The complement system is an important immune effector mechanism in autoimmune arthritis. During the current funding cycle, we have utilized both the collagen-induced arthritis (CIA) and the collagen antibody-induced arthritis (CAIA) models to evaluate the roles of complement in disease pathogenesis. Our studies have defined an important role for complement receptors CR2/CR1 in the development of humoral and cellular autoimmunity to type II collagen. In addition, we have studied in depth the in vivo mechanisms whereby complement is activated in the effector phase of this disease and plays a central role in mediating immune complex injury. Our most unanticipated results have come from studies that have demonstrated an absolute requirement for the alternative pathway and the alternative pathway amplification loop to develop robust inflammatory joint injury during the effector phase of disease. Indeed, using informative gene targeted mice we have found that the presence of the alternative pathway alone is uniquely able to support full arthritis development in the CAIA model. Proposed aims in this competing renewal application will focus substantially upon these particular unanticipated findings and clarify for the first time the relative in vivo role of the soluble complement regulatory protein factor H as compared to membrane regulatory proteins in an immune complex-initiated disease. We will also pursue a new hypothesis that the alternative pathway is primed in vivo for the development of pathologic injury by the activities of the MBL associated serum protease (MASP) protein MASP1 on pro-factor D, as well as define the role of the receptors for the chemotactic peptides C3a and C5a as compared to the membrane attack complex (MAC) in the generation of joint inflammation, and finally explore how complement activation is differentially regulated by the acellular cartilage surface in apposition to the cellular synovium. Our overall goal is to precisely define the in vivo molecular mechanisms by which the alternative pathway is initiated on the cartilage surface and the alternative pathway amplification loop is subsequently engaged in a cascade that results in full complement activation and locally destructive inflammatory joint damage. To accomplish these goals, we will pursue the following specific aims:
Specific Aim #1 : Determine the contribution of MASP-1/3 to priming the alternative pathway for activation as well as the roles of the C3aR, C5aR and MAC in mediating tissue injury during CAIA;
Specific Aim #2. Define the roles of individual soluble and membrane-bound complement regulatory proteins on cartilage and synovium in the control of complement activation and amplification loop engagement;
and Specific Aim #3 : Utilize informative in vitro systems in order to define the contribution of individual soluble and membrane-bound complement regulatory proteins on cartilage and synovium to the generation of pathogenic C3 and C5 activation fragments.

Public Health Relevance

The studies focus on the pathogenesis of joint inflammation and damage in a murine model of rheumatoid arthritis. They are based on the unanticipated finding that one component of a complex multi-protein cascade designated the complement system plays a key role in vivo in the generation of all pro-inflammatory molecules that are derived from this pathway. Studies are designed to develop a more complete understanding of the mechanisms underlying this finding in arthritis models, and to determine how this component of complement integrates with other pro-inflammatory pathways important in disease pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR051749-07
Application #
8122285
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Mao, Su-Yau
Project Start
2004-09-10
Project End
2014-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
7
Fiscal Year
2011
Total Cost
$358,491
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
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
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
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
Hannan, Jonathan P; Laskowski, Jennifer; Thurman, Joshua M et al. (2016) Mapping the Complement Factor H-Related Protein 1 (CFHR1):C3b/C3d Interactions. PLoS One 11:e0166200
Wang, Guankui; Chen, Fangfang; Banda, Nirmal K et al. (2016) Activation of Human Complement System by Dextran-Coated Iron Oxide Nanoparticles Is Not Affected by Dextran/Fe Ratio, Hydroxyl Modifications, and Crosslinking. Front Immunol 7:418
Laskowski, Jennifer; Renner, Brandon; Le Quintrec, Moglie et al. (2016) Distinct roles for the complement regulators factor H and Crry in protection of the kidney from injury. Kidney Int 90:109-22
Renner, Brandon; Tong, Hua Hua; Laskowski, Jennifer et al. (2016) Annexin A2 Enhances Complement Activation by Inhibiting Factor H. J Immunol 196:1355-65
Mehta, Gaurav; Scheinman, Robert I; Holers, V Michael et al. (2015) A New Approach for the Treatment of Arthritis in Mice with a Novel Conjugate of an Anti-C5aR1 Antibody and C5 Small Interfering RNA. J Immunol 194:5446-54

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