Peptidylarginine Deiminase 2 and Citrullination of IgG in Immunity and Rheumatoid Arthritis
Abstract
Rheumatoid arthritis, an autoimmune arthritis with a lifetime risk of about 3 percent, can lead to pain, disability, and early mortality despite lifelong treatment. Moreover, many of the medications are unpleasant to inject and extremely costly. Most people with rheumatoid arthritis produce autoimmune antibodies that underpin the main diagnostic tests for rheumatoid arthritis. Unfortunately, about 25 percent of rheumatoid arthritis patients are negative for these tests, which delays diagnosis and treatment. With about 1 percent of Veterans affected by rheumatoid arthritis costing more than $15,000 per year for most medications, this is a major problem. In addition to these clinical dilemmas, important pathophysiologic mysteries remain in rheumatoid arthritis. Despite decades of research on rheumatoid autoimmune antibodies, why different types of autoimmune antibodies develop and why immune tolerance is broken to generate some of them is unknown. Some of these autoimmune antibodies target citrullinated proteins. The peptidylarginine deiminases (PADs), which catalyze this citrullination, are found in immune cells. However, the understanding of how citrullination and PADs regulate immunity and arthritis beyond simply generating autoimmune antibody targets is rudimentary at best. Identifying the mechanisms by which the PADs and citrullination impact the immune system is critical to define fundamental pathways in immunity and aberrant pathways in rheumatoid arthritis to develop optimal diagnostics and treatments. The objective of this application is to identify mechanisms by which PADs and citrullination regulate antibodies and autoantibodies in immunity and rheumatoid arthritis. Aim 1 will identify new ways by which PADs and citrullination regulate normal antibody-based immunity to influenza and antibody-based protection from vaccines, addressing two Fiscal Year 2017 (FY17) Peer Reviewed Medical Research Program (PRMRP) Topic Areas (Influenza and Vaccine Development for Infectious Disease). Aim 2 will identify new ways by which PADs and citrullination contribute to rheumatoid arthritis, addressing a FY17 PRMRP Topic Area (Rheumatoid Arthritis), including how smoking, a major problem among Veterans, may increase the citrullination of specific proteins leading to autoimmune antibodies in people who are genetically susceptible, addressing an Area of Encouragement. The successful completion of these aims will establish a new mechanistic basis for how PAD2 and citrullination regulate immunity and drive inflammation in rheumatoid arthritis. These advances will usher in new translational opportunities to innovate diagnostics and therapeutics to allow for faster diagnosis and more effective treatment in rheumatoid arthritis.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810717
Entities
People
- Miriam A. Shelef
Organizations
- United States Army
- University of Wisconsin–Madison