title: Matrix metalloproteinase-10 is a target of T and B cell responses that correlate with synovial pathology in patients with antibiotic-refractory Lyme arthritis.
abstract: 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.
authors.affiliation: Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States. Electronic address: jcrowley6@mgh.harvard.edu.
authors.forename: Jameson T
authors.initials: JT
authors.lastname: Crowley
authors.affiliation: Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.
authors.forename: Klemen
authors.initials: K
authors.lastname: Strle
authors.affiliation: Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.
authors.forename: Elise E
authors.initials: EE
authors.lastname: Drouin
authors.affiliation: Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pianta
authors.affiliation: Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.
authors.forename: Sheila L
authors.initials: SL
authors.lastname: Arvikar
authors.affiliation: Center for Biomedical Mass Spectrometry, Boston University School of Medicine, Boston, MA, United States.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Center for Biomedical Mass Spectrometry, Boston University School of Medicine, Boston, MA, United States.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Costello
authors.affiliation: Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.
authors.forename: Allen C
authors.initials: AC
authors.lastname: Steere
mesh_terms: D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D017951:Antigen Presentation; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D025065:Borrelia burgdorferi / Q000276:immunology; D004351:Drug Resistance; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007075:Immunoglobulin M / Q000097:blood / Q000276:immunology; D007150:Immunohistochemistry; D008193:Lyme Disease / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D053506:Matrix Metalloproteinase 10 / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000276:immunology; D010455:Peptides / Q000276:immunology; D013582:Synovial Fluid / Q000276:immunology / Q000378:metabolism; D013583:Synovial Membrane / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001323:Autoantibodies; D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D010455:Peptides; D019278:Matrix Metalloproteinase 3; D053506:Matrix Metalloproteinase 10
keywords: Autoimmunity; Erythema migrans; HLA-DR-presented peptides; Lyme arthritis; MMP-10