Published in UAB Insight, Winter 2008
UAB Researchers Awarded $1.2 Million
Rheumatoid arthritis (RA) affects 2 million Americans and costs $80 billion annually. Its cause is unknown, and no cure is available, although great advances in treatment have been made in recent years. Research funding remains significantly lower for RA compared with many other less common chronic diseases.
Research has led to improved therapy and emphasis on early diagnosis and treatment of RA, but scientists need to direct more study toward cure and prevention. Research into the molecular development of RA and the mechanisms that lead to arthritis and joint damage may result in new medicines and drug targets to slow or halt the disease. Identification of hereditary and biological differences among some arthritis patients may reveal genetic markers that could improve early diagnosis and treatment of the disease by allowing physicians to identify which drugs are more likely to work for each patient.
UAB rheumatologists searching for solutions to the RA puzzle recently won 3 of 15 awards funded by the American College of Rheumatology (ACR) Research and Education Foundation “Within Our Reach” campaign, which aims to accelerate innovative RA research focused on disease causes and prediction of onset. The three awards of $400,000 each will facilitate UAB investigators in their search for improved treatment, cure, and prevention of RA.
Specific B-cell Subset Targeting
Knowledge of B-cell biology and the role B cells play in immune response and autoimmunity has increased dramatically in the last 5 years, broadening the opportunity to identify therapeutic targets to halt the autoimmune process. Rituximab, an antibody to the B-cell-specific protein CD20, has shown clinical efficacy in RA patients, but how it works is unknown. After B-cell depletion, autoantibody levels are reduced, but clinical improvement occurs without serological improvement, suggesting that B cells contribute to disease both by producing autoantibodies and by other means, such as effects on T cells and dendritic cells.
Robert H. Carter, MD, is principal investigator for an ACR grant to explore disease-specific B-cell autoreactivity in RA. “Our understanding of B-cell autoimmunity is limited. We know that autoimmune B cells break tolerance in RA and that the pattern of autoreactivity is relatively specific. We do not know what causes loss of tolerance in B cells,” he says. To determine why B cells persist in RA rather than being removed, researchers need to study the pathogenic B cells themselves. Carter proposes developing reagents to track autoreactive B cells, specifically those that produce the anti-citrullinated protein antibodies (ACPA) that are increased in individuals with severe RA. ACPA are present in 68% to 80% of RA patients and are highly specific to the disease.
Carter will use tetramers of citrullinated peptides to identify and analyze B cells that express ACPA to determine the tolerance mechanism and why it fails in RA. Using the tracking tools he develops, Carter aims further to study ACPA-expressing cells in tissues, such as the synovium, to understand the cellular and inflammatory context of this activation. This knowledge can direct efforts to block autoreactive antibody production more directly than total B-cell depletion. Furthermore, B-cell subset targeting may avoid adverse events related to depletion of nonpathogenic B-cell populations, thereby improving B-cell immune intervention.
Autoantibody Production
Principal investigator John D. Mountz, MD, PhD, hopes his research in arthritic mice will lead to new drug targets that alter cell pathways leading to autoantibodies. Mountz proposes that interleukin 17 (IL-17), a pro-inflammatory cytokine, may directly regulate production of pathogenic autoantibodies that promote or increase RA severity.
Mountz has demonstrated that IL-17 plays a major role in shaping B cells’ ability to create antibodies. After blocking IL-17 in an autoimmune mouse immune system, the number of B-cell clusters decreased from 17% to 2%. “IL-17 decreases, rather than increases, cells’ motion, enhancing their interaction with other immune regulatory cells,” he says.
The ACR grant enables Mountz to build on that discovery. “Our research suggests IL-17 can promote autoantibody production directly and independently of its inflammatory effects, he says. Mountz theorizes that IL-17 enhances development of spontaneous germinal centers — lymphatic system clusters where B cells mature and form highly arthrogenic autoantibodies — and that it regulates chemotaxis of B and T cells by upregulating genes that regulate G-protein signaling.
“These changes may arrest migration of T cells and B cells in the germinal centers, prolonging their interaction and thus contributing to stimulation of autoantibody production,” he says.
Mountz will manipulate IL-17 levels in novel mouse models that spontaneously develop erosive arthritis with molecular characteristics similar to those in humans with RA. “Research thus far has neglected this area of RA pathology, but it may help pinpoint new molecular targets for drug therapy,” he says.
Genetic Profiles and CRP
S. Louis Bridges Jr, MD, PhD, is principal investigator for the ACR grant exploring the genetic, racial, and ethnic differences among RA patients to determine if there is a hereditary or biological link between arthritis severity and the gene that encodes C-reactive protein (CRP), a common marker of inflammation.
Rheumatologists commonly use plasma levels of the acute phase reactant CRP to assess RA severity. CRP levels influence changes in disease-modifying antirheumatic drug therapy, and elevated levels are associated with cardiovascular mortality in RA patients (Arthritis Rheum. 2007;57[1]:125-132).
Genetic polymorphisms in the CRP gene have been shown to influence plasma CRP levels and to vary by race and ethnicity. Correlations of CRP single nucleotide polymorphisms (SNPs) with plasma CRP levels and radiographic severity have not been analyzed in either whites or African Americans with RA. Bridges proposes that plasma CRP levels and/or CRP SNP alleles and haplotypes have an independent effect on radiographic severity of RA in African Americans and whites with early disease. He hopes to determine the contribution of plasma CRP levels and CRP SNP alleles and haplotypes to annualized progression rate of radiographic severity in African Americans with longstanding RA.
A study strength is access to a database of 1500 white and African American patients with RA. Researchers have collected comprehensive demographic, clinical, serologic, and radiographic data. Serum, plasma, and genomic DNA also are available. Bridges will include multiple covariates, such as HLA-DRB1 shared epitope alleles, rheumatoid factor, anticyclic citrullinated peptide status, body mass index, joint counts, and smoking status in the analyses.
RA Research a Priority
Investigation into RA remains a priority and strength at UAB, which has long been a center of world-renowned rheumatic disease research. Notable achievements have included use of needle arthroscopy in the investigation of RA pathogenesis and the first use of peptide vaccines directed against death receptor 4 in RA. UAB researchers were the first in the United States to use a monoclonal antibody for RA, and the university’s research was pivotal in the development of antitumor necrosis factor therapy for patients with RA.
UAB Rheumatoid Arthritis Clinic
Bridges, along with rheumatologists Graciela S. Alarcón, MD, MPH, Jeffrey R. Curtis, MD, MPH, and Laura B. Hughes, MD, MSPH, cofounded UAB’s new Rheumatoid Arthritis Clinic at The Kirklin Clinic®. The clinic provides state-of-the-art care to adult RA patients. To avoid irreversible radiographic damage that results from delayed treatment, physicians can see patients with new-onset inflammatory synovitis who have urgent needs within 2 weeks of referral. An integrated research component allows customized care with the goal of tailoring therapy to each individual.
Patients will have access to UAB’s many ongoing clinical trials for those with various stages of disease, if they so desire. Additionally, the clinic serves as a gateway to ACR-funded RA trials based on the research of Carter, Mountz, and Bridges. For scheduling call 205.801.8187. Physicians with RA patients needing immediate attention may e-mail Bridges at lbridges@uab.edu or Curtis at jcurtis@uab.edu.
For more information:
Dr. Lou Bridges
Dr. Robert Carter
Dr. John Mountz
1.800.UAB.MIST
mist@uabmc.edu