Congenital heart block (CHB) is associated with transplacental passage of maternal autoantibodies to the ribonucleoproteins (RNP), 48kD SSB/La, and 52kD and 60kD SSA/Ro. The affected mothers might have SLE, or Sjogren's syndrome or might be asymptomatic. Why the developing fetal heart is specially vulnerable to such autoantibodies and why CHB occurs in the children of only a fraction of mothers with the autoantibodies, are not known. Moreover, the putative autoantigens are intracellular RNP particles, therefore it is not clear how they cause damage to the fetal cardiocytes.
In Aim 1, the applicants propose to identify proteins that interact with the Ro and La RNP complexes and are selectively expressed in the human fetal heart. Novel autoantigens unique to fetal heart that are recognized by antisera from mothers of children with CHB might be discovered and a better understanding of the biological function of the Ro and La autoantigens may result from these studies.
In Aim 2, the applicants will determine if the candidate autoantigens associated with autoimmune-CHB come to the surface membrane of cardiocytes during apoptosis thus being accessible to the maternally transmitted autoantibodies.
In Aim 3, the applicants will develop a mouse model of CHB to understand the pathogenesis of the human disease in depth.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR042455-06
Application #
2871610
Study Section
Special Emphasis Panel (ZRG4-GRM (06))
Program Officer
Serrate-Sztein, Susana
Project Start
1994-02-01
Project End
2003-01-31
Budget Start
1999-02-01
Budget End
2000-01-31
Support Year
6
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Hospital for Joint Diseases Ortho Institute
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10003
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

Showing the most recent 10 out of 82 publications