The complement system is a major component of innate immunity and plays a central role in the pro-inflammatory mechanisms that drive the pathogenesis of human rheumatoid arthritis (RA). In this process, inappropriate complement activation that is directed to self-tissues drives cellular influx, synovial inflammation and bone erosions. Recent findings suggest that this pathogenic process is likely to be especially important in the early phases of disease when circulating autoantibodies initially react with antigens which develop and are displayed in the joint. We have used an animal model of RA designated collagen antibody-induced arthritis (CAIA) to understand the molecular basis for these injurious roles of complement. One major focus of the proposed studies will be on how complement is activated within the joint by injured tissues through the engagement of the lectin pathway, which we recently unexpectedly found to play a major role in CAIA. Once activated, the lectin pathway leads to pathogenic engagement of the alternative pathway amplification loop. We will also determine whether factor H (FH), a soluble protein that we have shown plays an essential role in controlling complement activation on the acellular cartilage and stressed fibroblast-like synovial (FLS) cells, is itself the target of de-regulatory proteins from the facor H related (FHR) protein family which modulate its function. Finally, we have made the surprising finding that distal complement effector pathways initiated by anaphylatoxin C5a and C3a receptor engagement amplifies anti-collagen antibody deposition and proximal complement C3 activation, resulting in greatly increased joint damage. We intend to characterize the molecular mechanisms by which this distal amplification process occurs and determine what effector cells and danger signals mediate this effect. As a major focus of this effort, we have identified and wil explore a new injury mechanism through the engagement of hard-wired pathogenic natural antibodies that recognize injury- associated neoepitopes as danger signals and further increase complement activation. Through these efforts we hope to identify novel means by which we can beneficially modulate complement in a therapeutically efficacious manner.

Public Health Relevance

Complement activation is believed to play a major role in the development of inflammatory arthritis, including rheumatoid arthritis (RA) in humans. Studies in animal models identify specific processes that appear to allow complement to be activated and result in tissue destruction. However, important gaps remain in our knowledge of these effects. A better understanding of the regulation of complement in arthritis will provide not only important basic science insights but also potentially help to identify new targets and therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR051749-12
Application #
9247015
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Mao, Su-Yau
Project Start
2015-04-03
Project End
2020-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
12
Fiscal Year
2017
Total Cost
$307,890
Indirect Cost
$109,890
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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