Many autoimmune diseases are linked to variants of HLA (immunity) genes such as those encoding the MHC class II complex. Antibiotic-refractory Lyme arthritis is associated with MHC class II variants that are able to bind to fragments of the B. burgdorferi protein OspA (outer surface protein A) encompassing amino acid residues 165 through 173. Antigen-presenting cells whose MHC class II molecules display OspA165-173 peptides on their surface stimulate T cells that recognize the OspA peptide. How OspA165-173-reactive T cells cause autoimmunity has been an area of intensive research, yet a clear answer has not emerged.
One potential pathway to autoimmunity is molecular mimicry, in which a cross-reactive host protein in the joint continues to stimulate OspA165-173-specific T cells even after the eradication of B. burgdorferi by antibiotics. Although the simplicity of the molecular mimicry model is appealing, exhaustive efforts to find a cross-reactive autoantigen that stimulates OspA165-173-specific T cells have failed. Moreover, levels of OspA165-173-reactive T cells decline soon after initiation of antibiotic therapy despite continuing arthritis following treatment. Thus, chronic arthritis does not seem to involve molecular mimicry driven by a cross reaction between the OspA165-173 epitope and a self-antigen in the joint. It is possible that molecular mimicry involves another B. burgdorferi antigen that is able to bind the MHC class II variants found in genetically susceptible individuals.
Other potential routes to autoimmunity in antibiotic-refractory Lyme arthritis patients emphasize the role of the high levels of key proinflammatory cytokines and chemokines found in their joint fluid, levels even higher than those found in treatment-responsive patients prior to initiation of antibiotic therapy:
- In a model known as bystander activation, the immune response to OspA165-173 (or another B. burgdorferi antigen) causes an excessive inflammatory response that activates other T cells that react to autoantigens in the joint.
- The immune system is unable to turn off the intense inflammatory response associated with OspA165-173 after the spirochetes are cleared from the joint.
The authors found that all 7 Lyme arthritis patients infected with RST1 strains had the antibiotic-refractory form. Joint fluid was obtained after antibiotic treatment from 5 of the 7 patients; all 5 samples tested negative for B. burgdorferi DNA by PCR. In contrast, 2 of 6 and 3 of 4 infected with RST2 and RST3 strains, respectively, were successfully treated with antibiotics (see the table below from the Jones et al. 2009 article). A larger number of samples is needed to demonstrate that the difference observed between RST1 and RST2 strains is statistically significant, but there is a clear trend towards RST1 infections having the greatest association with antibiotic treatment failure and RST3 having the least, with RST2 having an intermediate effect. The duration of arthritis also depended on the infecting RST strain.
How do RST1 strains cause arthritis to persist even after the apparent eradication of the spirochetes by the recommended course of antibiotics? The investigators proposed that RST1 strains provoke a stronger inflammatory response in the joint than RST2 or RST3 strains. Coupled with an immune response to OspA165-173 in genetically susceptible patients, this could cause inflammation to continue at high levels even after elimination of the spirochetes from the joints. RST1 strains may be more likely than the other genotypes to spark intense joint inflammation even in patients who are not genetically prone to antibiotic-refractory arthritis.
In future studies, it would be interesting to see if proinflammatory cytokine levels are related to the RST type that infects the joint. Ultimately, researchers need to identify the B. burgdorferi gene or genes whose variation among the RSTs causes the different treatment outcomes of Lyme arthritis.
Jones, K.L., McHugh, G.A., Glickstein, L.J., & Steere, A.C. (2009). Analysis of Borrelia burgdorferi genotypes in patients with Lyme arthritis: High frequency of ribosomal RNA intergenic spacer type 1 strains in antibiotic-refractory arthritis
Arthritis & Rheumatism, 60 (7), 2174-2182 DOI: 10.1002/art.24812
Drouin E.E., Glickstein, L., Kwok, W.W., Nepom, G.T., and Steere, A.C. (2008). Human homologues of a Borrelia T cell epitope associated with antibiotic-refractory Lyme arthritis. Molecular Immunology 45(1):180-189. DOI: 10.1016/j.molimm.2007.04.017
Kannian, P., Drouin, E.E., Glickstein, L., Kwok, W.W., Nepom, G.T., and Steere A.C. (2007). Decline in the frequencies of Borrelia burgdorferi OspA161-175-specific T cells after antibiotic therapy in HLA-DRB1*0401-positive patients with antibiotic-responsive or antibiotic-refractory Lyme arthritis. The Journal of Immunology 179(9):6336-6342.
Shin J.J., Glickstein, L.J., and Steere, A.C. (2007). High levels of inflammatory chemokines and cytokines in joint fluid and synovial tissue throughout the course of antibiotic-refractory Lyme arthritis. Arthritis & Rheumatism 56(4):1325-1335. DOI: 10.1002/art.2241
Steere, A.C., Klitz, W., Drouin, E.E., Falk, B.A., Kwok, W.W., Nepom, G.T., and Baxter-Lowe, L.A. (2006). Antibiotic-refractory Lyme arthritis is associated with HLA-DR molecules that bind a Borrelia burgdorferi peptide. The Journal of Experimental Medicine 203(4):961-971. DOI: 10.1084/jem.20052471