HLA-DR alleles determine responsiveness to Borrelia burgdorferi antigens in a mouse model of self-perpetuating arthritis.
OBJECTIVE
Arthritis 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.


METHODS
We 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.


RESULTS
T cells from OspA-immunized and Bb-infected DR11-Tg mice had defective production of interferon-gamma 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.


CONCLUSIONS
This 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.
Iliopoulou
Bettina Panagiota
BP
Tufts University, Boston, Massachusetts 02111, USA.
Guerau-de-Arellano
Mireia
M
Huber
Brigitte T
BT
D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology; D000954:Antigens, Surface / Q000276:immunology; D001170:Arthritis, Infectious / Q000276:immunology / Q000382:microbiology*; D001425:Bacterial Outer Membrane Proteins / Q000276:immunology; D001428:Bacterial Vaccines / Q000276:immunology; D025065:Borrelia burgdorferi / Q000276:immunology*; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens / Q000235:genetics* / Q000276:immunology; D059810:HLA-DR Serological Subtypes; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008074:Lipoproteins / Q000276:immunology; D008193:Lyme Disease / Q000150:complications* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology
D000907:Antibodies, Bacterial; D000954:Antigens, Surface; D001425:Bacterial Outer Membrane Proteins; D001428:Bacterial Vaccines; D006684:HLA-DR Antigens; D059810:HLA-DR Serological Subtypes; C080766:HLA-DR11 antigen; D008074:Lipoproteins; C072045:OspA protein; D007371:Interferon-gamma