Immune responses in autoimmune diseases

Transcription

1 Immune responses in autoimmune diseases Erika Jensen-Jarolim Dept. of Pathophysiology Medical University Vienna CCHD Lecture January 24, 2007

2 Primary immune organs: Bone marrow Thymus Secondary: Lymph nodes Spleen MALT, SALT, VALT

3 Lymphocyte maturation Wanted: Recognition of dangerous antigens BUT Non-reactivity against self antigens and harmless antigens

4 Bone marrow: T- & B- development and security measures 1.) Arrangement of antigen receptors: Constant and variable regions 2.) Test for autoimmune potential of B-cells: negative selection

5 B-Lymphocytes

6 VproB B-lymphocyte development Bone marrow VCAM-1 SCF IL-7 B-cell interaction VLA-4 ckit IL7 receptor naive antigen contactclonal expansion Plasma cells Memory cells Rag 1 and Rag 2 proteins mediate recombination Arstila et al, Science 1999: The naive repertoire is highly diverse (10^12), the memory compartment (10^5) contributes less than 1% of the total diversity

7 B-cell Central Tolerance Allelic exclusion and rearrangement Antigen receptor prevents further rearrangement crosslinking Antigen selection: BCR unresponsive to self antigen survive- Tolerant BCR autoreactive - Receptor editing: a) Reexpression of Rag: Production of alternate LC b) no Rag Expression: Apoptosis, clonal Deletion. crosslinking Mature B cells: Activation: Signaling only upon antigen cross-linking Autoreactivity but Escape from deletion Peripheral circulation in Anergic state. Possible activated with mimics of autoantigen. Pierce, S.K. (2002) Nat. Rev. 2:96.

8 B-Lymphocytes: Clonal Deletion or Anergy Depend on Antigen Nature crosslinking no crosslinking

9 How to activate a B-cell? 1.) Recognition of 3D-Antigen and BCR crosslinking 2.) Antigen peptides to TCR T-cell help: costimulation: B7/CD28, CD40/CD40L and cytokines Proliferation and clonal expansion

10 T-Lymphocytes

11 T-Lymphocytes: Education in Thymus Bone marrow: Receptor design Thymus Positive selection: Guarantee of low affinity MHC-restriction Negative selection Exclusion of Autoreactivity TOLERANCE Medullar thymus epithelia (mtec): Auto- Antigenpresentation via AIRE - AutoImmune REgulator

12 How to activate a T-cell? Signal 1: Specific interaction MHC/TCR Signal 2: costimulation B7/CD28 Then proliferation, and cytokine synthesis occur

13 Ignorance Peripheral T cell Tolerance The balance of CD28 and CTLA-4 derived signals is critical to T cell activation and tolerance. Anergy: inhibitory signaling of CTLA-4 counteracts stimulation by CD28 ligation (Signal 3) Activation: costimulation by CD28 ligation Apoptosis: FasL-Fas interaction Walker, L.S.K. & A.K. Abbas [2002] Nat. Rev. Immunol. 2:11.

14 Mechanisms of Autoimmunity Infektion Sequestered Antigens Release from immunologically privileged sites: trauma autoimmune sympathetic opthalmia Bypass of Tolerance Incomplete negative selection: AIRE defects modification. Neoantigen: Small molecule (eg a drug) alters MHCbinding peptide T-cell activation and bystander help for B-cells Inflammation. Activation of ignorant or anergic Lymphocytes: immunostimulatory environment: cytokine, activation of professional antigen presenting cells. Molecular mimicry. Crossreactivity of a danger epitope with a self protein. T cell bystander help for activation of B cells - crossreactive antibody.

15 Breakdowns in Tolerance lead to autoimmunity weak T cell activation by self peptide-mhc survival of naïve T cell Ab-mediated systemic Autoimmunity self-antigen Low MHCI, II, B7 Alteration of homeostasis self-antigen Deletion or anergy Defective deletion Tolerance Organ-specific, or multiorgan AutoImmunity High MHCI, II, B7 Activation foreign antigen Crossreactivity weak strong Immunity Transient AutoImmunity Organ-specific AutoImmunity Ohashi, P. (2002) Nat. Rev. Immunol. 2:427.

