title: Ro52 autoantibodies arise from self-reactive progenitors in a mother of a child with neonatal lupus.
abstract: The detection of cardiac conduction defects in an 18-24 week old foetus in the absence of structural abnormalities predicts with near certainty the presence of autoantibodies against 60kD and 52kD SSA/Ro in the mother regardless of her health status. Previous studies have emphasized these autoantibodies as key mediators of tissue injury. The aim of this study was to focus on the anti-Ro52 response to determine whether these autoantibodies originate from progenitors that are inherently self-reactive or from B-cells that acquire self-reactivity during an immune response. We traced the evolution of two anti-Ro52 autoantibodies isolated from circulating IgG1-switched B-cells from an asymptomatic mother of a child with third degree congenital heart block. The autoantibodies were expressed as their immune form and as pre-immune ancestors by reverting somatic mutations to germline sequence. The reactivity of pre-immune and immune antibodies for Ro52, Ro60, La and DNA was measured. Both anti-Ro52 autoantibodies exhibited a low frequency of somatic mutations (3-4%) and utilised the same heavy and light chain genes but represented distinct clones based on differing complementarity determining region sequences. Pre- and post-immune antibodies showed specific binding to Ro52 with no measurable reactivity for other autoantigens. Ro52 binding was higher for immune antibodies compared to pre-immune counterparts demonstrating that autoreactivity was enhanced by affinity maturation. These data indicate that Ro52 reactivity is an intrinsic property of the germline antibody repertoire in a mother with a pathogenic antibody defined by cardiac injury in her offspring, and implies defects in both central and peripheral tolerance mechanisms.
authors.affiliation: Dept. Immunology, Garvan Institute of Medical Research, Sydney, Australia. Electronic address: j.reed@garvan.org.au.
authors.forename: Joanne H
authors.initials: JH
authors.lastname: Reed
authors.affiliation: Dept. Pathology, New York University School of Medicine, New York, USA.
authors.forename: Miroslaw K
authors.initials: MK
authors.lastname: Gorny
authors.affiliation: Dept. Pathology, New York University School of Medicine, New York, USA.
authors.forename: Liuzhe
authors.initials: L
authors.lastname: Li
authors.affiliation: Dept. Pharmacology, New York University School of Medicine, New York, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Cardozo
authors.affiliation: Dept. Medicine, Division of Rheumatology, New York University School of Medicine, New York, USA.
authors.forename: Jill P
authors.initials: JP
authors.lastname: Buyon
authors.affiliation: Dept. Medicine, Division of Rheumatology, New York University School of Medicine, New York, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Clancy
mesh_terms: D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000276:immunology; D001323:Autoantibodies / Q000097:blood / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D001327:Autoimmune Diseases / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy / Q000276:immunology; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D007223:Infant; D008180:Lupus Erythematosus, Systemic / Q000151:congenital; D018811:Maternal Exposure; D009035:Mothers; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology* / Q000378:metabolism; D012261:Ribonucleoproteins / Q000276:immunology*; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics; D000099207:SS-A Antigen
chemical_list: D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D012261:Ribonucleoproteins; D000099207:SS-A Antigen