PROVIDED. Systemic lupus erythematosus (SLE) is an autoimmune disease with significant morbidity due to end organ damage mediated by autoantibodies that target nucleic acid-containing immune complexes, along with inflammatory cells and their products. While important observations related to immune regulation and effector mechanisms in SLE have suggested some therapeutic approaches to inhibit autoantibody production and abrogate tissue damage, it would be highly desirable to intervene at the afferent stage of SLE, when autoimmunity is developing. Unfortunately, less information is available regarding these early events. Recent data have documented prominent overexpression of mRNAs encoded by genes regulated by interferons (IFNs) in peripheral blood mononuclear cells from lupus patients. In view of the pleiotropic effects of IFNs on diverse aspects of immune function, many of which could contribute to generation of autoimmunity and inflammation, it would be of high importance to determine the upstream triggers and intracellular pathways that account for activation of the type I IFN (IFN-a) target genes in SLE. In that regard, our data indicate a potential role for RNA in the activation of the IFN pathway in SLE patients. The proposed research will focus on an analysis of the triggers and pathways that account for the increased expression of IFN-a and its downstream target genes. The research will address the hypothesis that activation of gene expression through an RNA-dependent Toll-like receptor (TLR) pathway is an important mechanism of IFN pathway activation, and altered immune system activation, in SLE.
The specific aims are: 1) To identify the TLR pathways that mediate IFN expression in SLE;2) To study the stimuli for TLR pathway activation in SLE;3) To characterize the downstream targets of TLR pathway activation in SLE;and 4) To study the response of SLE lymphocytes to IFN. Elucidation of this important pathway should lead to more targeted modulation of disease mediators in systemic autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI059893-05
Application #
7752864
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Johnson, David R
Project Start
2006-01-15
Project End
2011-12-31
Budget Start
2010-01-01
Budget End
2011-12-31
Support Year
5
Fiscal Year
2010
Total Cost
$400,787
Indirect Cost
Name
Hospital for Special Surgery
Department
Type
DUNS #
622146454
City
New York
State
NY
Country
United States
Zip Code
10021
Mavragani, Clio P; Nezos, Adrianos; Sagalovskiy, Irina et al. (2017) Defective regulation of L1 endogenous retroelements in primary Sjogren's syndrome and systemic lupus erythematosus: Role of methylating enzymes. J Autoimmun :
Mavragani, Clio P; Sagalovskiy, Irina; Guo, Qiu et al. (2016) Expression of Long Interspersed Nuclear Element 1 Retroelements and Induction of Type I Interferon in Patients With Systemic Autoimmune Disease. Arthritis Rheumatol 68:2686-2696
Nezos, Adrianos; Gravani, Fotini; Tassidou, Anna et al. (2015) Type I and II interferon signatures in Sjogren's syndrome pathogenesis: Contributions in distinct clinical phenotypes and Sjogren's related lymphomagenesis. J Autoimmun 63:47-58
Crow, Mary K; Olferiev, Mikhail; Kirou, Kyriakos A (2015) Targeting of type I interferon in systemic autoimmune diseases. Transl Res 165:296-305
Crow, Mary K (2014) Type I interferon in the pathogenesis of lupus. J Immunol 192:5459-68
Crow, Mary K (2014) Advances in understanding the role of type I interferons in systemic lupus erythematosus. Curr Opin Rheumatol 26:467-74
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
Pothlichet, Julien; Niewold, Timothy B; Vitour, Damien et al. (2011) A loss-of-function variant of the antiviral molecule MAVS is associated with a subset of systemic lupus patients. EMBO Mol Med 3:142-52
Crow, Mary K (2010) Interferon-alpha: a therapeutic target in systemic lupus erythematosus. Rheum Dis Clin North Am 36:173-86, x
Kariuki, Silvia N; Franek, Beverly S; Kumar, Akaash A et al. (2010) Trait-stratified genome-wide association study identifies novel and diverse genetic associations with serologic and cytokine phenotypes in systemic lupus erythematosus. Arthritis Res Ther 12:R151

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