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STRUCTURES AND FUNCTIONS OF THE IMMUNE SYSTEM

STRUCTURES AND FUNCTIONS OF THE IMMUNE SYSTEM. HISTORY:. link to microbiology 1798: vaccination second half of 19 th century: Pasteur, development of microbiology 1883: phagocytosis 19 th /20 th century: antibodies, complement, hypersensitivity, blood groups. HISTORY:.

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STRUCTURES AND FUNCTIONS OF THE IMMUNE SYSTEM

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  1. STRUCTURES AND FUNCTIONS OF THE IMMUNE SYSTEM

  2. HISTORY: link to microbiology 1798: vaccination second half of 19th century: Pasteur, development of microbiology 1883: phagocytosis 19th/20th century: antibodies, complement, hypersensitivity, blood groups

  3. HISTORY: 50´: structure and function of immunoglobulins clonal selection hypothesis immunological tolerance 60´: cellular immunity T, B lymphocytes 70´: HLA system hybridomas 80´: AIDS advent molecular base of specific recognition communication in the immune system recombinant technology 90´: immune system as a regulatory network innate immunity, identification of PAMPs

  4. IMMUNE SYSTEM – BASIC PRINCIPLES IMMUNE SYSTEM involved in the maitenance of homeostasis identification of adverse events external or internal immune memory diffused system nonrandom migration effectory and regulatory functions

  5. IMMUNE SYSTEM NEUROENDOCRINNE REGULATION information system membrane interactions communication network humoral mediators cytokines others

  6. NON-IMMUNOLOGICAL DEFENSE MECHANISMS Genetic resistance: interspecies differences intraspecies differences (HLA polymorphism, polymorphism in cytokine genes, other genes) Physiological defense bariers: skin and mucosal surfaces (histology, junctions, pH, mucus, etc.) normal microflora (gut, skin, vagina)

  7. IMMUNOLOGICAL DEFENSE MECHANISMS Immune system: cells, tissues, and organs diffused in body IMMUNE SYSTEM DIFFUSED SYSTEM organs PRIMARY -bone m. -thymus cells biologically active molecules tissues SECONDARY -lymph. nodes -spleen lymphoid mucosal system blood body fluids

  8. IMMUNE RESPONSE harmful inflammation induction of immunopathology metabolic consumption induction of cancer RISKY BODY REACTION inner body structures mucosal and skin surfaces slow reparation rapid renewal responsivness unresponsivness REMARKABLE TREND TO COMPARTMENTALISATION OF IMMUNE RESPONSE

  9. BASIC IMMUNOLOGICAL MECHANISMS  IMMUNITY INNATE (non-specific) ACQUIRED (specific) • identification • of danger signals • immediate reaction • - no memory • specific recognition of • „ non-self“ • - delayed reaction • - immunological memory

  10. IMMUNITY ACQUIRED (specific) INNATE (non-specific) cooperation cell-mediated humoral humoral cell-mediated B-cells interferons phagocytes T-cells dendritic cells immunoglobulins complement macrophages NK cells mast cells

  11. INNATE IMMUNITY non – self „safe“ „danger“ physiological microflora pathogenic microbes environmental microbes harmful substances harmless substances presence PAMPs absence PAMPs NO ACTIVATION of innate immunity ACTIVATION of innate immunity appoptosis cancer degraded tissues necrosis „safe“ self „dangerous“ self self

  12. SPECIFIC IMMUNITY non – self „any non – self = antigen“ (both „safe“ and „dangerous“) activation of specific immunity (theoretical) majority of specific immune activities are delineated by T cells T cells recognize only antigenic stimuli processed and presented by innate immune cells (dendritic cells, monocytes, macrophages) in context of HLA I, HLA II class molecules and costimulatory interactions specific immunity is also activated only by dangerous „non - self

  13. INNATE IMMUNITY AS A KEY MACHANISM OF IMMUNITY determine the „context“ of recognition for specific immunity fylogenetically conserved cooperation with other body systems INNATE IMMUNITY identification of „danger“ patterns ontogenetically stabile immediate reaction PPR  PAMPs evolutionary selected genetically transfered to off springs

  14. SPECIFIC ACQUIRED IMMUNITY B cells immunoglobulins T cells immunological memory SPECIFIC ACQUIRED IMMUNITY specific recognition of „ non-self“ cooperation with innate immunity „self“ tolerance context of recognition receptors TcR, BcR

  15. ACQUIRED IMMUNITY: receptors are formed in advance, without antigens gene rearrargement specific recognition of antigens (macromolecules) through receptors for antigens (weak chemical forces) fylogenetically young (only predisposition is genetically transfered) B cell repertoir is modified by the presence of antigens elimination of „self-reactive“ clones of T cells immunological memory  selection and clonal expansion

