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Novel etiology of autoimmune disorders: the role of acquired somatic mutations in lymphoid cells

Periodic Reporting for period 3 - M-Imm (Novel etiology of autoimmune disorders: the role of acquired somatic mutations in lymphoid cells)

Reporting period: 2018-09-01 to 2020-02-29

The pathogenesis of most immune-mediated disorders, such as of autoimmune diseases, is poorly understood. Current therapy is based on suppression of normal immune system, which results in several adverse effects. Patients with autoimmune disorders have often abnormal white blood cell populations. Our hypothesis is that these aberrant cell populations have originated due to acquired genetic changes (mutations) and they play a role in disease pathogenesis.
In the end, we hope that the results obtained from this project will lead to more targeted and efficient therapy options for patients with autoimmune disorders.
In this project we have collected blood samples from 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 major 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).
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).
The concept of somatic, acquired mutations as putative causal factors for non-malignant immune-mediated diseases is a paradigm-shifting observation. It advances our understanding of molecular pathogenesis of immune-mediated diseases and opens new avenues for more accurate diagnostics and targeted therapies. Currently we are aiming to study in more detail how the mutations affect the cell phenotype and participate in the actual autoimmune process.