Could Understanding HLA-C Lead to Precision Therapy in Psoriatic Arthritis?

Human leukocyte antigen c (HLA‐C), a protein encoded by the HLA-C gene, plays an important role in protecting against both cancer and viruses. At the same time, it has been implicated in autoimmune diseases, including rheumatic diseases, though the mechanism by which it contributes to the pathogenesis of these diseases is not yet clear.

According to a review article published this month in ACR Open Rheumatology, the association between HLA and rheumatoid arthritis was first described in the 1970s, and the contributions of HLA-C to rheumatic diseases were “eclipsed by the stronger association with HLA‐DRB1 alleles containing the ‘shared epitope’ with rheumatoid arthritis.”

Since then, genetic association studies have revealed that HLA-C, which function by presenting antigens to T cells and binding receptors on natural killer cells, is independently associated with rheumatic diseases, including psoriatic arthritis (PsA), which is developed by approximately one-third of patients with psoriasis.

Additionally, natural killer cells and HLA-C ligands appear to have a role in patients’ responses to pharmacologic therapies for rheumatic diseases, such as methotrexate or biologic agents. PsA in particular has been linked with the HLA‐C*06:02 allele, and when patients with PsA are treated with ustekinumab, a monoclonal antibody targeting the common p40 subunit of IL‐12 and IL‐23 cytokines, patients carrying HLA‐C*06 tend to show earlier, greater reductions in their disease activity scores than patients who do not.

This finding, say the authors, is clinically relevant, because the population of patients with psoriasis who carry HLA‐C*06:02 is estimated to be 47% to 64%.

Furthermore, a large case-controlled study showed an increased risk for PsA with other high-expression HLA-C alleles, and the association retained its significance after adjusting for the presence HLA‐C*06 in a logistic model. Interestingly, these high-expression alleles have been shown to also control HIV viremia, which highlights, write the authors, “the delicate balance between innate immunity and autoimmunity.”

The authors say that there is substantial evidence to link HLA-C with PsA, but more work will be necessary to confirm and further elucidate the nature of this association. “Overall,” they conclude, “the association of HLA‐C with rheumatic diseases merits further study considering its potential clinical application in precision medicine, such as predicting response to therapy.”

Reference

Siegel RJ, Bridges SL, Ahmed S. HLA-C: an accomplice in rheumatic diseases [published online September 6, 2019]. ACR Open Rheumatol. doi: 10.1002/acr2.11065.