? The innate immune system is centrally important to the development of collagen-induced arthritis (CIA), a widely studied model for the human disease rheumatoid arthritis (RA). Complement is a key component of the innate immune system, and complement activation in inflamed joints has been previously shown to both characterize active disease in patients with RA as well as to be essential to the development of CIA in mice and other similar animal models. There is little understanding, though, of the specific mechanisms by which complement influences cellular and humoral autoimmunity in CIA, or how complement activation fragments intersect with other innate immune mechanisms in the disease process. This proposal addresses three key issues relative to the roles of complement in the evolution of CIA, each with therapeutic implications. The first is the role of the alternative pathway of complement, which is arguably among the most evolutionarily ancient members of this system, in disease pathogenesis. The second is the role of complement at the interface of innate and adaptive immunity in disease, as manifest by functions of complement receptors 2 (CR2/CD21) and 1 (CR1/CD35). These receptors are highly expressed on B cells as well as follicular dendritic cells (FDC), and recent studies by the PI and his collaborators have strongly suggested that interruption of CR2/CR1 function results in a marked decrease in the generation of tissue injury in models of tissue-specific autoimmunity. In addition, B cells are increasingly recognized as key cell types in the development of rheumatoid arthritis in humans, and non-depleting mAbs that target the essential B ceil receptor (BCR) co-receptor complex that includes CR2 and CD19 may also be an effective therapy in the absence of B cell depletion. The third issue that will be evaluated is the relative contribution to the development of joint injury of serum-derived, as compared to infiltrating immune cell-derived, complement factors. These studies will build upon an emerging understanding of the key role of local complement production in tissue injury and immune responses. We propose the following specific aims:
Specific Aim #1 : Determine the role of the alternative pathway of complement in the development of joint inflammation and injury in CIA.
Specific Aim #2 : Experimentally manipulate the expression and function of the B cell co-receptor signal transduction complex containing complement receptors CR2/CR1 and CD19 in CIA in order to identify and characterize the specific roles played by complement receptors in the modulation of autoimmunity and tissue injury. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR051749-03
Application #
7118619
Study Section
Special Emphasis Panel (ZAR1-AAA-D (O2))
Program Officer
Mancini, Marie
Project Start
2004-09-10
Project End
2008-06-30
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
3
Fiscal Year
2006
Total Cost
$294,491
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Holers, V Michael; Banda, Nirmal K (2018) Complement in the Initiation and Evolution of Rheumatoid Arthritis. Front Immunol 9:1057
Antonioli, Alexandra H; White, Janice; Crawford, Frances et al. (2018) Modulation of the Alternative Pathway of Complement by Murine Factor H-Related Proteins. J Immunol 200:316-326
Banda, Nirmal K; Desai, Dhruv; Scheinman, Robert I et al. (2018) Targeting of Liver Mannan-Binding Lectin-Associated Serine Protease-3 with RNA Interference Ameliorates Disease in a Mouse Model of Rheumatoid Arthritis. Immunohorizons 2:274-295
Fridkis-Hareli, Masha; Storek, Michael; Or, Eran et al. (2018) The human complement receptor type 2 (CR2)/CR1 fusion protein TT32, a novel targeted inhibitor of the classical and alternative pathway C3 convertases, prevents arthritis in active immunization and passive transfer mouse models. Mol Immunol 105:150-164
Jubair, Widian K; Hendrickson, Jason D; Severs, Erin L et al. (2018) Modulation of Inflammatory Arthritis in Mice by Gut Microbiota Through Mucosal Inflammation and Autoantibody Generation. Arthritis Rheumatol 70:1220-1233
Banda, Nirmal K; Acharya, Sumitra; Scheinman, Robert I et al. (2017) Deconstructing the Lectin Pathway in the Pathogenesis of Experimental Inflammatory Arthritis: Essential Role of the Lectin Ficolin B and Mannose-Binding Protein-Associated Serine Protease 2. J Immunol 199:1835-1845
Thurman, Joshua M; Frazer-Abel, Ashley; Holers, V Michael (2017) The Evolving Landscape for Complement Therapeutics in Rheumatic and Autoimmune Diseases. Arthritis Rheumatol 69:2102-2113
Banda, Nirmal K; Acharya, Sumitra; Scheinman, Robert I et al. (2016) Mannan-Binding Lectin-Associated Serine Protease 1/3 Cleavage of Pro-Factor D into Factor D In Vivo and Attenuation of Collagen Antibody-Induced Arthritis through Their Targeted Inhibition by RNA Interference-Mediated Gene Silencing. J Immunol 197:3680-3694
Holers, V Michael; Tomlinson, Stephen; Kulik, Liudmila et al. (2016) New therapeutic and diagnostic opportunities for injured tissue-specific targeting of complement inhibitors and imaging modalities. Semin Immunol 28:260-7
Holers, V Michael (2016) Targeting mechanisms at sites of complement activation for imaging and therapy. Immunobiology 221:726-32

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