Disruption of Healthy Tissue by the Immune Response Autoimmune diseases: Inappropriate immune response against self-components

Transcription

1 Chapter 13 Disruption of Healthy Tissue by the Immune Response Autoimmune diseases: Inappropriate immune response against self-components

2 Humoral imm 胞外 胞內 CMI: CD8 T Self Ag Self(Auto) antigen (encoded by the host s genome)

3 1. The mechanism of self-tolerance 2. Autoimmune diseases 3. The pre-disposing factors of autoimmune diseases

4 B Lymphocytes Development Central lymphoid organs Activation & differentiation Peripheral lymphoid organs Effector function Inflamed sites T

5 In healthy individuals the immune system is tolerant of self antigens Central tolerance

6 Central T cell tolerance Major epitopes Self Ag presentation AIRE expression on thymic medulary cells Natural Treg CD4CD25 Clonal deletion Clonal anergy Clonal ignorant CTLA4 The presence of autoreactive lymphocytes in periphery

7 Central B cell tolerance Self Ag presentation By bone marrow stromal cells, hematopoietic cells, and macromolecules circulating in the blood plasma Negative selection Major epitopes Receptor editing Clonal deletion Clonal anergy Clonal ignorant The presence of autoreactive lymphocytes in periphery

8 Clonal ignorance Criptic epitopes Epitopes that normally hidden from the immune system The immune system is not tolerant, because these self peptides are not Normally presented by MHC molecules at sufficient levels. Normal: without tissue injury and cell death

9 Self-reactive B/T cells in periphery Affinity Self Cross reactivity High affinity to non-self Ag Signal 1 Anti-nonself Self tolerance

10 In periphery: no infection

11 Central role of CD4 T cells in tolerance Signal 1: Ag uptake and presentation on MHCII Professional APC

12 Lack of signal 2: T cell inactivation Clonal anergy

13 T cell anergy in periphery

14 Peripheral tolerance Cell-cell contact Cytokines: IL10, TGFb CTLA4

15 Maintenance of tolerance in the absence of infection 1. T cell anergy (signal 2) 2. Natural Treg (thymus) & adaptive Treg 3. No inflammatory cytokines (signal 3) Lack of CD4 T helper cells

16 Maintenance of tolerance in infection Cell death & self tolerance Apoptosis Effectors of effectors?

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18 Immune privileged sites Immunosuppressive cytokines: TGFb Tolerance induction Non-destructive response Th2 >> Th1 FasL expression CMI

19 1. The mechanism of self-tolerance 2. Autoimmune diseases 3. The pre-disposing factors of autoimmune diseases

20 Tissue injury and cell death Self Ag exposure to immune system Activation of autoreactive cells Clearance mechanism

21 Self(auto) antigen (encoded by the host s genome) Cell/organ-specific Systemic Self components Autoimmunity (B/T cells) Abnormal infiltration of leukocytes Inflammation Chronic diseases Interference or even loss of normal function

22 Hypersensitivity & autoimmune disease B cells: antibodies

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24 Cell destruction

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26 Graves disease: Stimulating antibody The need to increase cell metabolism Iodide Hyperthyroid

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28 Facilitating Functional blocking

29 Disease transfer 血漿

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31 Hashimoto s thyroiditis Chronic inflammation Intense leukocyte infiltration Tissue damage Hypothyroid Activation of thyroid Agspecific B and T cells

32 T cell mediated autoimmune diseases IDDM Juvenile-onset diabetes

33 IDDM Leukocyte infiltration Loss of b cells

34 Tissue injury and cell death Self Ag exposure to immune system Activation of autoreactive cells Clearance mechanism

35 Autoantibodies against commom components of human cells can cause systemic autoimmune disease Cell death Exposure of autoag dsdna Nucleoprotein Circulation Deposition

36 Deposition of immune complex Skin Kidney

37 (IgM, IgG, IgA specific for the Fc region of human IgG) Rheumatoid factor

38 HLA class II expression on inflammatory tissue

39 1. The mechanism of self-tolerance 2. Autoimmune diseases 3. The pre-disposing factors of autoimmune diseases

40 Self tolerance Clearance Cell death HLA

41 AutoAg presentation

42 Genetic pre-disposition: HLA

43 Under tissue stress (wound) or infection Activation of PAD (Peptidyl arginine deiminases) Self proteins or peptides RA 50% of patients Strong association with DR4 Autoantibody CD4 T cell activation Citrullinated epitopes Destabilization Degradation

44 New treatment of RA

45 Gender

46 Smoking Trauma Infection

47 Autoimmune T cells can be activated in a pathogen-specific or nonspecific manner by infection Infection

48 Molecular mimicry Cross-reactivity of TCR/Ab

49 Tissue injury and cell death Self Ag exposure to immune system Clearance mechanism Activation of autoreactive cells

50 Epitope spreading Complex Intermolecular epitope spreading

51 Intramolecular epitope spreading Under the conditions of infection or inflammation Exposure of criptic epitopes

52 Homework Analyze the biological significance of the survival of auto-reactive clones in the central lymphoid organs.