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Immune-dysregulation and autoimmunity in primary immunodeficiency

English title Immune-dysregulation and autoimmunity in primary immunodeficiency
Applicant Recher Mike
Number 181038
Funding scheme SNSF Professorships
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Immunology, Immunopathology
Start/End 01.01.2019 - 31.12.2019
Approved amount 397'213.00
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Keywords (6)

immune-dysregulation; immunodeficiency; SP110; RAG; antibody-deficiency; autoimmunity

Lay Summary (German)

Lead
Patienten mit Immunschwäche erleiden gehäuft Infektionen. Viele zeigen zudem Zeichen eines Immunangriffs gegen den eigenen Körper (Autoimmunität). Sehr viel häufiger als ursprünglich angenommen sind Immunschwächen durch Mutationen in Genen des Immunsystems bedingt (primäre Immunschwächen). Die Ursachen für die Autoimmunitäts-Neigung bei diesen Patienten sind ungenügend studiert. Dieses Projekt möchte für die Erforschung der Ursachen für diesen Zusammenhangs einen Beitrag leisten.
Lay summary

Inhalt und Ziel des Forschungsprojekts:
Wir studieren Mäuse, die aufgrund von Mutationen im Eiweiss RAG eine primäre Immunschwäche haben. Das RAG Eiweiss ist zentral für die Herstellung von T und B Lymphozyten. Verschiedene RAG Mutationen führen zu einem völligen Fehlen von RAG oder zu einem RAG Eiweiss welches noch eine Restfunktion hat. So können wir Mäuse mit leichten bis schweren Immunschwächen studieren, obwohl immer das gleiche Gen (RAG) verändert ist.
Die erwähnten Mausmodelle werden standardisiert mit einem Virus infiziert. Wir analysieren, welche Mäuse Autoimmunität entwickeln und ob diese durch die Virusinfektion angetrieben wird. Das Ziel ist es, die Entwicklung von Autoimmunität bei primärer Immunschwäche aber auch die Entwicklung von Autoimmunität generell besser zu verstehen und allenfalls neue Therapieansätze zu entwickeln.
Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts:
Das Projekt ist ein Grundlagenforschungsprojekt. Die erwähnten Mausmodelle stellen genetisch bedingte Immunschwächen beim Menschen nach, somit sind die Forschungsresultate relevant für viele Patienten mit Immunschwächen und Autoimmunität.
Das komplexe Zusammenspiel zwischen Infektion, Immunabwehr und Entwicklung von Autoimmunität lässt sich in diesem Ausmass nur im Mausmodell studieren.

