05/22/2019 | Press release | Distributed by Public on 05/22/2019 09:15
May 21, 2019
At a Glance
In rheumatoid arthritis (RA), immune cells mistakenly attack tissues lining the joints. This can lead to stiffness, swelling, pain, and disability.
More than a million people nationwide live with RA. Existing drugs can slow the progression of the disease in some people. But they don't work for everyone and can stop working in others over time.
The exact cause of RA isn't known. It involves complex interactions between immune cells and the cells in the joints responsible for normal tissue maintenance. A better understanding of these interactions could help scientists develop new drugs that work for more patients.
A large-scale collaboration among government, industry, and nonprofit organizations called the Accelerating Medicines Partnership (AMP) focuses on gene expression and signaling in tissues where disease is active, such as the joints of people with RA. AMP investigators led by Drs. Soumya Raychaudhuri and Michael Brenner at Brigham and Women's Hospital, Jennifer Anolik at the University of Rochester, and Laura Donlin at the Hospital for Special Surgery in New York examined synovium-the thin tissue that lines joints-to understand interactions at the single-cell level and find potential targets for treatment. They analyzed tissue collected by AMP investigators from 36 people with RA and 15 others with osteoarthritis for comparison.
The team used advanced laboratory techniques to examine gene expression patterns in single cells from groups of specific types of immune and joint cells. The work was funded by NIH's National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and others. Results were published in Nature Immunology on May 6, 2019.
The researchers identified 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. The team was also able to trace which specific cell types produced several molecules that promote inflammation in RA. Future work will be needed to understand the roles of these cells in RA and other immune diseases.
Donlin's team focused on a type of immune cell called macrophages. In tissue samples grown in the lab, a subset of macrophages cued fibroblasts to destroy joint tissue through a growth factor called HB-EGF. Blocking the receptor for HB-EGF, known as EGFR, with an experimental anti-cancer drug shut down this destructive process. These findings were published in Science Translational Medicine on May 8, 2019.
The drug used in these experiments may be too toxic to use in people with RA. However, these results show that the disease could potentially be treated by methods other than suppressing the immune system, which is the basis for most current RA therapies. Other experiments using the tissues provided new insights into how drugs currently used to treat RA work at the cellular level.
'Our work…has identified previously unknown subsets of cells and provided new insights about how some of these cell types interact with each other to drive RA,' Donlin says. 'We hope that through a better understanding of the cell populations in individual patients we can provide a means by which we can treat them with precision medicine strategies at the earliest stages of disease.'
References: Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Zhang F, Wei K, Slowikowski K, Fonseka CY, Rao DA, Kelly S, Goodman SM, Tabechian D, Hughes LB, Salomon-Escoto K, Watts GFM, Jonsson AH, Rangel-Moreno J, Meednu N, Rozo C, Apruzzese W, Eisenhaure TM, Lieb DJ, Boyle DL, Mandelin AM 2nd; Accelerating Medicines Partnership Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Consortium, Boyce BF, DiCarlo E, Gravallese EM, Gregersen PK, Moreland L, Firestein GS, Hacohen N, Nusbaum C, Lederer JA, Perlman H, Pitzalis C, Filer A, Holers VM, Bykerk VP, Donlin LT, Anolik JH, Brenner MB, Raychaudhuri S. Nat Immunol. 2019 May 6. doi: 10.1038/s41590-019-0378-1. [Epub ahead of print]. PMID: 31061532.
HBEGF+ macrophages in rheumatoid arthritis induce fibroblast invasiveness. Kuo D, Ding J, Cohn IS, Zhang F, Wei K, Rao DA, Rozo C, Sokhi UK, Shanaj S, Oliver DJ, Echeverria AP, DiCarlo EF, Brenner MB, Bykerk VP, Goodman SM, Raychaudhuri S, Rätsch G, Ivashkiv LB, Donlin LT. Sci Transl Med. 2019 May 8;11(491). pii: eaau8587. doi: 10.1126/scitranslmed.aau8587. PMID: 31068444.
Funding: NIH's National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institute of Allergy and Infectious Diseases (NIAID), National Center for Advancing Translational Sciences (NCATS), and National Human Genome Research Institute (NHGRI); Accelerating Medicines Partnership; Rheumatology Research Foundation; Harvard Clinical and Translational Science Center; Doris Duke Charitable Foundation; Arthritis National Research Foundation; Arthritis Research UK; National Institute for Health Research/Wellcome Trust.