Systemic lupus erythematosus (SLE) is a chronic life threatening autoimmune disorder that afflicts well over one million Americans each year. It is characterized by the excessive production of a wide range of autoantibodies specific for self antigens such as chromatin, ribonucleoproteins and phospholipids. These antibodies and/or immune complexes containing these antibodies can deposit in blood vessel walls, glomeruli, and joints and contribute to complications ranging from glomerulonephritis to coagulation disorders. Studies conducted over the past funding cycle have demonstrated that the activation of autoreactive B cells is greatly enhanced by the ability of an autoantigen to effectively engage both the B cell receptor and either Toll-like receptor 9 (TLR9) or TLR7. It follows that the most prominent self-antigen targets in systemic autoimmune disease are essentially self-adjuvants. The purpose of this application is to further explore the factors that create and/or expose these self-adjuvants to the immune system. In particular, we will test the following hypotheses. (1) cell trauma and/or cell death may lead to modifications of host constituents that create novel endogenous TLR ligands;(2) endogenous TLR ligands serve as adjuvants for additional autoantigens with which they co-cluster;and (3) the autoantibody response is enhanced by type 1 IFN-induced upregulation of TLR7 expression in B cells. Specifically, we will: (1) determine whether DNA modifications, induced experimentally by treating DNA with agents that cause specific types of DNA damage or by exposing cells to UVA/UVB radiation, can increase the adjuvant activity of mammalian nucleic acid associated autoantigens, and evaluate the potential contribution of these self- adjuvants to the the development of SLE;(2) produce and characterize a panel of anti-phospholipid monoclonal antibodies that preferentially bind apoptotic cells at different stages of the apoptotic process and determine whether immune complexes consisting of membrane blebs bound by these antibodies can activate autoreactive B cells via a TLR-dependent mechanism;and (3) evaluate the direct effects of Type 1 IFN on the in vitro and in vivo proliferation, survival and function of autoreactive B cells Although current treatment regimens for SLE can reduce disease severity, they often have deleterious side effects that limit their extended use. A better understanding of the events that contribute to the initial activation of these autoreactive B cells will be critical to the development of more effective and less toxic therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
7R01AR035230-23
Application #
8013736
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Mancini, Marie
Project Start
1986-09-22
Project End
2011-06-30
Budget Start
2009-11-01
Budget End
2010-06-30
Support Year
23
Fiscal Year
2009
Total Cost
$219,984
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Baum, Rebecca; Nündel, Kerstin; Pawaria, Sudesh et al. (2016) Synergy between Hematopoietic and Radioresistant Stromal Cells Is Required for Autoimmune Manifestations of DNase II-/-IFNaR-/- Mice. J Immunol 196:1348-54
Nündel, Kerstin; Green, Nathaniel M; Shaffer, Arthur L et al. (2015) Cell-intrinsic expression of TLR9 in autoreactive B cells constrains BCR/TLR7-dependent responses. J Immunol 194:2504-12
Bossaller, Lukas; Rathinam, Vijay A K; Bonegio, Ramon et al. (2013) Overexpression of membrane-bound fas ligand (CD95L) exacerbates autoimmune disease and renal pathology in pristane-induced lupus. J Immunol 191:2104-14
Uccellini, Melissa B; Busto, Patricia; Debatis, Michelle et al. (2012) Selective binding of anti-DNA antibodies to native dsDNA fragments of differing sequence. Immunol Lett 143:85-91
Green, Nathaniel M; Moody, Krishna-Sulayman; Debatis, Michelle et al. (2012) Activation of autoreactive B cells by endogenous TLR7 and TLR3 RNA ligands. J Biol Chem 287:39789-99
Kiefer, Kerstin; Oropallo, Michael A; Cancro, Michael P et al. (2012) Role of type I interferons in the activation of autoreactive B cells. Immunol Cell Biol 90:498-504
Green, Nathaniel M; Marshak-Rothstein, Ann (2011) Toll-like receptor driven B cell activation in the induction of systemic autoimmunity. Semin Immunol 23:106-12
Avalos, Ana Maria; Busconi, Liliana; Marshak-Rothstein, Ann (2010) Regulation of autoreactive B cell responses to endogenous TLR ligands. Autoimmunity 43:76-83
Avalos, Ana M; Uccellini, Melissa B; Lenert, Petar et al. (2010) Fc?RIIB regulation of BCR/TLR-dependent autoreactive B-cell responses. Eur J Immunol 40:2692-8
Richez, Christophe; Yasuda, Kei; Bonegio, Ramon G et al. (2010) IFN regulatory factor 5 is required for disease development in the FcgammaRIIB-/-Yaa and FcgammaRIIB-/- mouse models of systemic lupus erythematosus. J Immunol 184:796-806

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