To assess the binding of outer surface protein A (OspA) and human lymphocyte function–associated antigen 1 (hLFA‐1) peptides to 5 major histocompatibility complex (MHC) molecules.

Peptide binding to the MHC molecules was determined by in vitro binding assays, and binding was correlated with the frequencies of the 5 MHC molecules in patients with treatment‐resistant Lyme arthritis.

The HLA–DRB1*0401 molecule bound both OspA_163–175 and hLFA‐1α_L330–342 well. Although the magnitude of the binding was less, the DRB1*0404 molecule also showed binding of both peptides. The DRB1*0101 molecule bound OspA_163–175 well, but hLFA‐1α_L330–342 only weakly; the DRB1*0801 or *1101 molecule bound both peptides weakly, if at all. The magnitude of OspA_163–175 binding correlated well with the frequencies of the DRB1 alleles in patients with treatment‐resistant arthritis, but the binding of hLFA‐1α_L330–342 showed only an association with the DRB*04 alleles.

These correlations support the hypothesis that OspA_163–175 is the critical epitope in triggering antibiotic treatment–resistant Lyme arthritis. However, the inability of the DRB*0101 molecule to bind hLFA‐1α_L330–342 suggests that this peptide may not be a relevant autoantigen, at least in DRB1*0101‐positive patients.