HLA association with autoimmune disease: a failure to protect?

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Abstract
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.

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