People with antibodies to modified self-proteins who later developed rheumatoid arthritis had an expanded population of activated naive B-cells with signs of senescence in their blood; these cells activate T-cells in vitro

People with antibodies to modified self-proteins who later developed rheumatoid arthritis had an expanded population of activated naive B-cells with signs of senescence in their blood; these cells activate T-cells in vitro

On October 14, Nature Aging published a study by William Robinson’s group at Stanford University. Among people with antibodies to proteins chemically modified to contain citrulline, those who later developed arthritis had a much higher proportion of activated naive B-cells than those who remained disease-free. Naive B-cells are early-stage lymphocytes that can subsequently develop into memory cells and antibody-producing cells.

These antibodies appear in the blood an average of three to five years before rheumatoid arthritis develops, but only some people who carry them develop the disease. Evidence for B-cell involvement came from the PRAIRI trial: people with these antibodies but without arthritis received a single infusion of either rituximab, a drug that depletes B-cells, or placebo. A quarter of the placebo group developed arthritis within 12 months, compared with a quarter of the rituximab group within 24 months. In 2023, Robinson’s laboratory showed that cytotoxic T-cells in arthritis recognize citrullinated proteins. The authors of the new study identify what activates these T-cells as one of the main unresolved questions.

The first version of the study, a 2025 preprint, compared blood samples from 13 women to distinguish features associated with future disease from those associated with the antibodies alone: five antibody-positive women developed arthritis, five remained disease-free, and three were antibody-negative. Analysis of gene expression in individual cells showed that, approximately a year before arthritis developed, activated naive B-cells (aNAV) accounted for about 43% of B-cells in women who later developed the disease, compared with about 11% in antibody-positive women who remained disease-free.

The aNAV cells of women who developed arthritis resemble senescent cells, which have stopped dividing but remain alive: they have higher expression of p21, a gene that stops cell division. In participants who remained free of arthritis, descendants of aNAV cells more often developed into later cell types, whereas in those who developed arthritis, a substantial proportion of these descendants remained at an early stage.

More mature cells secrete antibodies, while aNAV cells retain their antibody on the cell surface as a receptor. Of 24 antibodies recreated in the laboratory from the receptors of the most activated aNAV cells in women who developed arthritis, 14 bound to multiple substances in a panel of self-proteins and microbial components; among women who remained free of arthritis, 3 of 14 antibodies behaved this way. The authors therefore tested another B-cell function in aNAV cells: presenting protein fragments to T-cells on cell-surface HLA molecules. In vitro, aNAV cells from people with rheumatoid arthritis, loaded with citrullinated proteins, activated both helper and cytotoxic T-cells from the same person; blocking HLA suppressed the response. B-cells from healthy people, loaded with the same proteins, induced very little T-cell activation.

In the authors’ model, prolonged exposure to citrullinated proteins and CpG, a DNA sequence that the immune system uses to recognize viruses and bacteria, drives naive B-cells into an activated state with signs of senescence. In cells from people with arthritis, each stimulus induced these signs, and their combined effect was stronger; in cells from healthy people, only CpG had this effect. The preprint authors suggest that viruses may trigger senescence in these B-cells.

According to the authors’ responses to reviewers, aNAV expansion and signs of senescence were confirmed in new samples and in published data from a larger cohort for the Nature Aging article. The article also reports these cells in joint tissue in arthritis. The preprint authors describe the next step as follows:

Whether selectively eliminating senescent aNAV B-cells can reduce autoimmune flares or lower the risk of disease onset remains an important question for future research.