How Autoimmune Diseases Develop

Transcription

1 , Institut für Immunologie How Autoimmune Diseases Develop Thomas Kamradt Institut für Immunologie

2 Autoimmunity: When the Immune System Attacks Self "Our arsenals for fighting off bacteria are so powerful, and involve so many different defense mechanisms, that we are more in danger from them than from the invaders. We live in the midst of explosive devices; we are mined." Lewis Thomas, N. Engl. J. Med. 1972;287:553

3 Autoimmune Diseases: Any Organ can be targeted CNS: Multiple Sclerosis Thyroid: Grave s Disease, Hashimoto s Thyreoiditis GIT: Pernicious Anemia, Ulcerative Colitis Primary biliary Cirrhosis Adrenal Cortex: M. Addison Pancreas: Type I Diabetes Muscle: Dermatomyositis Kidney: Systemic Lupus erythematodes Skin: Scleroderma, Systemic Lupus erythematodes Joints: Rheumatoid Arthritis Systemic Lupus erythematodes

4 How autoimmunity develops Which cells are important? B-cells T-cells Others How is autoimmunity usually prevented? Which antigens are recognized? How is tolerance overcome? (Genes and Environment). How can autoimmunity be treated or cured?

5 Cines & Blanchette, N Engl J Med. 2002;346:995 Immune-thrombocytopenic Purpura (ITP)

6 Cines & Blanchette, N Engl J Med. 2002;346:995 Immune-thrombocytopenic Purpura (ITP)

7 Immune-thrombocytopenic Purpura (ITP) Cines & Blanchette, N Engl J Med. 2002;346:995 from R.S. Schwartz. N Engl J Med. 2007;357:2299

8 Immune-thrombocytopenic Purpura (ITP) Cines & Blanchette, N Engl J Med. 2002;346:995 Thrombocyte survival in blood reduced to several hours (normal: approx. 10 d) Taylor & Lindorfer Nat Clin Pract Rheumatol 2007; 3:86

9 Pathogenic effector functions of B-Lymphocytes: 1) Autoantibodies Martin & Chan. Annu Rev Immunol 2006 Martin & Chan Immunity 2004;20:517 27

10 Pathogenic effector functions of B-Lymphocytes: 1) Autoantibodies Martin & Chan. Annu Rev Immunol 2006 Martin & Chan Immunity 2004;20:517 27

11 Pathogenic effector functions of B-Lymphocytes: 2) IC and Complement Martin & Chan. Annu Rev Immunol 2006 Martin & Chan Immunity 2004;20:517 27

12 B-lymphocytes and antibodies: central players in autoimmunity Memory B cells and plasma cells important for (auto)antibody production and immunological memory. B cells: important APC for T cells. B cells connect innate and adaptive immune responses (e.g. via Fc and Complement Receptors) B cells produce chemokines and cytokines.

13 Targeting B cells in autoimmune disease Drugs Function Diseases treated Anti-CD20 (Rituximab) Depletes B cells Rheumatoid Arthritis, (SLE, others in clinical trials) Anti-CD22 (Epratuzumab) Downregulation of BCR, ADCC SLE (Phase III) Anti-BAFF (Belimumab) B-cell survival SLE (Phase III) TACI-Ig fusion protein (Atacicept) B-cell survival SLE (Phase II/III) IVIG FcR modulation (?)

14 Experimental Autoimmune Encephalitis (EAE) MyelinAg/CFA/PT

15 Experimental Autoimmune Encephalitis (EAE) MyelinAg/CFA/PT T-Lymphocytes

16 Susceptibility to Autoimmune Diseases is Associated With HLA Disease HLA % Patients % Controls Ankylosing Spondylitis B RA DR Multiple Sclerosis DR IDDM DR DR DR2 4 26

17 HLA-Molecules Present Antigen to T Lymphocytes Villadangos and Schnorrer Nat Rev Immunol 2007

18 Rheumatoid Arthritis (RA) Symmetric peripheral polyarthritis with systemic involvement. Ø Disease onset approximately 35 yrs. Ø Females more frequently affected than males (7:1). Photos: Prof. Burmester, Charité Berlin

