HMN 2026: What is the Mechanism behind persistent autoimmune joint destruction

Nearly 1.5 million Americans and nearly 5% of women over the age of 55 have rheumatoid arthritis (RA), an incurable autoimmune disease marked by joint inflammation and subsequent damage. Despite advances in treatment, such as targeted immunotherapies, joint erosion persists even during disease remission.

A new Yale School of Medicine study, published in the Proceedings of the National Academy of Sciences, explains the cellular underpinnings of this ongoing joint destruction.

For the study, investigators in the Yale Section of Allergy and Immunology examined arthritis in mice to better understand the function of a group of white blood cells, known as T lymphocytes.

Led by Edward Doherty, Ph.D., associate research scientist in the Bucala laboratory, in collaboration with Lais Osmani, MD, MHS, instructor, and Joshua Bilsborrow, MD, MHS, assistant professor of medicine, the study found that some of these lymphocytes have a receptor for the immune hormone macrophage migration inhibitory factor, or MIF, on their surface.

Previous research has shown that many individuals with autoimmunity have overactive forms of the MIF gene, which puts them at risk for more severe disease.

The researchers discovered that these T lymphocytes are expanded in mouse models of joint inflammation and that simply transferring these particular cells to healthy mice caused RA-like joint inflammation. The research team went on to identify these novel MIF-sensitive T lymphocytes in joint tissue from patients with RA who needed joint replacement.

“These T lymphocytes persist in the joints and have the characteristics of memory cells, meaning they retain their autoimmune properties long after the initial inflammatory response dies down, either spontaneously or after drug treatment,” says Richard Bucala, MD, Ph.D., Waldemar Von Zedtwitz Professor of Medicine (Rheumatology) and professor of pathology and of epidemiology (microbial diseases) and corresponding author of the study.

During a relapse of RA, joint inflammation often redevelops first in the same joints that were previously affected by disease. These particular memory T lymphocytes may explain this phenomenon, the researchers say.

The findings also suggest that the persistence of these memory lymphocytes is responsible for the continued, gradual joint destruction in many patients with RA who are in remission and feel well.

Biologic therapies developed over the last 25 years have been highly effective, removing much of the impetus for finding a cure for RA and increasing the need for new approaches that tackle the underlying disease process, according to Bucala.

“Even patients on the best current therapies with no or minimal joint complaints may still have smoldering levels of inflammation that damage their joints over their lifetime,” he says. “Our novel findings about memory T cells can help address this.”

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