Matrix metalloproteinase-10 is a target of T and B cell responses that correlate with synovial pathology in patients with antibiotic-refractory Lyme arthritis

• MMP-10 is a target of T and B cell responses in a subset of patients with Lyme arthritis.
• The presence of MMP-10 autoantibodies correlated with clinical features in patients with erythema migrans.
• In Lyme arthritis patients, autoantibody responses were specific for MMP-10 and not MMP-3.
• Magnitude of MMP-10 autoantibody responses correlated with disease specific pathology.

Infection-induced autoimmunity is thought to be a contributing factor in antibiotic-refractory Lyme arthritis, but studies of autoimmunity have been hindered by difficulty in identifying relevant autoantigens. We developed a novel approach that begins with the identification of T cell epitopes in synovial tissue using tandem mass spectrometry. Herein, we identified an immunogenic HLA-DR-presented peptide (T cell epitope) derived from the source protein matrix metalloproteinase-10 (MMP-10) from the synovium of a patient with antibiotic-refractory arthritis. This finding provided a bridge for the identification of autoantibody responses to MMP-10, the “first autoimmune hit” in a subgroup of patients with erythema migrans, the initial skin lesion of the infection. Months later, after priming of the immune response to MMP-10 in early infection, a subset of patients with antibiotic-responsive or antibiotic-refractory arthritis had MMP-10 autoantibodies, but only patients with antibiotic-refractory arthritis had both T and B cell responses to the protein, providing evidence for a “second autoimmune hit”. Further support for a biologically relevant autoimmune event was observed by the positive correlation of anti-MMP-10 autoantibodies with distinct synovial pathology. This experience demonstrates the power of new, discovery-based methods to identify relevant autoimmune responses in chronic inflammatory forms of arthritis.