HLA association with autoimmune disease: a failure to protect?
That certain HLA specificities are associated with predisposition to autoimmune disease does not necessarily imply that self-reactive T cells restricted to particular HLA alleles are eliciting the disease. In the present essay, we argue that HLA can be a major genetic factor in the development of autoimmune diseases without T cells being primarily involved in its initiation or perpetuation. There is now ample evidence that self-reactive, regulatory T cells can protect against pernicious autoimmunity. Hereafter, we propose that extended HLA haplotypes, such as DQ3-DR4, DQ3-DR9, DQ5-DR1 and DQ5-DR10 in the case of rheumatoid arthritis, predispose to impaired T-cell-mediated immune regulation. The haplotypes associated with impaired regulation are the combination of certain class II alleles and a yet unknown 'amplifier'. In this model, products of the HLA class II region are not involved in the presentation of particular organ-specific autoantigens. Therefore, HLA does not predispose to autoimmune disease per se, but rather fails to provide efficient protection.
Zanelli
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Department of Immunohaematology and Blood Bank, Leiden University Medical Centre, Leiden, The Netherlands.
Breedveld
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de Vries
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D000818:Animals; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology* / Q000517:prevention & control; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006680:HLA Antigens / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D013601:T-Lymphocytes / Q000502:physiology
D006680:HLA Antigens