Systemic lupus erythematosus (SLE) is a chronic inflammatory disease characterized by circulating antinuclear autoantibodies and dysfunction of T and B lymphocytes. Both genetic and environmental factors are believed to influence development of the disease. Common lupus autoantigens show potent immunological cross-reactivities with proteins of viruses and endogenous retroviral elements. Autoantibodies to HRES-1/p28, a 28 kD nuclear protein encoded by the HRES-1 human endogenous retrovirus, were found by several laboratories in up to half of the patients with SLE and overlap syndromes (OLS). We documented molecular mimicry between HRES-1, another nuclear autoantigen, the 70K component of U1 snRNP, and infectious viral core proteins. Analysis of molecular mimicries may provide clues to the identity of viral antigens responsible for triggering cross- reactive immune responses. We detected and cloned the HRES-1 human endogenous retrovirus and mapped it to chromosome 1 at q42. We identified polymorphic genotypes in the long terminal repeat (LTR)/promoter region of the HRES-1 genomic locus and revealed their association with SLE. HRES-1 is centrally located at 1q42 with respect to microsatellite markers associated with disease susceptibility. Thus, HRES-1 or a gene in linkage disequilibrium with this genomic locus may influence autoimmunity in SLE. Genetic variations of the HRES-1 LTR may be linked to a high degree of spontaneous and 5-azacytidine-inducible fragility of the 1q42 chromosomal region. 5-azacytidine, a demethylating agent, capable of triggering autoreactivity of T cells, may influence structure and activity of the HRES-1 LTR.
The specific aims will test the hypotheses that (i) identification of HRES-1 autoepitopes with regions of homology to viral proteins and other autoantigens may pinpoint pathogens responsible for initiating autoreactivities, (ii) genetic composition of the HRES-1 LTR directly or indirectly influences development of SLE, and (iii) genotypes of the LTR region determine promoter activity and expression of HRES-1/p28.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI048079-03
Application #
6511558
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Johnson, David R
Project Start
2000-07-01
Project End
2005-05-31
Budget Start
2002-07-01
Budget End
2003-05-31
Support Year
3
Fiscal Year
2002
Total Cost
$215,603
Indirect Cost
Name
Upstate Medical University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
058889106
City
Syracuse
State
NY
Country
United States
Zip Code
13210
Kato, Hiroshi; Perl, Andras (2017) The IL-21-mTOR axis blocks treg differentiation and function by suppression of autophagy in patients with systemic lupus erythematosus. Arthritis Rheumatol :
Perl, Andras (2017) Review: Metabolic Control of Immune System Activation in Rheumatic Diseases. Arthritis Rheumatol 69:2259-2270
Oaks, Zachary; Winans, Thomas; Huang, Nick et al. (2016) Activation of the Mechanistic Target of Rapamycin in SLE: Explosion of Evidence in the Last Five Years. Curr Rheumatol Rep 18:73
Buskiewicz, Iwona A; Montgomery, Theresa; Yasewicz, Elizabeth C et al. (2016) Reactive oxygen species induce virus-independent MAVS oligomerization in systemic lupus erythematosus. Sci Signal 9:ra115
Perl, Andras (2016) Editorial: LINEing Up to Boost Interferon Production: Activation of Endogenous Retroviral DNA in Autoimmunity. Arthritis Rheumatol 68:2568-2570
Perl, Andras (2016) Activation of mTOR (mechanistic target of rapamycin) in rheumatic diseases. Nat Rev Rheumatol 12:169-82
Oaks, Zachary; Winans, Thomas; Caza, Tiffany et al. (2016) Mitochondrial Dysfunction in the Liver and Antiphospholipid Antibody Production Precede Disease Onset and Respond to Rapamycin in Lupus-Prone Mice. Arthritis Rheumatol 68:2728-2739
Perl, Andras (2015) mTOR activation is a biomarker and a central pathway to autoimmune disorders, cancer, obesity, and aging. Ann N Y Acad Sci 1346:33-44
Lai, Zhi-wei; Marchena-Mendez, Ivan; Perl, Andras (2015) Oxidative stress and Treg depletion in lupus patients with anti-phospholipid syndrome. Clin Immunol 158:148-52
Joseph, Nidhin; Zhang-James, Yanli; Perl, Andras et al. (2015) Oxidative Stress and ADHD: A Meta-Analysis. J Atten Disord 19:915-24

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