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IMMUNOBIOLOGY OF THE INFLAMMATORY RESPONSE

IMMUNOBIOLOGY OF THE INFLAMMATORY RESPONSE. INFLAMMATION. is a complex local or systemic response to the · infectious agents · tissue (organ) injury · immunopathology. INFLAMMATION.

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IMMUNOBIOLOGY OF THE INFLAMMATORY RESPONSE

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  1. IMMUNOBIOLOGY OF THE INFLAMMATORY RESPONSE

  2. INFLAMMATION is a complex local or systemic response to the ·infectious agents ·tissue (organ) injury ·immunopathology

  3. INFLAMMATION       is a result of coordinate actions of both cellular and humoral factors of ·immune system ·coagulation system (endothelia) ·neuroendocrine system ( hypothalamus  hypophysis  adrenals axis) · other cells

  4. HUMORAL COMPONENTS CELLULAR COMPONENTS immune cells: neutrophils (eosinophils), macrophages, T and B cells, NK cells, mastocytes platelets: release of proinflammatory compounds endothelial cells: cell adhesion, diapedesis, angiogenesis fibroblasts: ECM production, tissue repair keratinocytes proteins of coagulation cascade proteins of complement system immunoglobulins cytokines and their natural inhibitors soluble forms of adhesion molecules and cytokine receptors hormones, neurotransmitters mediators (histamin), prostaglandins, leukotriens, thromboxanes, kinins

  5. INFLAMMATION multiple communications between various cellular components   cell to cell contacts (adhesion molecules) humoral factors (cytokines)

  6. CYTOKINES ·glycoproteins with molec. weight above 8 kD ·produced by various cell types (both immune and non-immune origins) after appropriate activation ·functionally active after binding to the specific cell membrane receptor ·action: - autocrine - paracrine - systemic ·activation of downstream signaling systems of cell (various kinases, STAT, phosphorylation of transcription factors) ·cell activation, proliferation, effector functions ·      recombinant forms for clinical applications

  7. ADHESION MOLECULES ·active interactions between cells ·provide additional activation signals ·changes in cytoskeletal system and morphology of cells ·changes in cell physiology ·monomers, homodimers, heterodimers ·either constitutive or inducibile expression ·low expression on resting cell ·high expression on activated cell ·upregulation is mediated by cytokines

  8. ADHESION INTERACTIONS: ·embryonal development ·immune response ·inflammatory response ·tissue repair · angiogenesis ·specific interaction between adhesion molecule and its ligand

  9. ADHESION MOLECULES ADHESION MOLECULES cadherins immunoglobuline family ICAM-1, 2, 3, VCAM-1 selectins E, P, L - selectins sugar ligands integrins family heterodimers 7 homing 1 integrins (VLA) interaction with ECM 3 integrins cytoadhesins 2 integrins leukocyte (LFA-1)

  10.  Krejsek, 2004

  11.  Krejsek, 2004

  12. PHASES OFINFLAMMATION • 1) ACUTE INFLAMMATION • ·minutes, hours • ·activation of blood coagulation • and complement systém • arachidonic acid metabolism upregulated • (prostaglandins, thromboxans, leukotriens) • ·release of proinflammatory factors (C5a, C3a) • ·activation of macrophages • ·release of proinflammatory cytokines • (IL-1, TNF, IL-6) • ·upregulation of adhesion molecules • on leukocytes and endothelial cells

  13. INFLAMMATION - INDUCTION epitelia (skin), mucosal (skin) immune system INJURY INFECTION AUTOIMMUNE IMMUNO- PATHOLOGY CANCER ACTIVATION COAGULATION CASCADE MACROPHAGES DENDRITIC CELLS COMPLEMENT SYSTEM PROINFLAMMATORY CYTOKINES ACTIVATION COMPONENTS, LEUKOTRIENS, TROMBOXANES ACTIVATION FRAGMENTS INITIATION OF INFLAMMATORY RESPONSE

  14. INFLAMMATION - EARLY PHASE UPREGULATION OF LEUKOPOIESIS IN BONE MARROW ROIs NOIs GENERATION microbes fibroblast ACUTE PHASE RESPONSE (LIVER) CSF PPR CHEMOATTRACTANS ACTIVATORS CYTOKINES CHEMOKINES M D.C. IL-6 TNF EXTRACELLULAR MATRIX DEGRADATION COMPLEMENT endothelia TNF IL-1 ACCUMULATION OF PMNLs matrix metalloproteinases upregulation of adhesion molecule Y basal membrane Y PMNL IIIrd: diapedesis PMNL IInd: adhesion ROIs generation Ist: rolling V E I N

  15. PHASES OF INFLAMMATION 2) LATE PHASE ·days, weeks ·accumulation of mononuclear cells (C-C chemokines) ·antigen processing and presentation to T-cells ·specific immune recognition (T, B-cells) ·clonal expansion ·effector and regulatory activities of T-cells (help, cytotoxicity) and B-cells (Ig synthesis)

  16. M M B B B T T T INFLAMMATION - LATE PHASE Y antigen recognition Y cytokines cytokines P.C. antibodies Y Y T Y B T CELL HELP costimulation costimulation CLONAL EXPANSION TH1 v. TH2 DICHOTOMY UPREGULATION OF HEMATOPOIESIS CELL ACCUMULATION, MIGRATION EFFECTORY FUNCTION REGULATORY FUNCTION C-C-CHEMOKINES Mast cells Eo Mast cells

  17. PHASES OFINFLAMMATION 3) REPAIR ·elimination of insult ·downregulation of the immune functions ·immune memory ·elimination of inflammatory cells by apoptosis ·downregulation of proteolytic enzymes - TIMMPs ·activation of fibroblasts (FGF) ·ECM production and remodelling ·repair of blood vessels (IGF) ·repair of skin integrity (EGF) ·scar formation

  18. IMMUNE MEMORY M TM BM T B IMMUNE CELLS APOPTOSIS INFLAMMATION - TISSUE REPAIR AND REMODELLING, IMMUNE MEMORY GENERATION SKIN REPAIR EPITHELIAL REPAIR BONE TISSUE ACTIVATION UPMODULATION OF TIMMPs DOWN-MODULATION OF IMMUNE RESPONSE IMMUNE CELLS INHIBITION OF MMPs FGF TGF PDGF PLATELES IGF FIBROSIS SMOOTH MUSCLE PROLIFERATION VEGF PDGF PROLIFERATION ECM SYNTHESIS PROTEIN ANABOLISM NEOANGIOGENESIS ENDOTHELIA

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