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Autoimmunitás/Autoimmunitás kialakulásának okai

Autoimmunitás/Autoimmunitás kialakulásának okai. Populáció ~5% szenved autoimmun betegségben. TÚLÉRZÉKENYSÉGI REAKCIÓK ÁTTEKINTÉSE/Autoimmunitás?. Igen gyakran autoimmun betegségek együttjárói . T olerancia. Molecular Mechanisms of Autoimmunity. How is autoimmunity induced?.

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Autoimmunitás/Autoimmunitás kialakulásának okai

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  1. Autoimmunitás/Autoimmunitás kialakulásának okai

  2. Populáció ~5% szenved autoimmun betegségben

  3. TÚLÉRZÉKENYSÉGI REAKCIÓK ÁTTEKINTÉSE/Autoimmunitás? Igen gyakran autoimmun betegségek együttjárói

  4. Tolerancia

  5. Molecular Mechanisms of Autoimmunity How is autoimmunity induced? What could go wrong here? 1-immunologic factor 2-genetic f. 3-enviroment f. 7

  6. Genetikai tényezők Much recent attention has focused on the role of T cells in autoimmunity, for two main reasons. First, helper T cells are the key regulators of all immune responses to proteins, and most self antigens implicated in autoimmune diseases are proteins. Second, several autoimmune diseases are genetically linked to the MHC (the HLA complex in humans), and the function of MHC molecules is to present peptide antigens to T cells.

  7. Immunológiai tényezők • Defects in deletion (negative selection) of T or B cells or receptor editing in B cells during the maturation of these cells in the generative lymphoid organs • Defective numbers and functions of regulatory T lymphocytes • Defective apoptosis of mature self-reactive lymphocytes • Inadequate function of inhibitory receptors • Activation of APCs, which overcomes regulatory mechanisms and results in excessive T cell activation

  8. Several ways in which infectious agents could break self tolerance

  9. Foszfatáz Ubiquitináció-degradáció +Citokin környezet CTLA-4 nagyobb affinitású, mint a CD28 mice lacking CTLA-4 develop uncontrolled lymphocyte activation with massively enlarged lymph nodes and spleen and fatal multiorgan lymphocytic infiltrates suggestive of systemic autoimmunity. The autoimmune disorders in PD-1 knockout mice are less severe than in CTLA-4 knockouts. It has been postulated that CTLA-4 functions mainly to control initial T cell activation in lymphoid organs whereas PD-1 is more important for limiting responses of differentiated effector cells in peripheral tissues.

  10. Peripheral B-cell anergy

  11. Patogén specifikus– kereszt reaktivitás

  12. Cross-Reactivity 22

  13. Patogén független Pl. fokozott MHC expresszió

  14. epitóp terjedés

  15. Intramolekuláris epitóp terjedés

  16. Szuperantigének (pl. bakteriális toxinok) az MHC II molekulákhoz és a T-sejt receptorokhoz kívülről ( nem a specifikus antigén-kötő helyen) kapcsolódnak, így egyszerre nagy számú nem specikus T-sejt proliferációját idézhetik elő.

  17. 4. Polyclonal Activation Hypothesis B-cell mitogens, e.g. LPS, EBV Bact. Superag.  TCR (V) -self or Th BUT Limited specificity, e.g. thyroiditis Clonally restricted e.g. -DNA in SLE 27

  18. Danger Theory Anti-self B & T-cells always present. AIR is due to release of “danger signals.” Response to tissue damage, necrosis or cell distress, e.g. infection or injury. BUT AIR can occur without tissue damage, e.g. immunisn. with self-ag; Tx; genetic defects. 28

  19. Summary Self reactive B-cells & T-cells are normally present but anergic. Several factors can induce an AIR:- Genetic Tissue damage & release of cryptic ag. Somatic mutation in Ig V-genes Ag mimicry Tr defects Danger signals 29

  20. BAFF– B cell activating faktor (B-sejtek fitnesz faktora) . A BAFF konstitutív expressziója kell az érett B-sejtek hosszútávú túléléséhez. Nincs BAFF nincs érett B-sejt, overexpressszió megnövekedett B-sejt szám. A BAFF normál körülmények között limitáltan termelődik. BAFFR van szerepe BCMA, TACI-nak nincs.

  21. BAFF A B-sejtek versenyeznek a limitált szabad BAFF-ért Több BAFF jelenléte esetén több B-sejt maradhat életben Michael P., 2009, Nat. Rev. Immunol.

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