One of the central questions in autoimmunity is whether autoantibodies are directly responsible for tissue injury. Complete congenital heart block, a serious and permanent manifestation of neonatal lupus, is of special importance since it serves as a model for passively acquired disease expressed in a fetus. Other manifestations of this syndrome include transient skin and hematologic abnormalities. Neonatal disease is attributed to the transplacental passage of maternal IgG autoantibodies reactive with the soluble ribonucleoproteins of the SSA/Ro-SSB/La system, from the mother affected with an autoimmune disease. Most intriguingly, there are no detectable abnormalities in maternal cardiac function despite exposure to the identical circulating antibodies. Although antibodies to components of the SSA/Ro-SSB/La ribonucleoprotein complex are essential to the development of CCHB in an offspring, another mechanism must be operative which converts risk to disease, since not all mothers with these autoantibodies have affected offspring. Two categorical approaches will be emphasized in this proposal, developmental and environmental.
Specific Aim I is based on the hypothesis that inductive events in utero alter the gene expression of SSA/Ro and/or SSB/La and promote surface expression of these candidate proteins uniquely during cardiac development. Human fetal and adult cardiac cells will be cultured and evaluated for SSA/Ro-SSB/La gene transcription and surface protein expression by northern blotting, ribonuclease protection assay, indirect surface immunofluorescence, immunoblotting and radiolabelled immunoprecipitation, under conditions of stress and in the presence of various gestational hormones. Environmental factors such as the effect of adenovirus infection will also be studied which may potentially explain why not all mothers with anti-SSA/Ro or SSB/La antibodies have affected children. An alternative hypothesis to be examined is that another autoantigen related to the SSA/Ro-SSB/La system is present in the fetal and not the adult heart. This will be approached by DNA hybridization cloning of cDNAs from heart tissue. A compounding problem may be the absence or decreased expression of complement regulatory surface molecules on the surface of fetal cardiac cells and this will be examined in the Specific Aim II. We will continue our experiments to define antigenic determinants on the 52kD SSA/Ro protein in Specific Aim III, to localize a region recognized by sera from mothers whose children have CCHB. The goal of our proposal is to further define the pathogenetic mechanisms of neonatal lupus using our current knowledge in the molecular biology of the SSA/Ro-SSB/La antigens and our extensive panel of clinical samples.

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National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
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Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
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Hospital for Joint Diseases Ortho Institute
New York
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Pelzek, Adam J; Grönwall, Caroline; Rosenthal, Pamela et al. (2017) Persistence of Disease-Associated Anti-Citrullinated Protein Antibody-Expressing Memory B Cells in Rheumatoid Arthritis in Clinical Remission. Arthritis Rheumatol 69:1176-1186
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