Direct link to Lay Summary Last update: 03.12.2018

Responsible applicant and co-applicants

Employees

Publications

Publication
Antibodies as biomarker candidates for response and survival to checkpoint inhibitors in melanoma patients
Fässler Mirjam, Diem Stefan, Mangana Joanna, Hasan Ali Omar, Berner Fiamma, Bomze David, Ring Sandra, Niederer Rebekka, del Carmen Gil Cruz Cristina, Pérez Shibayama Christian Ivan, Krolik Michal, Siano Marco, Joerger Markus, Recher Mike, Risch Lorenz, Güsewell Sabine, Risch Martin, Speiser Daniel E., Ludewig Burkhard, Levesque Mitchell P., Dummer Reinhard, Flatz Lukas (2019), Antibodies as biomarker candidates for response and survival to checkpoint inhibitors in melanoma patients, in Journal for ImmunoTherapy of Cancer, 7(1), 50-50.
Novel Missense Mutation inSP110Associated with Combined Immunodeficiency and Advanced Liver Disease Without VOD
Delmonte Ottavia M., Baldin Fabian, Ovchinsky Nadia, Marquardsen Florian, Recher Mike, Notarangelo Luigi D., Kosinski Slawomir M. (2019), Novel Missense Mutation inSP110Associated with Combined Immunodeficiency and Advanced Liver Disease Without VOD, in Journal of Clinical Immunology, 549-551.
SDHA gain-of-function engages inflammatory mitochondrial retrograde signaling via KEAP1–Nrf2
Burgener Anne-Valérie, Bantug Glenn R., Meyer Benedikt J., Higgins Rebecca, Ghosh Adhideb, Bignucolo Olivier, Ma Eric H., Loeliger Jordan, Unterstab Gunhild, Geigges Marco, Steiner Rebekah, Enamorado Michel, Ivanek Robert, Hunziker Danielle, Schmidt Alexander, Müller-Durovic Bojana, Grählert Jasmin, Epple Raja, Dimeloe Sarah, Lötscher Jonas, Sauder Ursula, Ebnöther Monika, Burger Bettina, Heijnen Ingmar, et al. (2019), SDHA gain-of-function engages inflammatory mitochondrial retrograde signaling via KEAP1–Nrf2, in Nature Immunology, 20(10), 1311-1321.
Syphilis Reactivates Latent Epstein-Barr Virus Reservoir via Toll-Like Receptor 2 and B-Cell Receptor Activation
Hirsiger Julia R, Fuchs Philipp S, Häusermann Peter, Müller-Durovic Bojana, Daikeler Thomas, Recher Mike, Hirsch Hans H, Terracciano Luigi, Berger Christoph T (2019), Syphilis Reactivates Latent Epstein-Barr Virus Reservoir via Toll-Like Receptor 2 and B-Cell Receptor Activation, in Open Forum Infectious Diseases, 6(9), 1-6.
Association of Checkpoint Inhibitor–Induced Toxic Effects With Shared Cancer and Tissue Antigens in Non–Small Cell Lung Cancer
Berner Fiamma, Bomze David, Diem Stefan, Ali Omar Hasan, Fässler Mirjam, Ring Sandra, Niederer Rebekka, Ackermann Christoph J., Baumgaertner Petra, Pikor Natalia, Cruz Cristina Gil, van de Veen Willem, Akdis Mübeccel, Nikolaev Sergey, Läubli Heinz, Zippelius Alfred, Hartmann Fabienne, Cheng Hung-Wei, Hönger Gideon, Recher Mike, Goldman Jonathan, Cozzio Antonio, Früh Martin, Neefjes Jacques, et al. (2019), Association of Checkpoint Inhibitor–Induced Toxic Effects With Shared Cancer and Tissue Antigens in Non–Small Cell Lung Cancer, in JAMA Oncology, 5(7), 1043-1043.
Genetic immune and inflammatory markers associated with diabetes in solid organ transplant recipients
Quteineh Lina, Wójtowicz Agnieszka, Bochud Pierre‐Yves, Crettol Severine, Vandenberghe Frederik, Venetz Jean‐Pierre, Manuel Oriol, Golshayan Dela, Lehmann Roger, Mueller Nicolas J., Binet Isabelle, Delden Christian, Steiger Jürg, Mohacsi Paul, Dufour Jean‐Francois, Soccal Paola M., Kutalik Zoltan, Marques‐Vidal Pedro, Vollenweider Peter, Recher Mike, Hess Christoph, Pascual Manuel, Eap Chin B. (2019), Genetic immune and inflammatory markers associated with diabetes in solid organ transplant recipients, in American Journal of Transplantation, 19(1), 238-246.
Serial IL-6 measurements in patients with tocilizumab-treated large-vessel vasculitis detect infections and may predict early relapses
Berger Christoph T, Rebholz-Chaves Birke, Recher Mike, Manigold Tobias, Daikeler Thomas (2019), Serial IL-6 measurements in patients with tocilizumab-treated large-vessel vasculitis detect infections and may predict early relapses, in Annals of the Rheumatic Diseases, 78(7), 1012-1014.
Immunoglobulin G and Subclasses as Potential Biomarkers in Metastatic Melanoma Patients Starting Checkpoint Inhibitor Treatment
Diem Stefan, Fässler Mirjam, Bomze David, Ali Omar Hasan, Berner Fiamma, Niederer Rebekka, Hillmann Dorothea, Mangana Joanna, Levesque Mitchell P., Dummer Reinhard, Risch Lorenz, Recher Mike, Risch Martin, Flatz Lukas (2019), Immunoglobulin G and Subclasses as Potential Biomarkers in Metastatic Melanoma Patients Starting Checkpoint Inhibitor Treatment, in Journal of Immunotherapy, 42(3), 89-93.

