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M-Imm SIGNED

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

Total Cost €

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EC-Contrib. €

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Partnership

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 M-Imm project word cloud

Explore the words cloud of the M-Imm project. It provides you a very rough idea of what is the project "M-Imm" about.

immune    host    antigen    discovery    understand    discovered    intriguing    neoplastic    50    expansion    molecular    small    gives    disorder    pathogenesis    adverse    organ    transform    prove    breakthrough    lgl    al    damage    disorders    heavy    disease    et    sensitive    examine    continuum    thought    proliferation    therapy    suffer    regulator    clinical    mediated    induce    mutated    engl    koskela    spectrum    functional    acquired    driver    diseases    cytotoxic    clone    mutations    cells    hypothesis    poorly    granular    carry    generation    group    burden    clones    lymphocytes    infections    patients    autoimmune    causes    determines    accurate    diagnostics    mechanisms    nk    leukemia    acquire    autocytotoxicity    cytopenias    lymphocyte    lymphoid    mutational    somatic    society    tissues    stat3    viral    oncogenic    2012    separate    rheumatoid    hit    expand    expanded    autoreactive    ra    arthritis    function    med    maladies    activating    drug    sequencing    gene    advantage    tissue   

Project "M-Imm" data sheet

The following table provides information about the project.

Coordinator
HELSINGIN YLIOPISTO 

Organization address
address: YLIOPISTONKATU 3
city: HELSINGIN YLIOPISTO
postcode: 14
website: www.helsinki.fi

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 Coordinator Country Finland [FI]
 Project website https://www.helsinki.fi/en/researchgroups/hematology-research-unit-helsinki/research
 Total cost 2˙047˙337 €
 EC max contribution 2˙047˙337 € (100%)
 Programme 1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
 Code Call ERC-2014-CoG
 Funding Scheme ERC-COG
 Starting year 2015
 Duration (year-month-day) from 2015-09-01   to  2020-08-31

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    HELSINGIN YLIOPISTO FI (HELSINGIN YLIOPISTO) coordinator 2˙047˙337.00

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 Project objective

Molecular pathogenesis of most immune-mediated disorders, such as of autoimmune diseases, is poorly understood. These common maladies carry a heavy burden both on patients and on society. Current therapy is non-targeted and results in significant short- and long-term adverse effects. Large granular lymphocyte (LGL) leukemia is characterized by expansion of cytotoxic T- or NK-cells and represents an intriguing clinical continuum between a neoplastic and an autoimmune disorder. Patients suffer from autoimmune cytopenias and rheumatoid arthritis (RA), which are thought to be mediated by LGL cells targeting host tissues. My group recently discovered that 40-50% of LGL leukemia patients carry in their lymphoid cells acquired, activating mutations in the STAT3 gene – a key regulator of immune and oncogenic processes (Koskela et al, N Engl J Med, 2012). This breakthrough discovery gives insight to the pathogenesis of autoimmune disorders at large. I present here a hypothesis that a strong antigen-induced proliferation is a mutational driver, which causes somatic mutations in lymphoid cells. When mutations hit key activating pathways, autoreactive cells acquire functional advantage and expand. The target antigen of the expanded clone determines the clinical characteristics of the autoimmune disease induced. To prove this hypothesis, we will separate small lymphocyte clones from patients with autoimmune diseases and use sensitive next-generation sequencing methods to characterize the spectrum of somatic mutations in lymphoid cells. Further, we will study the function of mutated lymphocytes and examine the mechanisms of autocytotoxicity and end-organ/tissue damage. Finally, we aim to understand factors, which induce somatic mutations in lymphoid cells, such as the role of viral infections. The results will transform our understanding of molecular pathogenesis of autoimmune diseases and lead to accurate diagnostics and discovery of novel drug targets.

