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BASIC TASKS : - PROTECTION FROM PATHOGENS - REMOVAL OF ABNORMAL SELF CELLS

H OW THE IMMUNE SYSTEM WORKS Václav Hořejší Inst. o f Molecular Genetics AS CR, Prague, Czech Republic. BASIC TASKS : - PROTECTION FROM PATHOGENS - REMOVAL OF ABNORMAL SELF CELLS. RECOGNITION.

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BASIC TASKS : - PROTECTION FROM PATHOGENS - REMOVAL OF ABNORMAL SELF CELLS

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  1. HOW THE IMMUNE SYSTEM WORKSVáclav HořejšíInst. of Molecular Genetics AS CR, Prague, Czech Republic

  2. BASIC TASKS:- PROTECTION FROM PATHOGENS- REMOVAL OF ABNORMAL SELF CELLS

  3. RECOGNITION

  4. RECOGNITION OF PATHOGENS AND ABNORMAL SELF CELLS BY MEANS OF:- SURFACE RECEPTORS - “SOLUBLE RECEPTORS”

  5. INNATE (NON-ADAPTIVE)SYSTEM

  6. SOLUBLE AND MEMBRANE RECEPTORS OF THE INNATE SYSTEM (MAINLY ON VARIOUS TYPES OF PHAGOCYTES) RECOGNIZE:PATHOGEN-ASSOCIATED MOLECULAR PATTERNS (PAMPs)The number of the innate receptors is limited, shared structural features are recognized

  7. MANNOSE-BINDING LECTIN, COMPLEMENT

  8. TOLL-LIKE RECEPTORS

  9. SURFACE LECTINS

  10. A SPECIAL SORT OF THE CELLS OF THE INNATE (NON-ADAPTIVE) SYSTEM ARE NK (NATURAL KILLER) CELLS.SPECIALIZE IN KILLING OF ABNORMAL SELF CELLS CONSPICUOUS BY LOW EXPRESSION OF MHC MOLECULES (e.g. many tumors).

  11. ADAPTIVE (ANTIGEN-SPECIFIC)SYSTEM

  12. THE ADAPTIVE SYSTEM:- Based on huge repertoir of B- and T-lymphocyte clones, each carrying a slightly different receptor (BCR or TCR)- The “soluble receptors” of the adaptive system are antibodies (= soluble BCR)- The system is “anticipating”, clonal, “wasteful”- Clonal receptors arise mainly by gene rearrangement and somatic mutations.

  13. B CELL DIFFERENTIATION

  14. T LYMPHOCYTE DEVELOPMENT AND SELECTION IN THYMUS

  15. T-CELL RECEPTORS:MAINLY RECOGNITION OF MHC-PEPTIDE COMPLEXES ON OTHER CELL’S SURFACEPURPOSE:DETECTION OF CELLS INFECTED BY “HIDDEN” INTRACELLULAR PARASITES (e.g. VIRUSES)

  16. PRODUCTIVE STIMULATION OF T LYMPHOCYTES REQUIRES PROFESSIONAL APC (DC)ANDCOSTIMULATION

  17. T LYMPHOCYTES: IMPORTANT FUNCTIONAL SUBSETS

  18. Leo A., Schraven B.Curr Opin Immunol 2001 Jun;13(3):307-16

  19. BASIC DOGMA FOR THE ADAPTIVE RESPONSES:ANTIBODY RESPONSES (B, Th2) – EFFECTIVE FOR EXTRACELLULAR PARASITESINFLAMMATORY RESPONSES (Th1, Tc) – EFFECTIVE FOR INTRACELLULAR PARASITESMUTUAL INHIBITION Th1 vs. Th2 (POSITIVE FEEDBACK REGULATION)WRONG CHOICE Th1 vs. Th2 CAN BE FATAL (LEPROSY…)

  20. Th1 x Th2

  21. ESSENTIAL LINK BETWEEN THE INNATE AND ADAPTIVE SYSTEMS:DENDRITIC CELLS

  22. DENDRITIC CELLS MUST BE PRE-STIMULATED BYDANGER SIGNALS TO BE ABLE TO ACTIVATE T LYMPHOCYTES

  23. DANGER SIGNALS:- EXOGENOUS (PAMPs)-ENDOGENOUS (e.g. STRESS PROTEINS RELEASED FROM NECROTIC CELLS)

  24. DISPOSAL

  25. EFFECTOR MECHANISMS OF PATHOGEN REMOVAL (FOLLOWING RECOGNITION BY EITHER INNATE OR ADAPTIVE RECEPTORS):- KILLING BY MIROBICIDAL PEPTIDES, REACTIVE OXYGEN SPECIES, OR OTHER“CHEMICAL WEAPONS”- PHAGOCYTOSIS- INFLAMMATION (BASED ON CYTOKINES, CHEMOKINES)- KILLING (NOT CURING!!)OF INFECTED CELLS

  26. PHAGOCYTOSIS

  27. SELF-TOLERANCE

  28. BIG PROBLEM:HOW TO MAINTAIN SELF-TOLERANCE AND PREVENT AUTOIMMUNITY?

  29. IMMUNOLOGICAL HIT(WITH EMBARRASSING HISTORY…)REGULATORY (= SUPPRESSOR) T LYMPHOCYTES (Treg, Ts, Th3, Tr1…)

  30. REGULATORY T LYMPHOCYTES ARISE IN:- THYMUS (SUPPRESS AUTOIMMUNITY)- PERIPHERY (THESE DOWN-REGULATE EXCESSIVE IMMUNE RESPONSES

  31. PRACTICAL CONSEQUENCES?

  32. HOPEFULLY:- BETTER VACCINES (WEAK ANTIGENS, TUMORS?)- IMMUNOSUPPRESSION (AUTOIMMUNE DISEASES, TRANSPLANTATION)

  33. 21st CENTURY – THE AGE OF IMMUNOTHERAPEUTICS?WE WILL SEE IN 20, 50,100 YEARS…

  34. SUMMARY:- RECOGNITION BY SOLUBLE OR MEMBRANE-ASSOCIATED RECEPTORS- INNATE SYSTEM (LIMITED NUMBER OF PAMP-RECEPTORS)- ADAPTIVE SYSTEM (HUGE REPERTOIR OF HIGHLY SPECIFIC CLONAL RECEPTORS)- CRUCIAL ROLE OF DENDRITIC CELLS IN LINKING OF THE INNATE AND ADAPTIVE SYSTEM- DANGER SIGNALS (EXOGENOUS OR ENDOGENOUS) “WAKE UP” DC’s FOR STIMULATION OF T CELLS- CRUCIAL ROLE OF THE DECISSION FOR THE ANTIBODY-BASED (Th2) vs. INFLAMMATORY (Th1, Tc) RESPONSES- CRUCIAL ROLE OF SELF-TOLERANCE MECHANISMS (DELETION OF AUTOREACTIVE LYMPHOCYTES, REGULATORY T CELLS)

  35. MOLECULAR MECHANISMS:THOUSANDS OF MOLECULES, RECEPTORS, CYTOKINES, PATHWAYS…

  36. Leo A., Schraven B.Curr Opin Immunol 2001 Jun;13(3):307-16

  37. TMprotein TM protein CD48 TMprotein CD55 CD59 GLP LAT Lck Fyn LIPID RAFTS (GEMs)

  38. RAFTs - DISTRIBUTION ANDHETEROGENEITY

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