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.
|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|
|Izmirly, Peter; Saxena, Amit; Buyon, Jill P (2017) Progress in the pathogenesis and treatment of cardiac manifestations of neonatal lupus. Curr Opin Rheumatol 29:467-472|
|Grönwall, Caroline; Clancy, Robert M; Getu, Lelise et al. (2016) Modulation of natural IgM autoantibodies to oxidative stress-related neo-epitopes on apoptotic cells in newborns of mothers with anti-Ro autoimmunity. J Autoimmun 73:30-41|
|Brito-Zerón, Pilar; Izmirly, Peter M; Ramos-Casals, Manuel et al. (2015) The clinical spectrum of autoimmune congenital heart block. Nat Rev Rheumatol 11:301-12|
|Saxena, Amit; Izmirly, Peter M; Mendez, Barbara et al. (2014) Prevention and treatment in utero of autoimmune-associated congenital heart block. Cardiol Rev 22:263-7|
|Reed, Joanne H; Jain, Manish; Lee, Kristen et al. (2013) Complement receptor 3 influences toll-like receptor 7/8-dependent inflammation: implications for autoimmune diseases characterized by antibody reactivity to ribonucleoproteins. J Biol Chem 288:9077-83|
|Briassouli, Paraskevi; Halushka, Marc K; Reed, Joanne H et al. (2013) A central role of plasmin in cardiac injury initiated by fetal exposure to maternal anti-Ro autoantibodies. Rheumatology (Oxford) 52:1448-53|
|Ramos, Paula S; Marion, Miranda C; Langefeld, Carl D et al. (2012) Brief report: enrichment of associations in genes with fibrosis, apoptosis, and innate immunity functions with cardiac manifestations of neonatal lupus. Arthritis Rheum 64:4060-5|
|Saxena, Amit; McDonnell, Erin; Ramos, Paula S et al. (2012) Preferential transmission of genetic risk variants of candidate loci at 6p21 from asymptomatic grandparents to mothers of children with neonatal lupus. Arthritis Rheum 64:931-9|
|Phoon, Colin K L; Kim, Mimi Y; Buyon, Jill P et al. (2012) Finding the ""PR-fect"" solution: what is the best tool to measure fetal cardiac PR intervals for the detection and possible treatment of early conduction disease? Congenit Heart Dis 7:349-60|
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