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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Johnson, David R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Upstate Medical University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Lai, Zhi-Wei; Kelly, Ryan; Winans, Thomas et al. (2018) Sirolimus in patients with clinically active systemic lupus erythematosus resistant to, or intolerant of, conventional medications: a single-arm, open-label, phase 1/2 trial. Lancet 391:1186-1196
Perl, Andras (2018) mTOR-dependent autophagy contributes to end-organ resistance and serves as target for treatment in autoimmune disease. EBioMedicine 36:12-13
Minchenberg, Scott Brian; Chaparala, Geeta; Oaks, Zachary et al. (2018) Systemic lupus erythematosus-myasthenia gravis overlap syndrome: Presentation and treatment depend on prior thymectomy. Clin Immunol 194:100-104
Kato, Hiroshi; Perl, Andras (2018) Blockade of Treg Cell Differentiation and Function by the Interleukin-21-Mechanistic Target of Rapamycin Axis Via Suppression of Autophagy in Patients With Systemic Lupus Erythematosus. Arthritis Rheumatol 70:427-438
Doherty, Edward; Perl, Andras (2017) Measurement of Mitochondrial Mass by Flow Cytometry during Oxidative Stress. React Oxyg Species (Apex) 4:275-283
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
Perl, Andras (2016) Editorial: LINEing Up to Boost Interferon Production: Activation of Endogenous Retroviral DNA in Autoimmunity. Arthritis Rheumatol 68:2568-2570
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) Activation of mTOR (mechanistic target of rapamycin) in rheumatic diseases. Nat Rev Rheumatol 12:169-82

Showing the most recent 10 out of 56 publications