HLA–DR alleles determine responsiveness to Borrelia burgdorferi antigens in a mouse model of self‐perpetuating arthritis

Abstract

AbstractObjectiveArthritis is a prominent manifestation of Lyme disease, which is caused by infection with Borrelia burgdorferi (Bb). Chronic Lyme arthritis persisting even after antibiotic treatment is linked to HLA–DRB1*0401 (DR4) and related alleles. In contrast, patients whose Lyme arthritis resolves within 3 months postinfection show an increased frequency of HLA–DRB1*1101 (DR11). The aim of this study was to analyze the underlying mechanism by which HLA–DR alleles confer genetic susceptibility or resistance to antibiotic‐refractory Lyme arthritis.MethodsWe generated DR11‐transgenic (DR11‐Tg) mice on a murine MHCII−/− background and compared their immune response to Bb antigens with the response of DR4‐Tg mice after immunization with Bb outer surface protein A (OspA) or infection with live Bb.ResultsT cells from OspA‐immunized and Bb‐infected DR11‐Tg mice had defective production of interferon‐γ as compared with those from DR4‐Tg mice. In contrast, DR11‐Tg mice developed higher titers of anti‐OspA and anti‐Bb antibodies, respectively, than did DR4‐Tg mice. Consistent with this observation, we found that the Bb‐infected DR11‐Tg mice had a decreased spirochetal burden as compared with the DR4‐Tg mice, as measured by quantitative polymerase chain reaction.ConclusionThis study provides direct evidence that in the presence of HLA–DR11, the immune response against Bb antigens is directed toward a protective antibody response. In contrast, an inflammatory Th1 response is induced in the presence of DR4. These observations offer an explanation for the differential genetic susceptibility of DR4+ and DR11+ individuals to the development of chronic Lyme arthritis and, eventually, the progression to antibiotic‐refractory Lyme arthritis.

Key Biomarkers

Symptom Clusters