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

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

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

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

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)

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)

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-CExpressed on all nucleated cellsPresentation 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-DRExpressed by APC cells Macrophages, B lymphocytes, dendritic cells and Langerhans cells in skin.Present foreign antigens to Immune system to stimulate immune response

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

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.