In this project we have collected samples from healthy controls and patients with autoimmune disorders and investigated the presence of acquired mutations with next generation sequencing techniques. In addition, we have aimed to understand which factors cause these mutations (such as the role of virus infections) and the importance of mutated cell populations in disease biology.
From patients with rheumatoid arthritis (RA), we have collected blood samples at the time of diagnosis and analyzed CD4+ and CD8+ T-cell fractions. We have discovered that RA patients have cytotoxic CD8+ T cell clones, which carry somatic mutations in genes known to play a role in autoimmune processes. Mutations existed exclusively in the expanded CD8+ effector-memory cells, persisted during follow-up, and were predicted to change protein functions. RNA sequencing of mutation-harboring cells showed an upregulated proliferation signature (Savola, Kelkka et al, Nat Commun 2017). Also in our other studied immune mediated diseases such as in aplastic anemia (Lundgren&Keranen, Leukemia 2021), chronic graft versus host disease (Kim et al Nat Commun 2020), and common variable immune deficiency (Savola et al, Haematologica) we have discovered that T cell somatic mutations are common and they affect the phenotype and function of mutation carrying cells.
We have also investigated the pathogenesis and drug responses in aggressive NK-cell leukemia (ANKL) which is a rare EBV virus associated NK cell malignancy. Our results have highlighted new signaling pathways which are essential in both healthy and malignant T and NK cells and possible new drug targets (Dufva et al, Nat Commun 2018).