16 Autoimmune pathology Direct antibody mediated effects T cell mediated effects (cellular immune) Immune complex mediated effects

17 Direct antibody mediated pathology I. Graves' disease: anti-tsh receptor Abs: Activating TSH T 3, T 4 Myasthenia Gravis: anti-acetylcholine receptor Abs: Blocking

18 Direct antibody mediated pathology II. 19 days Rheumatic fever Crossreactive antibody Molecular mimicry - Antibodies against beta-hemolytic streptococci group A crossreact with human (heart) tissue. Complement activation and inflammation Lysis inflammation

19 Direct antibody mediated pathology III. Hashimoto Thyreoiditis TPOs Antibodies against threoidal Peroxidase CTL cellular? Cytotoxicity TH Zellen NK ADCC Hypothyreosis

20 T cell mediated damage I. Direct T cell cytotoxicity via CD8+ CTL: Diabetes Macrophage recruitment, activation of T-cells Rheumatois arthritis (RA) Cytokines mediate self-destruction of tissues, eg. TNF Target tissue apoptosis by FasL in tissues expressing Fas constitutively or as a consequence of inflammation.

21 T-cell mediated damage II. Diabetes mellitus Type I. (T1D, IDDM): autoreactive CD4+ and CD8+ T cells Normal Islets: Glucagon+ Insulin+ cells Insulin Insulitis T-cells NOD: non-obese diabetes mouse

22 Immune-complex mediated Autoimmune disease Lupus nephritis Systemic diseases: SLE and vasculitis Systemic Lupus erythematodes (LE) patients: Autoantibodies to cytoplasmic and nuclear Ag IgG anti double- stranded DNA (IgM not) Depletion of complement (C3) Depletion of neutrophils dsdna Complement deficiencies impairing IC clearance (C1,C2 or C4) are strong predisposing factors for SLE.

23 Genetic factors I. MHC molecules associated with autoimmunity: HLA DR2: SLE and multiple sclerosis HLA DR3: Sjörgen s S., myasthenia gravis, SLE, IDDM HLA DR4: RA, IDDM and Pemphigus vulgaris HLA B27: Ankylosing spondylitis HLA I HLA II Structure limits the repertoire of presented peptides Selective advantage to TCRs for interaction with MHC rather than peptide Negative selection impaired due to lack of negatively selecting peptides Logunova et al., JEM 2005

24 Genetic factors II. AIRE gene Transient transskription of genes for autoantigens: mtec Mutation Failure in negative selection and autoimmune polyglandular syndrome type 1 (APS-1) FCRL3 gene Encodes an immune receptor, NF-kB promotes expression Mutant variant affects binding of NF-kB greater production of both FCRL3 and autoantibodies. Associated with rheumatoid arthritis, thyroid disease and lupus. Yamada et al, Nature Genetics 2005.

25 Malignancies I. Tolerated Autoantigens and Immune Escape Impaired antigen presentation with limited CTL activation Expression of decoy receptor DcR3 on cancer cells neutralization of Fas ligand produced by CTL and NK cells Expression of Fas ligand may kill tumor-infiltrating CTL, NK cells, granulocytes or macrophages; Mucins, such as DF3/MUC1, or the new ligand RCAS1, block T-cell proliferation

26 Malignancies II. Immune Escape II. Antigen capping, shedding Local Dendritic cells (DCs) immature: Ag presentation, no migration Tumor cells express aberrant MHC class I molecules or β2-microglobulin Suppressive cytokines, such as IL-6, IL-10, and TGF-β.

27 Immune responses in autoimmune - and tumor diseases Erika Jensen-Jarolim Dept. of Pathophysiology Medical University Vienna CCHD Lecture January 24, 2007