Collaboration

Group / person Country
Types of collaboration
Prof Karl S Lang Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Luigi Notarangelo United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Jolan Walter United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Fortbildung Hämatologie Unispital Basel Individual talk Immundefizienz 20.11.2019 Basel, Switzerland Recher Mike;
DBM Immunomeeting Individual talk New PID Entities 18.11.2019 Basel, Switzerland Recher Mike;
Fortbildung Innere Medizin, Kantonsspital Liestal Individual talk Immundefizienz und Immundysregulation 07.11.2019 Liestal, Switzerland Recher Mike;
Immune Thrombopenia International Study Group Meeting Talk given at a conference Keynote Lecture: ITP in primary Immunodeficiency 13.09.2019 Locarno, Switzerland Recher Mike;
Burghalde Symposium, Lenzburg Talk given at a conference Immundefizienz 22.08.2019 Lenzburg, Switzerland Recher Mike;
Personalized Medicine Talk given at a conference Personalized Immunology 24.05.2019 Basel, Switzerland Recher Mike;
Rheumatage Bern Talk given at a conference Keynote Lecture: Immunodeficiency and Immune dysrgeulation 25.04.2019 Bern, Switzerland Recher Mike;
Fortbildung Hämatologie, Kanstonsspital Thun Individual talk Immundysrgeulation 28.03.2019 Thun, Switzerland Recher Mike;
Retreat University of Basel Immunology Community (UBICO) Talk given at a conference New Primary Immunodeficiency Entities 25.03.2019 Engelberg, Switzerland Recher Mike;
Pflegenetzwerk Immundefizienz Talk given at a conference Ursachen und Therapie von Antikörpermangel 22.03.2019 Basel, Switzerland Recher Mike;
50 Jahre Klinik für Immunologie, Universitätspital Zürich Talk given at a conference Immunglobuline: Wann und wie 21.03.2019 Zürich, Switzerland Recher Mike;
Fortbildung innere Medizin, Kantonsspital Bruderholz Individual talk Immunodeficiency and Immundysrgeulation 15.02.2019 Bruderholzspital, Switzerland Recher Mike;
AIU Update Grindelwald Talk given at a conference Immunodeficiency and Immune Dysregulation 26.01.2019 Grindelwald, Switzerland Recher Mike;


Associated projects

Number Title Start Funding scheme
192652 The role of ZNF74 in the generation and maintenance of immunological memory 01.04.2020 Project funding (Div. I-III)
173186 Immune-dysregulation and autoimmunity in primary immunodeficiency 01.01.2018 SNSF Professorships

Abstract

Primary immunodeficiencies (PID) comprise more than 350 different clinical entities that affect the development, function -or both- of the immune system due to mutations in immune-related genes. Besides their association with infection, PID are associated with autoimmunity and immune-dysregulation, probably due to the impaired immune-tolerance.PID related autoimmunity is strongly linked to clinical complications and increased mortality. Since PID are monogenic diseases, PID-patients with autoimmunity, or relevant mouse models, represent a valuable tool to understand general mechanisms involved in the induction of autoimmunity and immune dysregulation. It has been recently demonstrated that different mutations in the same PID gene may lead to different clinical entities depending on the functional impact of the mutation. This is exemplarily demonstrated in PID associated with mutations in the recombination activating genes RAG1 and RAG2 that might lead to various clinical phenotypes ranging from severe combined immunodeficiency to late-onset autoimmunity.In this proposal, we aim to further analyze molecular mechanisms involved in the generation PID-associated immune-dysregulation and autoimmunity. We will do this by analyzing mouse models with a gradual decrease of RAG function due to complete loss-of function- or hypomorphic mutations in the RAG1 and RAG2 genes.In addition, as suggested by the mid-term SNF review, we will further characterize the function of SP110, another PID-gene that is associated with severe immunopathology and mortality following pneumocystis infection. This will be done by comparing the function of SP110 competent vs. deficient human T cells.In summary, the work proposed here might help to understand mechanisms involved in the development of immune-dysregulation, immunopathology and autoimmunity in patients with primary immunodeficiencies.
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