One in twelve people suffer from an autoimmune disease where their immune cells that normally attack viruses and bacteria “go rogue” and attack healthy parts of the body. There is no cure and treatments are limited to drugs that suppress the entire immune system, which have serious side effects including increased vulnerability to infection and bone loss. Biologic drugs that target specific components of immune cells are emerging, but their high cost and unpredictable effectiveness often prevents their use.

The purpose of this research was to identify rogue immune cells circulating in patients with rheumatic autoimmune diseases to determine how rogue cells differ to normal immune cells. By defining the key characteristics of rogue cells, two major outcomes were anticipated: 1) improved monitoring of disease activity by tracking rogue cells in patients over time; 2) identification of therapeutic targets to selectively eliminate rogue cells with existing biologic drugs.

Genomic technology was pioneered that enabled the identification, isolation and examination of rare rogue B cells responsible for causing inflammation in the skin and kidneys of patients with Sjogren’s syndrome. Deep analysis of the rogue B cells revealed a series of genetic changes that caused their transition from a normal immune cell into a rogue cell that causes inflammation. The rogue B cells harboured mutations in genes that are usually mutated in blood cancers and confer advantages for cell survival, activation and persistence. The rogue B cells produce antibodies called rheumatoid factors which aggregate or clump in the small blood vessels to cause inflammation. Mutations also occurred in the rheumatoid factor antibodies themselves which, cause aggregation and inflammation.

This work was published in Cell and has received considerable attention, including selection by the American College of Rheumatology as top 3 most influential basic science papers of 2020 and editorials in Science, Kidney International, The Rheumatologist and F1000Prime. These commentaries about this work have highlighted the innovation and potential for personalised medicine to prevent the development of cancer in patients with autoimmune disease.

Overall, the findings explain why rheumatoid factors are common in patients with autoimmune disease and only cause skin and kidney inflammation in a few. Future research involves developing a test that can detect aggregation causing mutations in rheumatoid factors to predict which patients are at risk of severe disease for early intervention prior to permanent organ damage. A clinical trial to test the effectiveness of using this genomic technology to profile rogue B cells for selective targeting with repurposed biologic drugs is being developed.

This genomic approach has been extended to patients with other autoimmune diseases: lupus and rheumatoid arthritis. Rogue B cells producing antibodies that react with DNA and citrullinated proteins, which are diagnostic indicators of lupus and rheumatoid arthritis, respectively, have been identified. Ongoing work will determine whether mutation plays a major role in causing inflammation in these diseases.