Identifying Antigen-Specific T and B Cells in Seronegative Rheumatoid Arthritis Synovial Tissue: Implications for Antigen-Specific Immunotherapy
Abstract
Rheumatoid arthritis (RA) is a disease of the immune system in which multiple joints are chronically painful and swollen. It comes in two main types – “seropositive” (70%), which comprises patients with disease-associated antibodies, and “seronegative” (30%), which comprises patients without these antibodies. RA is easier to control when treated within the first year after symptom onset. A major stumbling block to treatment success in seronegative RA is that RA is more difficult to diagnose in the absence of antibodies. Active Service members and their dependents with seronegative RA commence treatment later and respond less well, leading to increased disability, absence from work, and reduced quality of life. Furthermore, we currently have little understanding of whether seronegative RA is really the same disease as seropositive RA, or whether it is a mixture of different disease subtypes. This seems likely, as the treatments that are available for seropositive RA do not work as effectively for patients with seronegative RA. Understanding more about the diseased tissue in seronegative RA will help to answer these questions. Recent technological advances are shedding light on the underlying contributions of key immune cells in inflammatory rheumatic diseases including RA. This entails deep genomic sequencing of thousands of individual cells extracted from joint tissue to identify their likely functions, including whether they make disease-associated antibodies. In this project, we will leverage these advances and our bank of joint biopsies from seronegative and seropositive RA patients to determine whether some or all seronegative RA patients have antibody-producing cells and T cells that help antibody production in the joint. At the end of the project, we will have developed a new diagnostic strategy to stratify seronegative RA patients into (1) those who produce disease-associated antibodies that were previously not identified, (2) those who have lymphocyte expansion and no antibodies, and (3) those who have activation of other inflammatory cell types. These findings will be directly applicable to the development of new therapies for patients with seronegative RA in a more personalized way that captures the underlying immune activity. In particular, groups 1 and 2 would be able to take advantage in the future of new “antigen-specific tolerizing” immunotherapies that are currently in early-phase clinical trials and that aim to restore immune regulation safely and persistently in patients with recent-onset RA.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010063
Entities
People
- Ranjeny Thomas
Organizations
- United States Army
- University of Queensland