Rheumatoid arthritis (RA) is a chronic, progressive autoimmune disease directed at the synovial joints. Its etiology and pathogenesis remain controversial. A performant model of RA is provided by the K/BxN mouse, which spontaneously develops a disorder with striking similarities to the human one (though with some differences as well). Disease development in this model depends on combined T and B cell reactivity to the glycolytic enzyme glucose-6-phosphate isomerase, or GPI. Sera or anti-GPI antibodies (Abs) from arthritic K/BxN mice can rapidly, robustly and repeatedly transfer arthritis into healthy recipients. This system has permitted significant progress in dissecting the end-stage effector mechanisms that culminate in K/BxN arthritis - implicating inflammatory cytokines, a limited set of cell types, both Fc receptors and the complement network, and GPI-containing immune complexes. On the basis of these findings, a pathogenetic scenario capable of accounting for the joint specificity of this model has been constructed. In this competing renewal application, three Specific Aims will be undertaken: 1. An assessment of the roles of un- or under-explored elements of the complement network in K/BxN serum-transferred arthritis. 2. An integration of the key molecular and cellular requirements for anti-GPI-induced arthritis, with a focus on neutrophil functions. 3. An exploration of the relevance of K/BxN disease mechanisms to human RA. Results from these experiments should prove important from two perspectives: First, they will provide a deeper understanding of the end-stage effector mechanisms that come into play during K/BxN arthritis. Second, they will allow a more informed assessment of the relationship between K/BxN and human arthritis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR046580-09
Application #
7392787
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Mancini, Marie
Project Start
2000-03-01
Project End
2009-12-31
Budget Start
2008-01-01
Budget End
2008-12-31
Support Year
9
Fiscal Year
2008
Total Cost
$343,439
Indirect Cost
Name
Joslin Diabetes Center
Department
Type
DUNS #
071723084
City
Boston
State
MA
Country
United States
Zip Code
02215
Huang, Haochu; Benoist, Christophe; Mathis, Diane (2010) Rituximab specifically depletes short-lived autoreactive plasma cells in a mouse model of inflammatory arthritis. Proc Natl Acad Sci U S A 107:4658-63
Monach, Paul A; Nigrovic, Peter A; Chen, Mei et al. (2010) Neutrophils in a mouse model of autoantibody-mediated arthritis: critical producers of Fc receptor gamma, the receptor for C5a, and lymphocyte function-associated antigen 1. Arthritis Rheum 62:753-64
Jacobs, Jonathan P; Wu, Hsin-Jung; Benoist, Christophe et al. (2009) IL-17-producing T cells can augment autoantibody-induced arthritis. Proc Natl Acad Sci U S A 106:21789-94
Stangenberg, Lars; Ellson, Chris; Cortez-Retamozo, Virna et al. (2009) Abrogation of antibody-induced arthritis in mice by a self-activating viridin prodrug and association with impaired neutrophil and endothelial cell function. Arthritis Rheum 60:2314-24
Binstadt, Bryce A; Hebert, Jennifer L; Ortiz-Lopez, Adriana et al. (2009) The same systemic autoimmune disease provokes arthritis and endocarditis via distinct mechanisms. Proc Natl Acad Sci U S A 106:16758-63
Monach, Paul A; Hueber, Wolfgang; Kessler, Benedikt et al. (2009) A broad screen for targets of immune complexes decorating arthritic joints highlights deposition of nucleosomes in rheumatoid arthritis. Proc Natl Acad Sci U S A 106:15867-72
Johnsen, Alyssa K; Plenge, Robert M; Butty, Vincent et al. (2008) A broad analysis of IL1 polymorphism and rheumatoid arthritis. Arthritis Rheum 58:1947-57
Monach, Paul A; Verschoor, Admar; Jacobs, Jonathan P et al. (2007) Circulating C3 is necessary and sufficient for induction of autoantibody-mediated arthritis in a mouse model. Arthritis Rheum 56:2968-74
Nigrovic, Peter A; Binstadt, Bryce A; Monach, Paul A et al. (2007) Mast cells contribute to initiation of autoantibody-mediated arthritis via IL-1. Proc Natl Acad Sci U S A 104:2325-30
Nguyen, Linh T; Jacobs, Jonathan; Mathis, Diane et al. (2007) Where FoxP3-dependent regulatory T cells impinge on the development of inflammatory arthritis. Arthritis Rheum 56:509-20

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