Graduation Date

Fall 12-15-2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Medical Sciences Interdepartmental Area

First Advisor

Geoffrey M. Thiele

Second Advisor

Ted R. Mikuls

MeSH Headings

Rheumatoid Arthritis, Malondialdehyde, Lipid Peroxidation, Synovitis, Interstitial Lung Disease

Abstract

Rheumatoid arthritis (RA) is a systemic, autoimmune disease primarily characterized by perpetual synovial inflammation that results in synovial tissue proliferation and fibrosis (pannus). Although joint involvement is the predominant manifestation of RA, extra-articular features, such as interstitial lung disease (ILD), contribute significantly to the elevated mortality associated with the condition. Post-translational modifications play a significant role in RA and RA-ILD pathogenesis. Circulating anti-citrullinated protein antibodies (ACPAs) are a highly diagnostic tool implicating a potential role for citrullinated antigens in RA and RA-ILD.

Recently, antibodies to malondialdehyde acetaldehyde adducts (MAA) have been markedly elevated in patients with RA and RA-ILD. MAA modified proteins strongly co-localize with citrullinated proteins in the synovial and lung tissues of RA and RA-ILD patients, respectively. While there have been significant advancements in the RA field, the mechanism(s) by which citrulline and MAA-modified proteins propagate disease-specific inflammatory and fibrotic responses, to promote the development and progression of RA and RA-ILD remains largely unknown.

To this end, the overall objective of this dissertation is to determine whether MAA-modification and citrullination of extracellular matrix protein (fibrinogen) act alone or in concert to promote cellular activation and resulting crosstalk mechanisms between macrophages and fibroblasts, driving disease-related inflammation and fibrosis.

The work herein provided for the first time a mechanistic understanding of how MAA-modified and/or citrullinated fibrinogen altered macrophage activation and function. Further, these studies provided a novel insight into the regulatory role of these modifications in macrophage-to-fibroblast communication mechanisms. Importantly, results presented in this dissertation strongly support that dual modifications of protein with both citrulline and MAA promote more robust macrophage and fibroblast responses than either single protein modification alone. Overall, the findings of this dissertation specifically support the concept that MAA and citrulline modifications are likely playing a synergistic role in driving macrophage-fibroblast crosstalk contributing to the initiation and propagation of inflammation with subsequent fibrosis associated with RA and RA-ILD. Results from this study ultimately propose novel biomarkers in addition to molecular targets that may be leveraged as informative biomarkers or in future disease management strategies.

Comments

2023 Copyright, the authors

Download

Available for download on Sunday, November 30, 2025

Share

COinS