A key to treating rheumatoid arthritis (RA) and other autoimmune diseases may be found in identifying "activated" cells inside the target tissue -- tissue from the joint itself.
A paper published in Nature Immunology details the results of a study looking at cell populations that contribute to RA, a common disease with chronic inflammation in the joint lining tissue or synovium. Jennifer H. Anolik M.D., Ph.D., professor of Medicine and associate chair for Research in the Department of Medicine, is one of four senior authors of the paper, "Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry."
While previous RA studies focused on analyses of blood samples, this is the first time researchers have comprehensively evaluated the immune cells and joint cells that interact to produce the inflammation and tissue damage seen in RA. The researchers applied single-cell RNA sequencing, mass cytometry, bulk RNA sequencing and flow cytometry to B cells, T cells, monocytes and fibroblasts from the joint tissue. Single-cell sequencing enabled researchers to identify 18 unique cell populations in the joints based on gene-expression patterns. Some of the cell types were seen in large numbers in samples from people with RA. These included both certain immune cells and other cells like fibroblasts, which build connective tissue in the joints.
One of the unique immune cell populations identified in the RA joints included activated B cells. These findings extend Anolik's prior RA research demonstrating a key role for B cells in joint damage and bone erosion by pinpointing a specific population of B cells in the tissue that may be particularly pathogenic. "This study gives us a unique window into rheumatoid arthritis that we never had before," says Anolik. "We now have the tools to obtain joint biopsies and thoroughly dissect their cellular and molecular composition using state-of-the-art technology."
Phase 1 of the study included 36 people with RA and 15 others with osteoarthritis, for comparison, from ten U.S. and international clinical sites. A much larger group of 100 RA patients and 200 lupus patients will participate in the ongoing Phase 2. A longer-term goal of this study is to better understand how cell populations in individual patients, including the activated B cells, predict treatment response.
"With RA patients, there is no way to know who will or will not respond to a particular therapy," adds Anolik. "A more personalized approach will provide a higher likelihood of success, and our findings of novel inflammatory cell populations represent exciting new targets for therapies to treat RA and potentially other autoimmune diseases. The single-cell analysis approaches of target tissue developed here offer tremendous potential for understanding other human diseases as well."
This work represents a large-scale collaboration among government, industry, nonprofit organizations and academic investigators called the Accelerating Medicines Partnership (AMP). The AMP is funded by the National Institutes of Health and focuses on gene expression and signaling in tissues where disease is active, yielding tools to accelerate drug discovery for RA, lupus, diabetes, Alzheimer's and Parkinson's.