1. Autoimmunity and Tolerance Chris Lancaster, Emily Mathews, Jake Turner Questions: c.j.lancaster@warwick.ac.uk Jake.Turner@warwick.ac.uk E.K.Mathews@warwick.ac.uk

2. Definitions Immunological Tolerance: Unresponsiveness of the immune system to an antigen Not only self-antigens, but also foetus, gut flora, plant pollens etc. Antigen: Substance capable of generating an immune response -Usually a biological substance & not just an inflammatory response

3. How does Immunological tolerance work? Central tolerance: Targets immature lymphocytes that recognise self-antigens Develops in thymus & bone marrow 1) “clonal deletion” (by apoptosis) 2) “clonal anergy” (inactivated by regulatory T lymphocytes) Peripheral tolerance: Targets mature lymphocytes that recognise self or benign antigens 1) “clonal suppression” supressed by other T and B cells Active throughout life

4. Define autoimmunity 1) An immune response to self antigens 2) Due to a failure of immunological tolerance 3) Leading to immune-mediated damage to specific tissues 4) Usually due to a combination of genetic & environmental factors

5. How Can Autoimmunity Occur ? The immune system can respond to an “infinite” number of threats due to genetic recombination within T & B cells “infinite” variety of receptors on different T & B cells- cell- cytotoxicity & antibody production If a specific T or B cell is stimulated by a specific antigen, then it will replicate massively to provide a specific response. What is this called? Pre-programmed T & B cells that recognise self antigens need to be controlled (immunological tolerance)

6. How Can Autoimmunity Occur ? Genetics What is the difference between monozygotic and Dizygotic twins? Monozygotic: Identical twins from one zygote Dizygotic: Non-identical twins from two zygotes Twin studies identified that genetic issues are involved in the loss of immunological tolerance What is the gene type that has been implicated? Give some examples? HLA-B27 : ankylosing spondylitis, reactive arthritis HLA-DR2 : systemic lupus erythematosus (SLE) HLA-DR3 : autoimmune hepatitis, Sjögren’s syndrome, T1DM, SLE HLA-DR4 : rheumatoid arthritis, Type 1 diabetes mellitus (T1DM)

7. Differences between MHC class I and II Proteins? What is the chromosome number that codes for MHC's? 6P MHC class I- HLA-A + HLA-B + HLA-C Expressed on all nucleated cells Presentation of virus produced proteins to the immune system to produced T cell response. If MHC I is missing or foreign, NK cells destroy the cell. MHC Class II- HLA-DP + HLA-DQ + HLA-DR Expressed by APC cells Macrophages, B lymphocytes, dendritic cells and Langerhans cells in skin. Present foreign antigens to Immune system to stimulate immune response

8. How Can Autoimmunity Occur ? Environmental Molecular mimicry? The possibility that sequence similarities between foreign and self- peptides are sufficient to result in the cross-activation of autoreactive T or B cells by pathogen-derived peptides. Upon the activation of B or T cells, it is believed that these "peptide mimic" specific T or B cells can cross-react with self-epitopes (part of the antigen recognised antibodies), thus leading to tissue pathology (autoimmunity) Triggered by environmental causes: Infections : streptococcal infection, gastroenteritis, campylobacter Chemicals : antibiotics, Halothane Neoplasm, Trauma

9. Diagnosis and treatment Diagnosis: - Specific auto-antibodies e.g. TSH receptor, RhF, ANA, dsDNA - HLA-typing (eg. HLA-B27) 1) Steroids : anti-inflammatory & immunosuppressive ↓cytokines (IL-2), cell-mediated & humoral immunity 2) DMD’s : anti-inflammatory & immunosuppressive methotrexate, azathioprine, sulphasalazine 3) Monoclonal antibodies : Infliximab = anti-TNF cytokine used in RA, Crohn’s, ank. spond. etc. Rituximab = anti-CD20 on B lymphocytes used in leukaemia, rejection, RA, SLE etc.