Sjögren’s disease is the second most common autoimmune disease and mostly affects women later in life. In the disease, the body attacks secretory cells, causing profound dryness of the mouth, eyes, vagina and skin. Patients can also experience extreme tiredness, muscle aches and a persistent cough, and have an increased risk of B-cell lymphoma. There are few treatment options, and although biological therapies can often help patients with other autoimmune conditions like rheumatoid arthritis, none have yet been approved for Sjögren’s disease. There is an urgent need for new treatments to improve the quality of life for patients. For this to happen, we need to understand the process by which the body keeps attacking itself.
TRIM21 is a normal protein in the body, but for a patient with an autoimmune condition it can be mistaken for a threat and attacked by the immune system. TRIM21 is abundant at entry sites for infection, e.g. the mouth – which is consistent with where the symptoms of Sjögren’s disease occur. However, it isn’t known why the body attacks TRIM21 and maintains inflammation.
Research at the Kennedy Institute of Rheumatology, led by Dr Esther Jones Evans, who was a DPhil student at the time, has shed light on the role of TRIM21 in Sjögren’s disease. This project was a significant collaboration between four research groups at the Kennedy Institute, plus several external collaborators. It was published this month in Science Immunology.
Cell death, often a helpful, automatic process where the body destroys damaged cells, can happen in a few different ways. ‘Apoptotic’ cell death is generally careful, controlled, and non-inflammatory. ‘Lytic’ cell death is messier, with the release of proteins from the cell. Lytic cell death often triggers inflammation as the cells respond to those released proteins. TRIM21 can be one of those released proteins.
The researchers found that TRIM21 is released during lytic, but not apoptotic, cell death. The strong ability of TRIM21 to bind to antibodies explains why TRIM21, but not other released proteins, forms large immune complexes with serum antibodies. These complexes are then recognised by macrophages, which perceive the TRIM21 complexes as a threat and elicit a pro-inflammatory response. This work could explain the role of TRIM21 in maintaining and perpetuating the disease.
Esther said: ‘Sjögren’s disease remains one of most publicly unknown and understudied autoimmune diseases. We hope our work goes some way to understanding why this protein TRIM21, which is abundantly expressed in healthy individuals, might become pathogenic in Sjögren’s disease. This project was a massive undertaking, and I am so grateful to everyone at the Kennedy and beyond, who supported this work. It was truly a team effort!’
Professors Lynn Dustin and Jelena Bezbradica, corresponding authors and Esther’s DPhil Supervisors, said: ‘We believe this work could lead to a better understanding of the pathogenesis of autoimmune diseases, and may open new avenues for therapeutic development. We are grateful to the Kennedy Trust for Rheumatology Research, whose funding underpinned much of this research and supported DPhil studentships for Esther Jones Evans, Han Cai, and Yavuz Yazicioglu. The work benefited from the unique multidisciplinary and collaborative environment at the Kennedy Institute of Rheumatology, including T cell expert Audrey Gérard, clinical rheumatologist and immunometabolism expert Alex Clarke, adaptive immunity and virology expert Lynn Dustin, and innate immunity expert Jelena Bezbradica.’