Autoimmune aspects of psoriasis: Heritability and autoantigens

- HLA alleles are causative risk genes in autoimmune diseases.
- Autoantigen presentation by HLA molecules facilitates autoimmune responses.
- HLA-class I-restricted autoimmune responses are directed against select target cells.
- Antigen processing decides if human proteins become HLA-presented self-antigens.
- HLA-restricted autoimmune responses require additive effects of many modifier genes.

Chronic immune-mediated disorders (IMDs) constitute a major health burden. Understanding IMD pathogenesis is facing two major constraints: Missing heritability explaining familial clustering, and missing autoantigens. Pinpointing IMD risk genes and autoimmune targets, however, is of fundamental importance for developing novel causal therapies. The strongest association of all IMDs is seen with human leukocyte antigen (HLA) alleles. Using psoriasis as an IMD model this article reviews the pathogenic role HLA molecules may have within the polygenic predisposition of IMDs. It concludes that disease-associated HLA alleles account for both missing heritability and autoimmune mechanisms by facilitating tissue-specific autoimmune responses through autoantigen presentation.