Autoimmune arthritis associated with Lyme disease is yet another example where susceptibility to autoimmunity is strongly associated with expression of a specific HLA-DR allele. However, unlike almost all other autoimmune diseases, a causative agent for this autoimmune disease is known. Lyme disease is caused by an infection with Borrelia burgdorferi and the autoimmune arthritis develops as a sequela to this infection. Approximately 10% of infected individuals develop a chronic joint inflammation that resists treatment with antibiotics . This arthritis persists long after B. burgdorferi is detectable in the patient and is believed to be an autoimmune response triggered by molecular mimicry involving a self protein, human leukocyte function-associated antigen 1 (LFA-1), and a bacterial protein, outer surface protein A (OspA), expressed by the infecting organism . Treatment-resistant Lyme arthritis that persists for an extended duration (12-48 months) is strongly associated with the expression of either HLA-DR4 or HLA-DR2 . 57% of the patients that develop Lyme arthritis express HLA-DR4 (DRB1*0401), whereas 75% of the non-HLA-DR4 patients express HLA-DR2.
Humanized mouse models have been instrumental in advancing our understanding of the mechanism of autoimmunity associated with Lyme arthritis. Mice expressing HLA-DRB1*0401 as a transgene have been used to identify and characterize the antigenic peptides thought to drive the development of autoimmune arthritis in Lyme disease. In 1994, Steere et al. identified the OspA protein from B. burgdorferi as a primary immunogenic protein that contains an antigenic peptide that binds to HLA-DRB1*0401, and is recognized by T-cell lines developed from patients with treatment-resistant arthritis [69, 70, 72, 73]. Using HLA-DRB1*0401 transgenic mice for in vivo studies, these investigators were able to identify specific epitopes of OspA that stimulated CD4+ T-cells restricted to this DR4 subtype. Of the peptides identified, the OspA(165-173) peptide bound with the highest affinity to DR4. While the identification of this antigenic peptide was informative, how an immune response to this peptide or the OspA protein led to the development of autoimmune arthritis was still unknown. Steere and colleagues proposed that molecular mimicry between the OspA protein and a human protein was the mechanism by which autoimmunity developed, and identified a human protein, LFA-1, that contained a similar peptide sequence, LFA-1(326-343). When tested with T-cells from the synovial fluid of patients with treatment-resistant Lyme arthritis, this LFA-1 peptide was found to stimulate these T-cells . The association between OspA and LFA-1 was confirmed by Trollmo et al. who discovered CD4+ T-cells reactive for both OspA and LFA-1 peptides in both OspA-immunized HLA-DR4 transgenic mice and in human Lyme arthritis patients .
One drawback of this humanized mouse model is that these mice are not susceptible to autoimmune arthritis when they are infected with B. burgdorferi . The obvious explanation for this, based on the molecular mimicry data, is that the sequence of the mouse LFA-1 protein is different from the human LFA-1 protein within the 326-343 region, and this is indeed the case . It would be interesting to see this model of molecular mimicry tested by the production of a mouse model expressing both the DR4 molecule and human LFA-1. If such a mouse model were susceptible to OspA-induced autoimmune arthritis, these data would provide strong evidence of a role for molecular mimicry in B. burgdorferi-mediated autoim-munity.
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