19 HLA-DR: The Shared Epitope for RA Susceptibility DRβ-chain: Amino acid residues DR Allel B1*0101 D L Q R A G B1*0401 D L Q K A G B1*0402 D I D E A V B1*0403 D L Q R E V B1*0404 D L Q R A V B1*0405 S L Q R A G B1*0408 D L Q R A G B1*1402 D L Q R A G B1*1001 D L R R A G Consensus L Q/R R/K A J. Hammer J Exp Med 1995;181:1847

20 Relevance of Th cells for rheumatoid arthritis HLA-association (shared epitope) most relevant genetic susceptibilityfactor for rheumatoid arthritis.

21 Relevance of Th cells for rheumatoid arthritis HLA-association (shared epitope) most relevant genetic susceptibilityfactor for rheumatoid arthritis. Genetics (2): signal transduction (PTPN22), T-cell function (cytokines), Regulation (e.g. PD-1)

22 Relevance of Th cells for rheumatoid arthritis HLA-association (shared epitope) most relevant genetic susceptibilityfactor for rheumatoid arthritis. Genetics (2): signal transduction (PTPN22), T-cell function (cytokines), Regulation (e.g. PD-1) Therapeutic efficacy of CTLA4-Ig (Abatacept) in RA

23 Targeting T cells in autoimmune disease Drugs Function Diseases treated CTLA4-Ig fusion protein (Abatacept) Anti-CD3 (Eplizumab), Anti-IL-2R (Daclizumab) LFA3-Ig fusion protein (Alefacept) Blockade of T-cell costimulation Modulation of T cell functions Blockade of T-cell activation Rheumatoid Arthritis, Type I Diabetes Transplant rejection, Type I Diabetes Plaque Psoriasis Anti-IL-17 Neutralization of IL-17 Rheumatoid Arthritis

24 How autoimmunity develops Which cells are important? B-cells T-cells Others How is autoimmunity usually prevented? Which antigens are recognized? How is tolerance overcome? (Genes and Environment).

25 Arthritis: Inflammation AND Destruction! Backhaus et al. Arthritis & Rheumat 1999

26 Macrophages and Cytokines in Rheumatic Inflammation Cartilage Fibroblasts TNF, IL-1, IL-6, IL MMPs, Cathepsins Osteoclasts

27 Macrophages and Cytokines in Rheumatic Inflammation Inhibitors of kinases, NFκB CTLA4-Ig Neutralising antibodies, soluble receptors: CD20, CD22, BAFF, TACI Fibroblasts Cartilage Inhibitors of inflamasome, caspase 1 P2X7 inhibitors, Ca ++ channel blockers TNF, IL-1, IL-6, IL MMPs, Cathepsins Statins, ACE Inhibitors, PPAR-α agonists Neutralising antibodies, soluble receptors: IL-1β, IL-6R, IL-12/23, IL-17, TNF Osteoclasts

28 Macrophages and Cytokines in Rheumatic Inflammation Inhibitors of kinases, NFκB CTLA4-Ig Neutralising antibodies, soluble receptors: CD20, CD22, BAFF, TACI Fibroblasts Cartilage Inhibitors of inflamasome, caspase 1 P2X7 inhibitors, Ca ++ channel blockers TNF, IL-1, IL-6, IL MMPs, Cathepsins Statins, ACE Inhibitors, PPAR-α agonists Neutralising antibodies, soluble receptors: IL-1β, IL-6R, IL-12/23, IL-17, TNF Osteoclasts Immunosuppression cannot cure rheumatic inflammation.

29 Fibroblast-like synovial cells modulate inflammation Cartilage Fibroblasts TNF, IL-1, IL-6, IL MMPs, Cathepsins Osteoclasts Immunosuppression cannot cure rheumatic inflammation.

