL-10 TH3 (T reg.) TGF  TH SUBSETS - CYTOKINES PRODUCTION

  15. B-CELLS AND IMMUNOPAHOLOGY limited selection machinery somatic mutations presence of high affinity autoreactive B clones no T cell help = no B cell activity B-1 subset (CD5/CD19+), increased in early infancy natural antibodies: broad polyreactivity low avidity, IgM isotype autoantibodies are produced in patients suffering from immunopahology

  16. INDUCTION OF AUTOIMMUNE IMMUNOPATHOLOGICAL REACTIVITY infection agents -molecular mimicry (hsp) -autoantigens release -cytokines induction -induction of costimulatory interactions immune reaction - cytotoxicity - induction of apoptosis genetic predisposition polymorphism: -HLA -TAP-1 -TNF -chemokines apoptosis - autoantigens release T-cells loss of suppression enhanced presentation of autoAg thymic selection failed - selection ? - autoAgs presentation B-cells deregulation of immunoregulatory subsets TH1 TH2 TH3 epitope spreading clonal expansion AUTOIMMUNE IMMUNOPATHOLOGICAL REACTIVITY SYSTEMIC ORGAN- SPECIFIC

  17. IMMUNOPATHOLOGY: predominant TH pattern could be delineated for particular immunopathological diseases the immunopathology –driven inflammation is regulated by the mix of both subsets activities immunopathological autoimmune diseases are always complex there are substantial overlaps between particular mechanisms

  18. AUTOIMMUNE IMMUNOPATHOLOGICAL REACTIONS ( COOMBS, GELL) IST ATOPIC REACTIVITY ( ALLERGY) IIIRD IMMUNE COMPLEX- MEDIATED REACTIONS IIND ANTIBODY-MEDIATED CYTOTOXICITY IMMEDIATE (IgE) DELAYED (T-CELL,M, EOSINOPHILS) ALLERGIC IFLAMMATION (TH2- DRIVEN) - SYSTEMIC LUPUS ERYTHEMATODES - ANTINUCLEAR AUTOANTIBODIES (ANF) (IMMUNE ANEMIAS, TROMBOCYTOPENIAS) IVST CELL-MEDIATED (DELAYED) CYTOTOXICITY VST IMMUNOREACTIVITY TO SIGNALLING SYSTEMS HORMONES MEDIATORS ENDOCRINE TISSUES -T-CELLS, MACROPHAGES - TH1 DRIVEN (GRANULOMA FORMATION) MULTIPLE SCLEROSIS RECE PTORS

  19. IMMUNOPATHOLOGICAL REACTIONS: 1ST Immediate hypersensitivity (atopy, allergy) original concept: IgE mediated disease current paradigma: allergic inflammation T cell TH2 subset, macrophages, eosinophils, IgE immediate phase:allergen-triggered IgE mediated mast cell degranulation late phase:allergic inflammation Allergic inflammation:

  20. TH1 TH0 TH2 ATOPIC IMMUNOPATHOLOGICAL REACTION GENETIC PREDISPOSITION (HLA GENES, OTHERS) DOWNMODULATION DEREGULATION OF IMMUNE SYSTEM INF ENVIRONMENTAL MICROBIAL EXPOSURE AVOIDANCE LACK OF REGULATION STRONG, PREMATURE EXPOSURE TO ALLERGENS UPMODULATION IL-4,2 IgE SYNTHESIS CYTOKINES ALLERGIC INFLAMMATION

  21. ALLERGEN ATOPIC IMMUNOPATHOLOGICAL REACTIVITY - EFFECTOR FUNCTIONS IMMEDIATE REACTIVITY DELAYED REACTIVITY TH2 REGULATION MACROPHAGE mastocyt DIFFERENTIATION MIGRATION FcR-I Y IgE Eo DEGRANULATION B (CROSSLINK) MEDIATORS RELEASE (HISTAMIN, OTHERS) EFFECTOR FUNCTIONS: CLINICAL SYMPTOMS: BRONCHOCONSTRICTION TISSUE SWELLING VASODILATATION SMOOTH MUSCLE CONSTRICTION IgE -CYTOKINES RELEASE - PG AND LT PRODUCTION - O2 AND N2 REACTIVE SPECIES - CYTOTOXICITY - TISSUE DESTRUCTION - TISSUE REMODELLING (FIBROSIS) ALLERGIC INFLAMMATION ANAPHYLAXIS

  22. 2) Cytotoxic hypersensitivity: cell-mediated humoral immune complexes with abnormal molecular structures are formed abnormal complexes are not cleared immune complexes are deposited in tissues (skin, kidney) complex inflammatory response is mounted via complement activation prototypical disease - SLE 3) Immune-complex deposition hypersensitivity:

  23. 4) Delayed hypersensitivity mediated by activated T-cells and macrophages TH1-driven cytotoxicity mononuclear cells inflammatory infiltrate granuloma formation multiple sclerosis binding of autoantibody resembles agonistic action of hormons (Grave’s hyperthyreoiditis) binding of autoantibody blocks activity of mediator (myastenia gravis) 5) Hypersensitivity directed against receptors for hormons

  24. CURRENT CONCEPT: autoimmune immunopathological diseases are the results of dysregulated activity of TH1 and TH2 subsets of helper inducer T-cells IMMUNOPATHOLOGICAL DISEASES: systemic (organ non-specific): SLE organ specific:multiple sclerosis

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