Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by excess production of type I interferon (IFN) and inflammatory cytokines, as well as by a lack of tolerance to self-nucleic acids, especially double stranded DNA (dsDNA). Evidence suggests that both extra-cellular and intracellular DNA stimulates IFN production in SLE. Indeed, Dr. Pascual's group recently found that oxidized mitochondrial DNA (mtDNA) may be a relevant source of extra-cellular DNA in SLE. While this DNA can be internalized by pDCs to trigger endosomal TLR9 activation and production of IFN, whether the same mtDNA stimulates cytosolic sensors in a cell-autonomous manner is unknown. The 3'repair exonuclease 1, known as TREX1, is the main 3'-^5'exonuclease in mammalian cells and degrades both single-stranded DNA (ssDNA) and dsDNA. TREX1 plays a critical role in removing the store of endogenous DNA to avoid inappropriate sensing and IFN production. Mutations in TREX1 lacking DNA nuclease activity result in Aicardi-Goutieres syndrome and SLE. DNA that accumulates in TREX1 deficient cells signals through STING, but little is known about the cytosolic sensor(s) that respond to this accumulation and connect downstream with the STING pathway. Most nucleic acid cytosolic sensors use adaptors to activate the inflammasome response and MAVS or STING to activate an IFN response. Our studies indicate that DDX41 is the critical cytosolic sensor to recognize dsDNA and trigger the IFN host immune response mediated by STING. Other studies indicate that DDX41 as well as IFI16 play little role in sensing self-DNA. In an effort to identify novel sensors recognizing self-DNA, we isolated and characterized DNA-binding proteins in monocytes and found known as well as novel DNA sensors. Among the latter, the apurinic/ apyrimidinic endonuclease 1, APEX1, works downstream of TREX1 and uses the STING pathway to trigger IFN and inflammatory cytokine responses. Based on our findings, we hypothesize that APEX1 is a critical molecule to sense self DNA in autoimmune diseases such as SLE.
Our specific aims will (1) establish the role of APEX1 as a key cytosolic sensor for self-DNA, including mtDNA, in SLE;(2) characterize the role of the APEX1-STING-TBK1 complex in SLE.

Public Health Relevance

The body is equipped to fight microbes by sensing their DNA and RNA as foreign and mounting an immune response against them. In autoimmune diseases such as Lupus, self RNA and DNA are recognized as foreign and trigger unwanted immune and inflammatory responses. Identifying the molecules that sense these self nucleic acids inside the cells will provide important information for better, more relevant therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
2U19AI082715-06
Application #
8732914
Study Section
Special Emphasis Panel (ZAI1)
Project Start
2014-05-01
Project End
2019-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Baylor Research Institute
Department
Type
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75204
Caielli, Simone; Veiga, Diogo Troggian; Balasubramanian, Preetha et al. (2018) A CD4+ T cell population expanded in lupus blood provides B cell help through interleukin-10 and succinate. Nat Med :
Horiuchi, Shu; Ueno, Hideki (2018) Potential Pathways Associated With Exaggerated T Follicular Helper Response in Human Autoimmune Diseases. Front Immunol 9:1630
Gu, Jinghua; Wang, Xuan; Chan, Jinyan et al. (2017) Phantom: investigating heterogeneous gene sets in time-course data. Bioinformatics 33:2957-2959
Cepika, Alma-Martina; Banchereau, Romain; Segura, Elodie et al. (2017) A multidimensional blood stimulation assay reveals immune alterations underlying systemic juvenile idiopathic arthritis. J Exp Med 214:3449-3466
Banchereau, Romain; Cepika, Alma-Martina; Banchereau, Jacques et al. (2017) Understanding Human Autoimmunity and Autoinflammation Through Transcriptomics. Annu Rev Immunol 35:337-370
Ueno, Hideki (2016) T follicular helper cells in human autoimmunity. Curr Opin Immunol 43:24-31
Banchereau, Romain; Hong, Seunghee; Cantarel, Brandi et al. (2016) Personalized Immunomonitoring Uncovers Molecular Networks that Stratify Lupus Patients. Cell 165:551-65
Schmitt, Nathalie; Liu, Yang; Bentebibel, Salah-Eddine et al. (2016) Molecular Mechanisms Regulating T Helper 1 versus T Follicular Helper Cell Differentiation in Humans. Cell Rep 16:1082-1095
Blanco, Patrick; Ueno, Hideki; Schmitt, Nathalie (2016) T follicular helper (Tfh) cells in lupus: Activation and involvement in SLE pathogenesis. Eur J Immunol 46:281-90
Caielli, Simone; Athale, Shruti; Domic, Bojana et al. (2016) Oxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in human lupus. J Exp Med 213:697-713

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