Rheumatoid Arthritis: Somatic Mutations In Mature T-Cells Unearthed

Mutations in the genes encoding immune function have been detected in CD8+ T-cells in rheumatoid arthritis patients in a study undertaken by the University of Helsinki and the Helsinki University Central Hospital, suggesting that such mutations might be contributing to the evolution of autoimmune diseases such as rheumatoid arthritis. The findings of the study were published in the Nature Communications journal.

Large Granular Lymphocyte (LGL) Leukemia and Rheumatoid Arthritis Connection – The Basis of the Study

• Rheumatoid arthritis has often been found to occur in LGL leukemia, a type of lymphoproliferative disorder.
• Studies have shown that expanded clones of CD8+ve T-cells in LGL leukemia show STAT3 (Signal transducer and activator of transcription 3) gene mutations.
• The incidence of rheumatoid arthritis (an autoimmune disease) in LGL leukemia patients with STAT3 gene mutation was 43% compared to only 6% of patients who did not have the mutation.
• This association between LGL leukemia and rheumatoid arthritis raises the possibility that CD8+ve T-cell clones harboring somatic mutations could contribute to autoimmune disease.

Taking a cue from the above observations, the research team hoped to pursue the matter further and investigate whether persons with only autoimmune disease (eg., rheumatoid arthritis) in the absence of any lymphoproliferative cancer could also show somatic mutations in their T-cells.

Testing for Mutations in Rheumatoid Arthritis Patients

• The study included 80 newly diagnosed rheumatoid arthritis patients and 20 healthy controls.
• Blood samples of both the patients and the controls were analyzed for the presence of mutations by employing the latest sequencing techniques.
• 20 percent of the patients showed somatic mutations of genes affecting immune function and cell proliferation in contrast to just 1 among the control group.
• All the mutations were found in cytotoxic CD8+ve clonal T-cells associated with rheumatoid arthritis; the CD4+ve helper T-cells did not demonstrate any mutations.

"This indicates that mutations are formed only in mature T cells, not at the stem cell level," say BM Paula Savola and PhD Tiina Kelkka, the main authors of the article. "If mutations were formed at the earlier differentiation stage, they would have been present in CD8+ T cells and CD4+ helper cells expressing other T cell receptor types as well."

• The mutations were permanent i.e. the same mutations and identical clonal T-cells were found in the patients several years after the initial finding.

Scope of the Study and Future Plans

• The significance of these findings is not yet clear. More research is required to validate the role of mutations in effector T-cells and the mechanisms involved in the development of rheumatoid arthritis or similar autoimmune disease. Nevertheless, this study has demonstrated a connection between somatic mutations and a non-malignant autoimmune process.

"In any case, this research project revealed a new connection on the molecular level between autoimmune diseases and cancer, which brings us one step closer to understanding these diseases."

• The study findings suggest that chronic inflammatory conditions such as rheumatoid arthritis may predispose to the accumulation of somatic mutations. In future, the study team plans to analyze similar mutations in other chronic inflammatory diseases.

"In the future, we intend to study the prevalence of this phenomenon in other inflammatory conditions and the practical significance of these mutations as regulators of inflammatory reactions," says Mustjoki.

In conclusion, the idea of mutations leading to autoimmunity is indeed novel, and only time will tell whether this hypothesis proves to be a game-changer in the way autoimmune diseases are approached in the future.

Reference:

1. Somatic Mutations in Clonally Expanded Cytotoxic Lymphocytes in Patients with Newly Diagnosed Rheumatoid Arthritis - (http://acrabstracts.org/abstract/somatic-mutations-in-clonally-expanded-cytotoxic-lymphocytes-in-patients-with- newly-diagnosed-rheumatoid-arthritis/)

Source-Medindia