Tolerance & Autoimmunity
Establishment & Maintenance of Tolerance
The response of the immune system against self-components
Initial trigger – probably virus
Formation of autoreactive T cells
Special circumstances - Genetic background - Complement deficiency - Hormones Failure of negative-selection processes No problem Cytotoxic T cells and Autoantibodies Significant tissue damage Autoimmune disease
Normal pathway Negative selection
Autoimmune Diseases in Humans
Animal Models for Autoimmune Diseases
Role of CD4+ T cell, MHC, & TCR in Autoimmunity
HLA ALLELES ASSOCIATED WTH INCREASED RISK FOR VARIOUS AUTOIMMUNE DISEASE
Disease Ankylosing spondylitis Goodpasture's syndrome Graves’s disease Insulin-dependent diabetes mellitus Juvenile rheumatoid arthritis Multiple sclerosis Myasthenia gravis Pernicious anemia HLA allele B27 DR2 B8/DR5 DR4/DR3 DR3/DQW8 B27/DR5 DR2 DR3 DR5 Relative risk* 90 16 3-4 20 100 4 5 10 5
Psoriatic arthritis (central)
Reiter’s syndrome Rheumatoid arthritis Sjogren's syndrome Systemic lupus erythematosus
B27
B27 DW4/DR4 DW3 DR3
11
57 10 6 5
Ulcerative colitis B5 4 *Likelihood of developing disease compared to the general population which is assigned a risk value of 1.
Proposed Mechanisms for Induction of Autoimmunity
Release of sequestered antigens. Molecular mimicry. Inappropriate expression of class II MHC. Cytokine imbalance. Dysfunction of the Idiotype network regulatory pathway. Dysfunction of T-cell mediated immune regulation. Polyclonal B cell activation.
Molecular Mimicry
Treatment of Autoimmune Diseases
Immunosuppressive Drugs. Plasmapheresis. Thymectomy. T-cell vaccination. Peptide blockade of MHC molecules. Monoclonal antibody treatment. Tolerance induction by oral antigen.
A view of MS pathogenesis - from Prof. Hohlfeld's comprehensive review in Brain, 1997.
Autoimmunity & Left-Handedness
In humans, left-handed individuals are more likely to develop autoimmune disease than righthanded individuals. Thus in one study, 11% of lefthanded individuals and 4% of right-handed individuals suffered from autoimmune diseasesmainly autoimmune thyroiditis, ulcer-active colitis, and celiac disease. The reasons for this are obscure. It has been suggested, however, that left-handedness and immune malfunction may both result from abnormal endocrine function in fetal life.
Treatment of Autoimmune Diseases
T-cell Vaccination Peptide Blockade of MHC Molecules Monoclonal Antibodies Oral Antigens-Tolerance