# The role of complement citrullination in RA pathogenesis

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $359,865

## Abstract

PROJECT SUMMARY/ABSTRACT
Understanding the mechanisms which drive immune responses to autoantigens is of high priority. In
rheumatoid arthritis (RA), protein citrullination is a major target of the immune system. Significant data
implicates the anti-citrullinated protein immune response in RA pathogenesis, with recent evidence suggesting
that mechanisms which enhance citrullination are associated with the worst disease outcome. While different
mechanisms likely promote citrullination in RA, our published and preliminary data suggest that citrullination
and the complement system are interacting pathways that amplify each other to enhance autoantigen
production and immune-mediated damage in a sizable subset of RA patients. Thus, we have found that cellular
membranolysis mediated by complement is a potent inducer of protein citrullination in the RA joint, and that
this process is associated with citrullination of critical regulatory components of the complement system
(complement factor H (CFH), and C3), enhancing complement activation. The previous finding that anti-CFH
antibodies are prevalent in RA further highlights the importance of CFH in this disease, adding an extra
mechanism that may dysregulate complement in RA. Taken together, we propose that citrullination-induced
complement dysregulation and anti-CFH antibodies are key amplifiers that propagate damage and citrullination
activity in the RA joint. We will examine this hypothesis in 3 Specific Aims. In Aim 1, we will use mass
spectrometry and biochemical assays to define the structural and functional effects of citrullination on CFH and
C3, as well as the effect of these modified proteins on the induction of the terminal complement complex,
neutrophil hypercitrullination and B cell activation mediated by citrullinated C3dg. Aim 2 will use multiple
reaction monitoring (MRM) to quantify citrullinated CFH and C3 in synovial fluid from RA and other arthritides
to define their association with complement deposition and lytic activity in the joint. Aim 3 will determine
whether anti-CFH antibodies participate in the dysregulation of complement in RA by defining their prevalence
and clinical significance in RA, their association with complement activation, and their effect on CFH function.
These studies will define novel interacting mechanisms of disease amplification relevant to sustain
inflammation and aggravate damage in the rheumatoid joint. Furthermore, the studies will show that these
pathways are active in vivo in RA, identifying markers and subgroups for precise therapeutic intervention.

## Key facts

- **NIH application ID:** 9980293
- **Project number:** 5R01AR069569-05
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Felipe Andrade
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $359,865
- **Award type:** 5
- **Project period:** 2016-07-16 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980293

## Citation

> US National Institutes of Health, RePORTER application 9980293, The role of complement citrullination in RA pathogenesis (5R01AR069569-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9980293. Licensed CC0.

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