Virus-Induced Loss of Tolerance Against IgG as a Driving Force in Rheumatoid Arthritis
Abstract
Rheumatoid arthritis (RA) carries a lifetime risk of ~3% and causes pain, disability, early mortality, and billions of dollars annually in the U.S. alone. There are no cures or preventative treatments for RA because we do not understand exactly, how, when, or why immune tolerance for self-molecules is lost and thus cannot develop preventative strategies or accurately identify who will imminently develop RA. Two main classes of antibodies develop prior to the swollen joints of RA: anti-citrullinated protein antibodies (ACPAs) that bind to many different citrullinated proteins and rheumatoid factors (RFs), antibodies that bind to parts of other antibodies that also form in other conditions like infections. However, the original targets and triggering stimuli for these antibodies are unknown. We recently discovered that both ACPAs and RFs can bind antibodies, making antibodies themselves a shared and potentially original target of both autoantibody types in RA. However, the stimuli for the loss of immune tolerance for antibodies in RA remains a mystery. Viral infection can lead to increased RFs and has long been believed to be a RA trigger, but determining if this is true has been prevented by a lack of unique biomarkers for immune activation by viruses and uniform groups of patients who recovered from viral infection to study over time. We recently found that about half of COVID-19 patients generate RFs that bind unique part of antibodies, different parts than those uniquely bound in RA. Thus, the COVID-19 pandemic provides both a unique opportunity to study virus-induced loss of tolerance, as well as, given the >500 million people infected with SARS-CoV-2, an urgent need to address the critical problem of determining if viruses could trigger RA and how. Indeed, some post-COVID-19 patients may already be close to RA, in particular, long COVID patients with joint pain but not swelling. The question to be addressed by this project is Could loss of immune tolerance for antibodies caused by viral infection be a key part of RA development? thereby addressing the Fiscal Year (FY22) Peer Reviewed Medical Research Program (PRMRP) Strategic Goal to identify factors impacting the onset and progression of associated immune-mediated diseases in the Rheumatoid Arthritis Topic Area and Autoimmune Disorders and Immunology Portfolio. To answer this question, we break down previous barriers by taking the innovative approach of utilizing the unique RFs that we recently discovered in RA and COVID-19 as biomarkers as well as people with a SARS-CoV-2 infection at a known time as a uniform cohort of post-viral patients. More specifically, we will evaluate conventionally detected RFs, viral RFs, RA RFs, and multiple ACPAs in (1) individuals who recovered from COVID-19 and provided blood multiple times over 4 years after infection, (2) individuals who developed RA who provided blood at multiple times over the course of ~20 years prior to the development of RA, and (3) Veterans with long COVID and new joint pain. We expect to detect viral RFs at key points after infection (known infection in the case of COVID-19 and previously undetected in the case of pre-RA) that disappear over time followed by the presence of RA RFs and ACPAs, suggesting that (1) viral infection could be a trigger for the autoimmune antibody repertoire and loss of tolerance that drives RA and (2) that the subset of long COVID characterized by joint pain is a precursor of RA. The successful completion of this project will demonstrate that loss of tolerance for antibodies triggered by viral infection could drive RA. In the short term, our findings will provide new insights into the field as well as the theoretical groundwork and essential preliminary data to serve as the foundation for future research projects that will evaluate virus-induced loss of tolerance in larger patient groups and after different infections. Further, demonstrating that at least some long COVID patients
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310124
Entities
People
- Miriam A. Shelef
Organizations
- United States Army
- University of Wisconsin–Madison