Abstract
Somatic mutations contribute to tumorigenesis. Although these mutations occur in all proliferating cells, their accumulation under non-malignant conditions, such as in autoimmune disorders, has not been investigated. Here, we show that patients with newly diagnosed rheumatoid arthritis have expanded CD8+ T-cell clones; in 20% (5/25) of patients CD8+ T cells, but not CD4+ T cells, harbour somatic mutations. In healthy controls (n=20), only one mutation is identified in the CD8+ T-cell pool. Mutations exist exclusively in the expanded CD8+ effector-memory subset, persist during follow-up, and are predicted to change protein functions. Some of the mutated genes (SLAMF6, IRF1) have previously been associated with autoimmunity. RNA sequencing of mutation-harbouring cells shows signatures corresponding to cell proliferation. Our data provide evidence of accumulation of somatic mutations in expanded CD8+ T cells, which may have pathogenic significance for RA and other autoimmune diseases.
Highlights
Rheumatoid arthritis (RA) often co-manifests in patients with large granular lymphocyte (LGL) leukaemia, a rare lymphoproliferative disorder in which we recently discovered that expanded CD8 þ T-cell clones harbour somatic STAT3 mutations[13]
LGL leukaemia patients with multiple STAT3 mutations have a higher incidence of RA (43%) than patients without STAT3 mutations (6%)[14], raising the possibility that patients with STAT3mutated LGL leukaemia and clonal-lymphocyte proliferation are at a greater risk of developing a non-malignant autoimmune disease and that CD8 þ T-cell clones carrying somatic mutations may participate in the autoimmune process
To assess the clonality in more detail, the samples were subjected to a next-generation sequencing (NGS)-based TCR b (TCRB CDR3) deep-sequencing assay
Summary
These mutations occur in all proliferating cells, their accumulation under non-malignant conditions, such as in autoimmune disorders, has not been investigated. We show that patients with newly diagnosed rheumatoid arthritis have expanded CD8 þ T-cell clones; in 20% (5/25) of patients CD8 þ T cells, but not CD4 þ T cells, harbour somatic mutations. We investigate whether T cells in people with a non-malignant autoimmune disorder without known lymphoproliferation harbour somatic mutations and analyse blood samples from individuals with newly diagnosed, untreated RA. We discover somatic mutations in purified CD8 þ T cells with a custom deep-sequencing panel including 986 immune-related genes and with exome and deep amplicon sequencing These results provide a link between cancerous processes and autoimmunity
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