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

Informations projet

M-Imm

N° de convention de subvention: 647355

DOI

10.3030/647355

Projet clôturé

Date de signature de la CE 28 Août 2015

Date de début 1 Septembre 2015

Date de fin 28 Février 2021

Financé au titre de

• EXCELLENT SCIENCE - European Research Council (ERC)

Coût total

€ 2 047 337,00

Contribution de l’UE

€ 2 047 337,00

Coordonné par

HELSINGIN YLIOPISTO
Finland

Periodic Reporting for period 4 - M-Imm (Novel etiology of autoimmune disorders: the role of acquired somatic mutations in lymphoid cells)

Période du rapport: 2020-03-01 au 2021-02-28

Résumé du contexte et des objectifs généraux du projet

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.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

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).

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

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.

T cells carrying somatic mutations kill patient's own fibroblast cells