  16. CELLS AND TISSUES OF THE IMMUNE SYSTEM origin of cells is in hematopoesis. cells diferentiate from pluripotent stem cell development is regulated by: - cell-to-cell contact - cytokines (CSF, IL) lymphoid cells: T, B lymphocytes, NK cells myeloid cells: granulocytes, monocytes, macrophages, dendritic cells, thrombocytes, erythrocytes mast cell

  17. STROMAL CELL DEVELOPMENT OF THE IMMUNE CELLS T cell T/NK LYMPHOID PROGENITOR NK Y B cell CD34 MYELOID PROGENITOR STEM CELL GRANULO + G-CSF SCF + self renew. + + CYTOKINES M-CSF, GM-CSF IMMUNE SYSTEME Mo/M ERYTHROPOIETIN ERY proinflammatory signals stress THROMBOPOIETIN cancer infection PLATELET trauma immunopahology

  18. DIFFERENTIATION STAGES: - morphology - cytochemistry - immunochemistry

  19. B Y IMMUNOPHENOTYPING: detection of surface (cytoplasmic, nuclear) molecules by monoclonal antibodies (hybridoma) active imunisation fusion of B-cell and myeloma cell hybridoma selection splenocytes antigen hybridoma Y B B Y Y B Y Y Y Y Y Y B Y Y B Y Y B Y Y splenocytes + myeloma cell B cell

  20. CD CLASSIFICATION: monoclonals reacting with identical molecule (molecularly-characterized) are clustered (CD,cluster designation)CD1-CD247 - adhesion molecules - costimulatory molecules - accessory molecules - receptors for cytokines - receptors for mediators

  21. LYMPHOID SYSTEM Cells of the immune system are accumulated in - lymphoid tissues - lymphoid organs Are present in blood, lymph and body fluids PRIMARY ORGANS - the source of immune cells bone marrow: - source of immune cells - differentiation B cells, myeloid cells    thymus: - differentiation of T cells - immunological repertoir - induction of self tolerance

  22. SECONDARY ORGANS Lymph nodes, spleen, lymphoid tissues associated with mucosa are places where :       specific immune response is developed immune system encounters with „non-self“ presented by dendritic cells       T and B cells are proliferation       compartmentalisation of T or B cells

  23. MIGRATION Rapid mobility of cells is essential for the immune response. It is regulated: exogenous chemoattractive factors (microbial) endogenous chemoattractivefactors (coagulation, complement, chemokines) cell-to-cell contact Homing is regulated movement of cells of specific immunity during development (homing molecules, addressins, HEV)

  24. COMMUNICATIONS IN THE IMMUNE SYSTEME immune cells are mobile immune systeme is difused immune system has to cooperate with other cells and body systems immune cells are rapidly proliferating HIGH LEVEL OF COMMUNICATION AND COOPERATION IS ESSENTIAL

  25. COMMUNICATIONS IN THE IMMUNE SYSTEME HUMORAL SIGNALLING mediators cytokines lipidic peptidic prostaglandins kinins hormones vasoactive peptides thromboxans leukotriens neuropeptides

  26. COMMUNICATIONS IN THE IMMUNE SYSTEME CELL TO CELL SIGNALLING - intimate contact between cells - inducibile by many stimuli costimulatory interactions accessory interactions cognitive interactions adhesion interactions

  27. COMMUNICATIONS IN THE IMMUNE SYSTEME growth factors FGF, IGF, VEGF, PDGF interferons , , ,  interleukins IL-1 až IL-27 CYTOKINES growth factors of hematopoiesis CSF, IL-3, EPO, TPO chemokines CXC, CC, C, CX3 pluripotent proinflammatory TNF, IL-1

  28. I I C C X C C V V C C C C CHEMOKINES – STRUCTURAL CHARACTERISTICS C-X-C -chemokines C-C -chemokines

  29. RECEPTOR FOR CHEMOKINES CCR-5 CCR5 macrophage

  30. P P CYTOKINES – INTRACELLULAR SIGNALLING cytokine receptor for cytokine P Jak(Tyk) kinases P S T A T S T A T dimerisation P S T A T S T A T P STAT cytokines growth factors cell-proliferation transcription P STAT regulatory region

  31. ADHESION INTERACTIONS • ACTIVE PROCESS • receptor  ligand • (leukocyte  endothelial cell) expression adhesion interactions constitutive homotypic heterotypic inducibile cell signalling Inside-out Outside-in oligomerisation, conformation changes activation of downstream kinases interaction with cytoskeleton

  32. 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)

  33. ADHESION MOLECULES family of cadherins family of immuno- globulins family of integrins family of selectins

  34. ADHESION MOLECULES inducibile proinflammatory cytokines, chemokines

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