Basic Immunology. Immunological tolerance. Cellular and molecular mechanisms of the immunological tolerance. Lecture 23 rd

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1 Basic Immunology Lecture 23 rd Immunological tolerance Cellular and molecular mechanisms of the immunological tolerance

2 Tolerated skin grafts on MHC (H2) identical mice

3 TOLERANCE & AUTOIMMUNITY Upon encountering an antigen, the immune system can either develop an immune response or enter a state of unresponsiveness called tolerance. Immunological tolerance is thus the lack of ability to mount an immune response to epitopes to which an individual has the potential to respond. Targeting type and tolerating type immune responses composed by the same cellular and molecular components, the differences are in the effector phase only. Targeting type immune response or tolerance needs to be carefully regulated since an inappropriate response whether it be autoimmune reaction to self-antigens or tolerance to a potential pathogen can have serious and possibly life-threatening consequences.

4 TOLERANCE - PASSIVE- central, peripheral - ACTIVE - natural antibodies, - idiotype network AUTOIMMUNITY - PHYSIOLOGIC REGULATION - AUTOIMMUNE DISEASES

5 Proliferation Proliferáció BcR (Ig)- or TcR-Gene rearrangement Antigenreceptor expression Figure 1-14 Primary lymphatic organs Selection central Szelekció Tolerance Antigen recogintion Peripheral lymphatic organs Proliferation or Deletion and Anergy peripheral Tolerance

6 Central T-cell -Tolerance thymic selection Positive Selektion: MHC RESTRICTION Negative Selection: TOLERANCE

7 Natural regulatory T-cell (Treg) CD4+/CD25+/FoxP3+

8 Development of natural and induced Tregs CD4+CD8+ Thymus Periphery CD25- Tnaiv Treg CD4+ CD25-CTLA-4+ FoxP3/- induced Treg Teff effector T sejt Treg CD4+ CD25+ CTLA-4+ FoxP3+ natural Treg

9 Development of induced Treg LPS, virus RNA, bacterial DNA idc no differentiation Parasite, allergen idc=immature (éretlen DC) DC1 DC2 IL-12 idc IL-4 Th1 IL-10 TGFβ Th2 Treg INFγ Cellular immunity, inflammation, IgG2 IL-10 und TGFβ Immunregulation, Tolerance, IgA IL-4 Humoral immunity, IgG1, IgE

10 B-cell Tolerance - Central tolerance - Peripheral tolerance

11 Central B-cell tolerance in BM 1. Receptor-Editing 2. Deletion with Apoptosis 3. Rezeptormodulation: BcR-downregulation Anergy

12 B cell selection in BM

13 Passive peripheral tolerance Unresponsiveness: no MHC recognition or inhibited cellular differentiation. Tolerance induced by the nature of the antigen Tolerance induced by the body

14 Passive tolerance induced by the nature of the antigen chemical nature dose of the antigen - low dose tolerance (T cell mediated, long ranging) - high dose tolerance (B cell mediated, short ranging) mode of the administration

15 T-cell tolerance Central Tolerance (selection in the Thymus) Peripheral Tolerance 1. Lack of Co-stimulation 2. Failure to Encounter Self Antigens 3. Receipt of Death Signal 4. Control by Regulatory T cells

16 Failed co-stimulation results low dose tolerance

17 Tolerance induced by the body sequestered antigens no MHC recognition no antigen presentation no systemic response heredited or acquired immunodeficiency clonal anergies tolerance induction

18 Role of intestinal Tregs in the maintenance of tolerance

19 The immunological Ying-Yang IgE IgG IgA The cytokines IL-12 and TGF beta 1 are predominant influences in "peripheral" and "mucosal" lymphatic tissues. Thus vectorial expression of these cytokines affect T cells and B cells in such a way that proliferating B cells become committed to secrete "peripheral" IgG or "mucosal" IgA, respectively.

20 Pathogen derived factors induce inflammation in the gut

21 ACTIVE TOLERANCE Anti-idiotype network Anti-idiotype antibodies against T cell and B cell receptors and immunoglobulins Antigen-specific inhibition and induction of memory Immunological homunculus Low affinity IgM natural autoantibodies produced by CD5+ B cells γ/δ T cells

22 Anti-idiotype antibodies

23 Anti-idiotype network (N. K. Jerne) paratop antigén idiotop T- & B-cell suppression idiotí pus Memory formation; anti-idiotípus 1 (paratop-specifikus) anti-idiotípus 2 (idiotop-specifikus) Biological mimicri (insulin anti-insulin anti-antiinsulin ~ insulin) anti-anti-idiot ípus 1 anti-anti-idiotípus 2 anti-anti-idiot ípus 1 anti-anti-idiotípus 2

24 Antigens recognized by natural antibodies Heatshock hsp65, hsp70, hsp90, ubiquitin proteins Enzymes aldolase, citockrom c, SOD, NAPDH Cell membrane β2-microglobulin, spectrin, components acetylcholin receptor Cytoplasmic actin, myosin, tubulin, myoglobin, components myelin basic protein Nuclear DNS, histones components Plasma proteins albumin, IgG, transferrin Cytokines, IL-1, TNF, IFN, insulin, hormones thyreoglobin

25

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