Somatic mutations in autoimmunity

Autoimmune diseases are caused by a dysregulated immune response against self-antigens. They affect more than 5% of the population in the Western countries, but curative therapies do not exist. However, the molecular mechanisms that cause autoimmune diseases are mostly unknown. In this thesis, we focused on T cells with the aim of characterizing the landscape of somatic mutations in immune-associated genes. We used rheumatoid arthritis (RA) patients and patients suffering from immunodeficiency and autoimmunity as disease models. In study I, we collected a cohort of 82 newly diagnosed RA patients. We performed deep T-cell receptor (TCR) profiling from 65 RA patients’ CD8+ cells. To discover somatic mutations, we sequenced CD4+ and CD8+ cells of 25 RA patients and 20 healthy controls with a targeted deep sequencing panel and complemented the results with exome sequencing in 3 cases. We discovered 30 novel somatic mutations in the CD8+ cells of 5 RA patients and one mutation in one of the healthy controls. Of the discovered mutations in RA, 30% affected cell proliferation and 20% were related to immune functions. Mutations were restricted to specific, expanded CD8+ memory T-cell populations. Felty’s syndrome (a rare form of RA) and large granular lymphocyte (LGL) leukemia often present with a similar patient phenotype. In study II, we showed that the diseases are unified by somatic, activating STAT3 mutations in CD8+ cells. Felty’s syndrome patients harbor similar STAT3 mutations, with a prevalence (43%) comparable to previously described LGL leukemia cohorts. In addition, these 2 diseases shared similar cytokine profiles. Since both diseases are treated similarly, we suggest that these entities could be considered parts of the same disease continuum. Study III investigated the prevalence of somatic mutations in hematopoietic stem cells (clonal hematopoiesis) in RA patients. Targeted deep sequencing from 59 RA patients’ whole blood samples revealed clonal hematopoiesis in 17% of cases. However, clonal hematopoiesis did not associate with clinical parameters in our study setting. Study IV aimed to investigate whether somatic mutations associate with autoimmunity and lymphoproliferation in the context of immunodeficiency. We sequenced 2533 genes from CD4+ and CD8+ cells of 17 immunodeficiency patients. Immunodeficiency patients harbored 45 somatic mutations in 65% of cases. Mutations in tumor suppressor and oncogenes occurred in 35%, but mutations in genes affecting lymphocyte functions, inflammation, and cell proliferation were also common. Clonal hematopoiesis variants also existed in 24% of patients. In summary, we have shown that somatic mutations in T cells and clonal hematopoiesis variants are common in RA and immunodeficiency patients. Our work provides a molecular link between autoimmune disease and cancerous processes, introducing a novel concept in the field of immunology.