Identification of T Cell Receptor Somatic Mutations Driving Autoimmunity in Human Rheumatoid Arthritis

Challenge: Somatic mutations are de novo non-inherited mutations which can be passed down to other cells through the course of cell division. Their role has been well-established in cancer. However, the presence of somatic mutations in non-malignant disease has never been explored since it is unlikely that a single point mutation would be sufficient to cause disease. Linking somatic mutations to autoimmune diseases is a novel concept that has not been tested before this project.

Solution: To better understand the causes of autoimmune diseases, the research team used exome sequencing to demonstrate that autoreactive T cells within the inflamed joints of rheumatoid arthritis patients carry de novo somatic mutations that are absent from non-autoreactive T cells circulating in the periphery. They first confirmed the presence of somatic mutations, which are expected to occur within the receptors of auto-reactive T cells. They then identified three de novo copy number changes within the T cells present in the aspirated joint space fluid, but absent from the circulating T cells. These copy number changes were identified on chromosome regions encoding genes implicated in autoimmunity (RAC1, CYTH3, GRID2IP, PMS2CL, SSH3 and PTPRCAP). Single nucleotide polymorphisms which were discordant between the joint space T cells and the circulating T cells were also detected.

Achievements/Impact: The identification of such mutations provide evidence suggesting an entirely novel paradigm for the etiology of autoimmunity. The results of this project pinpointed new critical drug targets for the pharmaceutical industry. Building on the results of this CQDM grant, Brent Richards’ group was able to secure a competitive grant to further pursue this research.