Rouse, J. R.; Danner, R.; Wahhab, A.; Pereckas, M.; McClune, M.; Steere, A. C.; Strle, K.; Jutras, B. L.; Lochhead, R. B.

Background: HLA-DR-expressing fibroblast-like synoviocytes (FLS) are a prominent cell type in synovial tissue in chronic inflammatory forms of arthritis. We recently showed that peptides from several extracellular matrix (ECM) proteins, including fibronectin (FN1), were immunogenic CD4+ T cell epitopes in patients with postinfectious Lyme arthritis (LA). However, the role of FLS in presentation of these T cell epitopes remains uncertain. Methods: Primary LA FLS and primary murine FLS stimulated with interferon gamma (IFN{gamma}), Borrelia burgdorferi, and/or B. burgdorferi peptidoglycan (PG) were assessed for properties associated with antigen presentation. HLA-DR-presented peptides from stimulated LA FLS were identified by immunopeptidomics analysis. OT-II T cells were cocultured with stimulated murine FLS in the presence of OT-II antigen to determine the potential of FLS to act as inducible antigen presenting cells (APC). Results: FLS expressed HLA-DR molecules within inflamed synovial tissue and tendons from patients with post-infectious LA patients in situ. MHC class II and costimulatory molecules were expressed by FLS following in vitro stimulation with IFN{gamma} and B. burgdorferi and presented both foreign and self MHC-II peptides, including T cell epitopes derived from two Lyme autoantigens fibronectin (FN1) and endothelial cell growth factor (ECGF). Stimulated murine FLS induced proliferation of naive OT-II CD4+ T cells, particularly when FLS were stimulated with both IFN{gamma} and PG. Conclusions: MHC-II+ FLS are inducible APCs that can induce CD4+ T cell activation and can present Lyme autoantigens derived from ECM proteins, thereby amplifying tissue-localized autoimmune CD4+ T cell responses in LA.