# Complement in the Pathogenesis of Autoimmune Arthritis

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2021 · $342,100

## Abstract

The complement system is a major pro-inflammatory and immunomodulatory pathway and plays a central role
in the mechanisms that drive the pathogenesis of experimental murine models of human rheumatoid arthritis
(RA). In these murine models, inappropriate complement activation that is directed to self-tissues drives initial
cellular influx into the joint as well as synovial inflammation and bone erosions. However, despite the extensive
insights into the murine disease that we have developed with support of this grant, including the activation
pathways involved, how control of the system is overcome and how individual effector pathways promote
tissue damage, we do not know how the complement system plays a pathogenic role in patients with RA.
Recent findings in our studies of the human disease have identified a prolonged preclinical phase in RA
characterized by the presence of circulating autoantibodies and mucosal inflammation that appears to drive the
initial break in tolerance to citrullinated self-antigens. Following that asymptomatic phase, where complement
activation is present in the mucosal site but not systemically, it is likely that complement activation and effector
mechanisms are then especially important as the disease transitions to the very early phases of synovitis when
circulating autoantibodies directed against citrullinated proteins initially react with antigens which develop and
are displayed in the joint. To build our understanding of the human disease and translate information from
models of disease to patients themselves, the major focus of this competing renewal proposal is to understand
how the complement system is involved in the early synovitis in RA. We are especially well positioned to
accomplish this important goal, as with other support mechanisms we are able to identify and follow subjects
from the preclinical period into the very first appearance of synovitis and the diagnosis of RA. By obtaining
synovial biopsies, a skill set also developed in our program in the last 3-4 years through other funding, and
informative blood samples from patients in this important transition period, we will work to characterize the role
of complement activation as well as its regulatory and effector mechanisms in the initial development of
inflammatory arthritis and synovitis in patients. In addition, as there are distinct sub-types of RA, designated
pathotypes, which have prognostic importance, we will determine what complement activation processes are
associated with individual pathotypes and how that influences clinical outcomes. Finally, we will focus special
attention on a major synovial cell type in human RA, which are highly inflammatory fibroblast-like synoviocytes,
whose importance is increasingly understood and for which there are reported complement signatures in
unbiased omics studies. We will define the mechanisms by which complement interacts with this cell type, both
with regard to how complement is regulated by inflammat...

## Key facts

- **NIH application ID:** 10115462
- **Project number:** 2R01AR051749-15A1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Vernon Michael Holers
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $342,100
- **Award type:** 2
- **Project period:** 2004-09-10 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10115462

## Citation

> US National Institutes of Health, RePORTER application 10115462, Complement in the Pathogenesis of Autoimmune Arthritis (2R01AR051749-15A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10115462. Licensed CC0.

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