30 Fibroblast-like synovial cells modulate inflammation Cartilage Fibroblasts TNF, IL-1, IL-6, IL MMPs, Cathepsins IL-6, IL15, Il-18, IL-23, IFN-α/β, GM-CSF, TNF-α TGF-β, Chemokines, VEGF Osteoclasts Immunosuppression cannot cure rheumatic inflammation.

31 Inflammation without T-cells or antibodies Muckle-Wells syndrome Pyogenic arthritis with pyoderma gangrenosum and acne (PAPA syndrome) Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) Deficiency of the IL-1 receptor antagonist (DIRA) Kastner et al. Cell 2010

32 Kastner et al. Cell 2010 Autoinflammatory diseases

33 Autoinflammatory diseases Disorders marked by abnormally increased inflammation, mediated predominantly by the cells and molecules of the innate immune system Myeloid effector cells. Germline-encoded danger receptors. Excessive IL-1 signalling. Kastner et al. Cell 2010

34 Two Signals are Required for IL-1 Production 2011 van de Veerdonk et al.

35 Two Signals are Required for IL-1 Production 2011 van de Veerdonk et al.

36 Two Signals are Required for IL-1 Production 2011 van de Veerdonk et al.

37 Inflammation without T-cells or antibodies Selected Autoinflammatory Diseases Disease Gene (Protein) Proposed Mechanism Familial Mediterranean fever (FMF) MEFV (pyrin) Increased inflammasome activation Adult-onset Still s disease Complex Unknown Crohn s disease Complex (NOD2, ATG16L1, IRGM) NF-κB activation disorder Deficiency in IL-1 receptor antagonist (DIRA) IL1RN (IL-1Ra) Absence of negative regulator of IL-1α and IL-1β Gout Complex (SLC2A9/GLUT9, ABCG2) Crystal-induced inflammasome activation Type 2 diabetes mellitus Complex Hyperglycemia-induced inflammasome activation Atherosclerosis (?) Complex Crystal-induced inflammasome activation Asbestosis/silicosis Complex Particle-induced inflammasome activation

38 How autoimmunity develops Which cells are important? B-cells T-cells Others How is autoimmunity usually prevented? Which antigens are recognized? How is tolerance overcome? (Genes and Environment).

39 TCRs: Diversity Created by Somatic Recombination Germline DNA α Vα1-70 Jα1-61 Cα Rearranged DNA Protein (T-Cell Receptor) α β Rearranged DNA Germline DNA β Vβ1-52 Dβ2 Jβ1-13 Cβ2

40 TCRs: Diversity Created by Somatic Hypermutation Protein (T-Cell Receptor) α β >10 15 different TCRs theoretically possible This creates a problem:

41 Diversity vs. Horror autotoxicus Paul Ehrlich (1908) : "Horror autotoxicus" Problem: Maximal diversity without damage to the Organism

42 Induction of T-Cell Tolerance in the Thymus Kamradt & Mitchison, N Engl J Med 2001;344:

43 Large Numbers of Autoreactive T cells Can Remain Harmless... Mice, transgenic for an Autoantigen-specific TCR remain healthy

44 Large Numbers of Autoreactive T cells Can Remain Harmless... Mice, transgenic for an Autoantigen-specific TCR remain healthy 63% CD4 Clonotype Transgenic T cells are not thymically deleted.

45 Large Numbers of Autoreactive T cells Can Remain Harmless... Mice, transgenic for an Autoantigen-specific TCR remain healthy 63% CD4 Proliferation Clonotype Transgenic T cells are not thymically deleted. cpm..and function normally in vitro [Ag]

46 Extra-Thymic Induction/Maintenance of T-Cell Tolerance Kamradt & Mitchison, N Engl J Med 2001;344:

47 Extra-Thymic Induction/Maintenance of T-Cell Tolerance Kamradt & Mitchison, N Engl J Med 2001;344:

48 Extra-Thymic Induction/Maintenance of T-Cell Tolerance Abb. verändert nach Strasser et al. Immunol Cell Biol 2008;86:57 Kamradt & Mitchison, N Engl J Med 2001;344:

49 Autoantigenes, which cannot be ignored induce T-cell deletion or anergy Abb. verändert nach Strasser et al. Immunol Cell Biol 2008;86:57

50 Critical Role Of APC For Peripheral Tolerance Antigens Innate Immune Cells: germline-encoded, non-clonal, non-rearranged receptors. Evaluate biology.

