title: Delineation of autoantibody repertoire through differential proteogenomics in hepatitis C virus-induced cryoglobulinemia.
abstract: Antibodies cross-reactive to pathogens and autoantigens are considered pivotal in both infection control and accompanying autoimmunity. However, the pathogenic roles of autoantibodies largely remain elusive without a priori knowledge of disease-specific autoantigens. Here, through a novel quantitative proteogenomics approach, we demonstrated a successful identification of immunoglobulin variable heavy chain (VH) sequences highly enriched in pathological immune complex from clinical specimens obtained from a patient with hepatitis C virus-induced cryoglobulinemia (HCV-CG). Reconstructed single-domain antibodies were reactive to both HCV antigens and potentially liver-derived human proteins. Moreover, over the course of antiviral therapy, a substantial "de-evolution" of a distinct sub-repertoire was discovered, to which proteomically identified cryoprecipitation-prone autoantibodies belonged. This sub-repertoire was characterized by IGHJ6*03-derived, long, hydrophobic complementarity determining region (CDR-H3). This study provides a proof-of-concept of de novo mining of autoantibodies and corresponding autoantigen candidates in a disease-specific context in human, thus facilitating future reverse-translational research for the discovery of novel biomarkers and the development of antigen-specific immunotherapy against various autoantibody-related disorders.
authors.affiliation: Department of Infectious Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Ogishi
authors.affiliation: Department of Infectious Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yotsuyanagi
authors.affiliation: Department of Infectious Control and Prevention, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Kyoji
authors.initials: K
authors.lastname: Moriya
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Koike
mesh_terms: D001323:Autoantibodies / Q000276:immunology*; D003449:Cryoglobulinemia / Q000276:immunology* / Q000821:virology*; D016174:Hepacivirus / Q000276:immunology; D006526:Hepatitis C / Q000276:immunology* / Q000628:therapy; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000276:immunology; D000071696:Proteogenomics / Q000379:methods*
chemical_list: D001323:Autoantibodies; D007143:Immunoglobulin Heavy Chains