The quest for better understanding of HLA-disease association: scenes from a road less travelled by.

Dozens of human diseases and health traits are significantly more common among individuals carrying particular human leukocyte antigens (HLA) alleles. The underlying mechanism of this phenomenon, commonly referred to as "HLA-disease association," has been the subject of a decades-long debate. The prevailing hypotheses implicate an auto-aggressive immune response due to aberrant presentation of self-, self-mimicking-, or altered self-antigens by HLA molecules. However, the identity of such putative antigens remains elusive in the vast majority of HLA-associated diseases. Moreover, antigen presentation-based hypotheses are difficult to reconcile with epidemiologic data and functional characteristics of HLA molecules. To provide better answers to these inconsistencies an alternative theory involving allele-based, antigen presentation-independent mechanism is proposed here. Recent research findings in rheumatoid arthritis, an emblematic HLA-associated disease, lend support to the proposed theory.