 Publications

year authors and title journal last update
List of publications.
2016 E. I. Andersson, T. Tanahashi, N. Sekiguchi, V. R. Gasparini, S. Bortoluzzi, T. Kawakami, K. Matsuda, T. Mitsui, S. Eldfors, S. Bortoluzzi, A. Coppe, A. Binatti, S. Lagstro m, P. Ellonen, N. Fukushima, S. Nishina, N. Senoo, H. Sakai, H. Nakazawa, Y.-L. Kwong, T. P. Loughran, J. P. Maciejewski, S. Mustjoki, F. Ishida
High incidence of activating STAT5B mutations in CD4-positive T-cell large granular lymphocyte leukemia
published pages: 2465-2468, ISSN: 0006-4971, DOI: 10.1182/blood-2016-06-724856
Blood 128/20 2020-04-23
2017 Miko Valori, Lilja Jansson, Anna Kiviharju, Pekka Ellonen, Hanna Rajala, Shady Adnan Awad, Satu Mustjoki, Pentti J. Tienari
A novel class of somatic mutations in blood detected preferentially in CD8 + cells
published pages: 75-81, ISSN: 1521-6616, DOI: 10.1016/j.clim.2016.11.018
Clinical Immunology 175 2020-04-23
2018 Tilman Schneider-Hohendorf, Dennis Görlich, Paula Savola, Tiina Kelkka, Satu Mustjoki, Catharina C. Gross, Geoffrey C. Owens, Luisa Klotz, Klaus Dornmair, Heinz Wiendl, Nicholas Schwab
Sex bias in MHC I-associated shaping of the adaptive immune system
published pages: 2168-2173, ISSN: 0027-8424, DOI: 10.1073/pnas.1716146115
Proceedings of the National Academy of Sciences 115/9 2020-04-23
2017 Emma I Andersson
Characterization of mature T-cell leukemias by next-generation sequencing and drug sensitivity testing
published pages: , ISSN: , DOI:
2020-04-23
2017 P. Savola, T. Kelkka, H. L. Rajala, A. Kuuliala, K. Kuuliala, S. Eldfors, P. Ellonen, S. Lagström, M. Lepistö, T. Hannunen, E. I. Andersson, R. K. Khajuria, T. Jaatinen, R. Koivuniemi, H. Repo, J. Saarela, K. Porkka, M. Leirisalo-Repo, S. Mustjoki
Somatic mutations in clonally expanded cytotoxic T lymphocytes in patients with newly diagnosed rheumatoid arthritis
published pages: 15869, ISSN: 2041-1723, DOI: 10.1038/ncomms15869
Nature Communications 8 2020-04-23
2018 Luca Trotta, Timi Martelius, Timo Siitonen, Timo Hautala, Sari Hämäläinen, Hanna Juntti, Mervi Taskinen, Mette Ilander, Emma Irene Andersson, Andrey Zavialov, Meri Kaustio, Riikka Keski-Filppula, Michael Hershfield, Satu Mustjoki, Terhi Tapiainen, Mikko Seppänen, Janna Saarela
ADA2 deficiency: Clonal lymphoproliferation in a subset of patients
published pages: 1534-1537.e8, ISSN: 0091-6749, DOI: 10.1016/j.jaci.2018.01.012
Journal of Allergy and Clinical Immunology 141/4 2020-04-23
2017 A Coppe, E I Andersson, A Binatti, V R Gasparini, S Bortoluzzi, M Clemente, M Herling, J Maciejewski, S Mustjoki, S Bortoluzzi
Genomic landscape characterization of large granular lymphocyte leukemia with a systems genetics approach
published pages: 1243-1246, ISSN: 0887-6924, DOI: 10.1038/leu.2017.49
Leukemia 31/5 2020-04-23
2018 Paula Savola, Sofie Lundgren, Mikko A. I. Keränen, Henrikki Almusa, Pekka Ellonen, Marjatta Leirisalo-Repo, Tiina Kelkka, Satu Mustjoki
Clonal hematopoiesis in patients with rheumatoid arthritis
published pages: , ISSN: 2044-5385, DOI: 10.1038/s41408-018-0107-2
Blood Cancer Journal 8/8 2020-04-23

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