The environmental factors associated with systemic lupus erythematosus (SLE) include Epstein-Barr virus (EBV). Once infected, EBV is well known to persist in all human hosts for life. We believe that novel approaches to the detection of this pathogen and to the assessment of the host response to this pathogen are warranted. Among the most interesting viral products is Epstein-Barr virus Nuclear Antigen-l (EBNAl), which contains a peptide sequence that inhibits antigen presentation and class I HLA-dependent cytotoxic T cell responses. Preliminary data show that EBNA-l also contains sequences that appear to be differentially bound by SLE as opposed to normal sera. We propose to study SLE from the perspectives of the anti-EBNA-l humoral immune response, of EBNA-l expression in B cells, and of EBNA-l sequence variants. We plan to use the Early-lmmediate antigen-l (El-l) of cytomegalovirus (CMV) as a control antigen. This project is a competitive renewal for AI 31584 for year 09. Work in the current funding period is focused upon serology before diagnosis of SLE, made possible by over 20,000,000 sera in the Army Navy Serum Bank. The results to date from the first 130 SLE patients and 520 controls have established that autoimmune serological changes are present years before clinical manifestations and that autoantibody specificities vary greatly with regard to their temporal relationship to illness. Because of the high EBV infection rate among women and African-American men, the temporal relationship between EBV infection and SLE could not be tested.
The final aim of this competitive renewal is to continue accruing the appropriate military cases and controls to provide sufficient power to test the hypotheses that EBV infection precedes clinical onset of SLE and that anti-EBNA-l precedes the onset of lupus autoantibodies. Establishing the role of ubiquitous agents, such as EBV, in chronic disease is especially difficult. In this situation, specific associations of SLE with immune response variations, with viral gene product expression, and with viral variants will be sought in an effort to explore particular mechanisms of pathogenesis as a strategy to more convincingly implicate EBV in the etiology of SLE.
|Liu, Ke; Kurien, Biji T; Zimmerman, Sarah L et al. (2016) X Chromosome Dose and Sex Bias in Autoimmune Diseases: Increased Prevalence of 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome. Arthritis Rheumatol 68:1290-1300|
|Kottyan, Leah C; Zoller, Erin E; Bene, Jessica et al. (2015) The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share. Hum Mol Genet 24:582-96|
|Morris, D L; Fernando, M M A; Taylor, K E et al. (2014) MHC associations with clinical and autoantibody manifestations in European SLE. Genes Immun 15:210-7|
|Molineros, Julio E; Maiti, Amit K; Sun, Celi et al. (2013) Admixture mapping in lupus identifies multiple functional variants within IFIH1 associated with apoptosis, inflammation, and autoantibody production. PLoS Genet 9:e1003222|
|Dozmorov, Igor; Dominguez, Nicolas; Sestak, Andrea L et al. (2013) Evidence of dynamically dysregulated gene expression pathways in hyperresponsive B cells from African American lupus patients. PLoS One 8:e71397|
|James, Judith A; Robertson, Julie M (2012) Lupus and Epstein-Barr. Curr Opin Rheumatol 24:383-8|
|Niewold, Timothy B; Kelly, Jennifer A; Kariuki, Silvia N et al. (2012) IRF5 haplotypes demonstrate diverse serological associations which predict serum interferon alpha activity and explain the majority of the genetic association with systemic lupus erythematosus. Ann Rheum Dis 71:463-8|
|Hughes, Travis; Adler, Adam; Kelly, Jennifer A et al. (2012) Evidence for gene-gene epistatic interactions among susceptibility loci for systemic lupus erythematosus. Arthritis Rheum 64:485-92|
|Hughes, Travis; Adler, Adam; Merrill, Joan T et al. (2012) Analysis of autosomal genes reveals gene-sex interactions and higher total genetic risk in men with systemic lupus erythematosus. Ann Rheum Dis 71:694-9|
|Castillejo-López, Casimiro; Delgado-Vega, Angélica M; Wojcik, Jerome et al. (2012) Genetic and physical interaction of the B-cell systemic lupus erythematosus-associated genes BANK1 and BLK. Ann Rheum Dis 71:136-42|
Showing the most recent 10 out of 109 publications