51 Critical Role Of APC For Peripheral Tolerance Antigens Innate Immune Cells: germline-encoded, non-clonal, non-rearranged receptors. Evaluate biology. Adaptive immune response Activation Proliferation, activation of effector functions

52 Critical Role Of APC For Peripheral Tolerance Antigens Innate Immune Cells: germline-encoded, non-clonal, non-rearranged receptors. Evaluate biology. Adaptive immune response Activation No Activation No adaptive immune response Proliferation, activation of effector functions Ignorance, clonal deletion, or anergy

53 T-Zell Toleranz: Inhibition CTLA4-Ig also effective against RA Nach Kamradt & Mitchison, N Engl J Med 2001;344:

54 Extra-Thymic Induction/Maintenance of T-Cell Tolerance Kamradt & Mitchison, N Engl J Med 2001;344:

55 Mechanisms of B-Cell Tolerance Clonal deletion Induction of apoptosis via inhibition of survival signals or activation of death receptors. Receptor editing Continued V(D)J recombination to avoid self-reactivity. B-cell intrinsic mechanisms Anergy, downregulation of the BCR, upregulation of CD5. B-cell extrinsic mechanisms Lack of T-cell help or survival factors. Abb. verändert nach Goodnow et al. Nature 2005;435:590

56 Mechanisms of B-Cell Tolerance Clonal deletion Induction of apoptosis via inhibition of survival signals or activation of death receptors. Receptor editing Continued V(D)J recombination to avoid self-reactivity. B-cell intrinsic mechanisms Anergy, downregulation of the BCR, upregulation of CD5. B-cell extrinsic mechanisms Lack of T-cell help or survival factors. Abb. verändert nach Goodnow et al. Nature 2005;435:590

57 How autoimmunity develops Which cells are important? B-cells T-cells Others How is autoimmunity usually prevented? Which antigens are recognized? How is tolerance overcome? (Genes and Environment).

58 Pathogenic effector functions of B-Lymphocytes: 1) Autoantibodies Martin & Chan. Annu Rev Immunol 2006 Martin & Chan Immunity 2004;20:517 27

59 Arthritis: T-Cell Recognition of Cartilage-Ag? HLA-DR4 CII?

60 Are Joint-Specific Antigens Attacked in Arthritis? Collagen Type II, IX? Fillagrin? Aggrecan? gp39? COMP?

61 From Systemic Immune Alteration to Arthritis MRL/lpr Genetic Defect in Apoptosis SKG Point Mutation in ZAP-70 Self-reactive CD4 + T cells Virus-infection HTLV-1 tax tg Cytokines, MMPs... Immune responses against systemic antigens K/BxN G6PI-induced arthritis Fibrinogen-induced arthritis Hemagglutin-induced arthritis Cytokines TNF-α tg IL-1β IL-RA KO gp130 F759/759 Ki

62 Systemically expressed autoantigens in human autoimmune diseases

63 How autoimmunity develops Which cells are important? B-cells T-cells Others How is autoimmunity usually prevented? Which antigens are recognized? How is tolerance overcome? (Genes and Environment).

64 Autoimmune Diseases: Genes & Environment Twin Studies: 70% Environment 30% Genetics Environment Genes Susceptibility Severity Chronicity

65 Gene-Environment Interactions: Smoking & RA Klareskog et al. Annu Rev Immunol. 2008

66 Which cells are important? Also think of the tissue response

67 How is autoimmunity usually prevented? Central and peripheral tolerance mechanisms MUST NOT be complete

68 Which antigens are recognized? Mounting evidence for systemic alterations