The majority of patients diagnosed with rheumatoid arthritis (RA) have developed autoantibodies against neoepitopes in proteins that have undergone post-translational modification, e.g., citrullination or carbamylation. There is growing evidence of their molecular relevance and their potential utility to improve diagnosis, patient stratification, and prognosis for precision medicine. Autoantibodies reacting to native proteins may also have a role in RA pathogenesis, however, their reactivity patterns remain much less studied. We hypothesized that a high-density protein array technology could shed light onto the normal and disease-related autoantibodies produced in healthy and RA patient subgroups. In an exploratory study, we investigated the global reactivity of autoantibodies in plasma pools from 15 anti-cyclic citrullinated peptide (CCP)-positive and 10 anti-CCP-negative RA patients and 10 healthy donors against more than 1600 native and unmodified human proteins using a high-density protein array. A total of 102 proteins recognized by IgG autoantibodies were identified, hereof 86 were recognized by antibodies from CCP-positive RA patients and 76 from anti-CCP-negative RA patients, but not by antibodies from healthy donors. Twenty-four of the identified autoantigens have previously been identified in synovial fluid. Multiple human proteins in their native conformation are recognized by autoantibodies from anti-CCP-positive as well as anti-CCP-negative RA patients.

Department of Clinical Immunology Aalborg University Hospital 9000 Aalborg Denmark

Department of Clinical Medicine Aalborg University 9000 Aalborg Denmark

Department of Health Science and Technology Aalborg University 9220 Aalborg Denmark

Department of Integrative Biomedical Sciences and Institute of Infectious Disease and Molecular Medicine University of Cape Town Cape Town 7700 South Africa

Institute for Inflammation Research Center for Rheumatology and Spine Diseases Copenhagen University Hospital Rigshospitalet 2100 Copenhagen Denmark

Institute of Rheumatology and Department of Rheumatology 1st Faculty of Medicine Charles University 121 08 Prague Czech Republic

Sengenics Corporation Pte Ltd Singapore 409051 Singapore

Sino Danish Center for Education and Research University of Chinese Academy of Sciences 380 Huaibeizhuang Huairou district Beijing 100049 China

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Applicability of Small-Molecule Inhibitors in the Study of Peptidyl Arginine Deiminase 2 (PAD2) and PAD4

Identification of potential autoantigens in anti-CCP-positive and anti-CCP-negative rheumatoid arthritis using citrulline-specific protein arrays