Systemic lupus erythematosus (SLE) is a chronic inflammatory disease characterized by circulating antinuclear autoantibodies and the dysfunction of T and B lymphocytes. Both genetic and environmental factors are believed to influence the development of the disease. We detected and cloned the HRES-1 human endogenous retrovirus, mapped it to chromosome 1 at q42, newly identified six haplotypes in the long terminal repeat (LTR), and revealed an association of polymorphic HindIII653C-containing alleles with SLE. A newly discovered 2,986-base antisense transcript encodes a 24 kD protein, HRES-1/Rab4, that regulates surface expression of CD4, and, to a lesser extent, expression of the transferrin receptor (TFR) through endosome recycling. The HRES-1 LTR serves as an enhancer of Rab4 expression and the lupus-associated HindIII653/rs451401 polymorhism influences transcription factor binding to the LTR. Thus, the HRES-1 locus may influence autoimmunity in SLE through expression of HRES-1/Rab4. Over-expression of HRES-1/Rab4 reduces surface expression of CD4 by inhibition of endocytic recycling and targets CD4 for lysosomal degradation, while dominant-negative HRES-1/Rab4S27N has the opposite effect both in Jurkat cells and peripheral blood T cells. HRES-1/Rab4 and CD4 protein levels inversely correlate both in healthy and lupus peripheral blood lymphocytes (PBL). CD4 protein levels are reduced, while HRES-1/Rab4 expression is increased in lupus T cells having at least one HindIII653C in the HRES-1 LTR. CD4 plays essential roles in formation of the immunological synapse (IS) during normal T-cell activation by a cognate MHC class II peptide complex. The key intracellular transducer of T-cell activation, Lck, is brought to the IS via binding to CD4. TCR6 chain binds to the TFR. Abnormal T-cell responses in SLE have been associated with reduced TCR6 chain and Lck levels in the lipid rafts of the IS. Although the regulatory roles of Rab GTP-ases in endosome trafficking are well recognized, their involvement in T-cell activation is largely unknown.
Under Specific Aim 1, we will test the hypothesis that HRES1/Rab4 regulates the composition of lipid rafts, the assembly of the T-cell synapse, and the functional outcomes of T-cell activation in peripheral blood T cells and Jurkat cells when stimulated with CD3 or superantigen.
Under Specific Aim 2 we will determine the role of increased HRES- 1/Rab4 expression in the altered lipid raft composition of lupus T cells.
Under Specific Aim 3, we will test the hypothesis that the HindIIIG653C allele, alone or in combination with other genetic factors of lupus-associated haplotypes, enhances the expression of HRES-1/Rab4. The proposed studies will establish the role the small GTPase HRES-1/Rab4 in the formation of the IS and, through integrating the genetic factors and mechanisms regulating its expression and activity, advance our understanding of T-cell dysfunction in SLE.

Public Health Relevance

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease that often has debilitating and potentially life-threatening consequences. While the cause of SLE is unknown, both genetic and environmental factors are thought to be involved in the development of the disease. The genetic factors confer susceptibility, while the environmental factors, such as viruses, have been implicated in triggering disease onset or flares. We previously identified the HRES-1 endogenous retrovirus that may have originated from an infectious virus, however, it is now part of the human genetic make-up. Our preliminary results show that a protein product of HRES-1, called HRES- 1/Rab4, regulates the expression and cell surface appearance of an important receptor, CD4, on T lymphocytes. Gene sequence variations, so called polymorphisms, of HRES-1 have been associated with SLE and increased production of the HRES-1/Rab4 protein in patients with SLE. The proposed experiments will test the hypothesis that HRES-1/Rab4 regulates normal functioning of the immune system and will investigate whether the inherited genetic variations of HRES-1 underlie abnormal functioning of the immune system in SLE.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI048079-09
Application #
8306185
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Johnson, David R
Project Start
2000-07-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
9
Fiscal Year
2012
Total Cost
$307,751
Indirect Cost
$111,731
Name
Upstate Medical University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
058889106
City
Syracuse
State
NY
Country
United States
Zip Code
13210
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 (2016) Editorial: LINEing Up to Boost Interferon Production: Activation of Endogenous Retroviral DNA in Autoimmunity. Arthritis Rheumatol 68:2568-2570
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
Talaber, Gergely; Miklossy, Gabriella; Oaks, Zachary et al. (2014) HRES-1/Rab4 promotes the formation of LC3(+) autophagosomes and the accumulation of mitochondria during autophagy. PLoS One 9:e84392
Gilkeson, Gary S; Mashmoushi, Ahmad K; Ruiz, Phillip et al. (2013) Endothelial nitric oxide synthase reduces crescentic and necrotic glomerular lesions, reactive oxygen production, and MCP1 production in murine lupus nephritis. PLoS One 8:e64650
Perl, Andras (2013) Oxidative stress in the pathology and treatment of systemic lupus erythematosus. Nat Rev Rheumatol 9:674-86
Perl, Andras (2012) Oxidative stress and endosome recycling are complementary mechanisms reorganizing the T-cell receptor signaling complex in SLE. Clin Immunol 142:219-22
Caza, Tiffany N; Talaber, Gergely; Perl, Andras (2012) Metabolic regulation of organelle homeostasis in lupus T cells. Clin Immunol 144:200-13

Showing the most recent 10 out of 41 publications