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Giant Cell Arteritis - towards a molecular understanding of pathogenesis

Applicant Berger Christoph
Number 148000
Funding scheme Ambizione
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Clinical Immunology and Immunopathology
Start/End 01.04.2014 - 31.03.2017
Approved amount 600'000.00
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All Disciplines (2)

Discipline
Clinical Immunology and Immunopathology
Immunology, Immunopathology

Keywords (9)

Vasculitis; Regulatory T cells; Th17 T cells; T cell receptor; Biomarker; Cytokine Milieu; Laser Capture Microscopy; MHC restriction; Epitope prediction

Lay Summary (German)

Lead
Attackiert das Immunsystem den eigenen Körper spricht man von Autoimmunität. Wie Autoimmunität genau entsteht ist unklar. Wir postulieren dass eine dysregulierte Freisetzung von Botenstoffen und/oder das Versagen regulierender Zellen Autoimmunität ermöglichen. Fehlende Regulation könnte eine Vermehrung von Abwehrzellen zur Folge haben welche Bestandteile des eigenen Körper erkennen und angreifen. Was solche auto-reaktiven Zellen erkennen ist bei den meisten Autoimmunerkrankungen unbekannt.
Lay summary

Inhalt und Ziel des Forschungsprojekts

Das übergeordnete Ziel des Projektes ist es, zu einem verbesserten Verständnis der Entstehung von Autoimmunität beizutragen.  Wir planen Menschen zu untersuchen welche an einer Autoimmunerkrankung der Blutgefässe –der sogenannten Riesenzellarteritis– leiden.  Konkret möchten wir definieren wie (i) immunologische Botenstoffe –sogenannte Zytokine– die Vermehrung von Abwehrzellen welche den eigenen Körper angreifen fördern; (ii) welche Strukture(en) fehlgeleitete Abwehrzellen genau erkennen; und (iii) ob regulierende Immunzellen, –welche Autoimmunität verhindern sollten– defekt sein könnten.  Moderne Labormethoden und computerisierte Datenanalysen werden dabei zur Anwendung kommen.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Unser Projekt wird Hinweise liefern über die Prozesse, welche die Entstehung von Autoimmunerkrankungen begünstigen.  Wenn es uns gelingt die dysregulierten Abwehrzellen präzise zu definieren, so ist dies die Basis um Tests zu entwickeln, welche in der Diagnostik oder Therapiekontrolle von betroffenen Patienten angewendet werden könnten.

Direct link to Lay Summary Last update: 22.08.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
A Genome-wide Association Study Identifies Risk Alleles in Plasminogen and P4HA2 Associated with Giant Cell Arteritis.
Carmona F David, Vaglio Augusto, Mackie Sarah L, Hernández-Rodríguez José, Monach Paul A, Castañeda Santos, Solans Roser, Morado Inmaculada C, Narváez Javier, Ramentol-Sintas Marc, Pease Colin T, Dasgupta Bhaskar, Watts Richard, Khalidi Nader, Langford Carol A, Ytterberg Steven, Boiardi Luigi, Beretta Lorenzo, Govoni Marcello, Emmi Giacomo, Bonatti Francesco, Cimmino Marco A, Witte Torsten, Neumann Thomas, Holle Julia (2017), A Genome-wide Association Study Identifies Risk Alleles in Plasminogen and P4HA2 Associated with Giant Cell Arteritis., in American journal of human genetics, 100(1), 64-74.
Characteristics of autoantibodies targeting 14-3-3 proteins and their association with clinical features in newly diagnosed giant cell arteritis.
Kistner Anne, Bigler Marc B, Glatz Kathrin, Egli Simon B, Baldin Fabian S, Marquardsen Florian A, Mehling Matthias, Rentsch Katharina M, Staub Daniel, Aschwanden Markus, Recher Mike, Daikeler Thomas, Berger Christoph T (2017), Characteristics of autoantibodies targeting 14-3-3 proteins and their association with clinical features in newly diagnosed giant cell arteritis., in Rheumatology (Oxford, England), 56(5), 829-834.
Factors associated with significant MRI findings in medical walk-in patients with acute headache.
Budweg Joris, Sprenger Till, De Vere-Tyndall Anthony, Hagenkord Anne, Stippich Christoph, Berger Christoph T (2017), Factors associated with significant MRI findings in medical walk-in patients with acute headache., in Swiss medical weekly, 146, 14349-14349.
Low immunoglobulin E flags two distinct types of immune dysregulation.
Elkuch M, Greiff V, Berger C T, Bouchenaki M, Daikeler T, Bircher A, Navarini A A, Heijnen I, Recher M (2017), Low immunoglobulin E flags two distinct types of immune dysregulation., in Clinical and experimental immunology, 187(3), 345-352.
Trametinib after disease reactivation under dabrafenib in Erdheim-Chester disease with both BRAF and KRAS mutations.
Nordmann Thierry M, Juengling Freimut D, Recher Mike, Berger Christoph T, Kalbermatten Daniel, Wicki Andreas, Paasinen-Sohns Aino, Cathomas Gieri, Tzankov Alexandar, Daikeler Thomas (2017), Trametinib after disease reactivation under dabrafenib in Erdheim-Chester disease with both BRAF and KRAS mutations., in Blood, 129(7), 879-882.
Vedolizumab as a successful treatment of CTLA-4-associated autoimmune enterocolitis.
Navarini Alexander A, Hruz Petr, Berger Christoph T, Hou Tie Zheng, Schwab Charlotte, Gabrysch Annemarie, Higgins Rebecca, Frede Natalie, Padberg Sgier Barbara-Christina, Kämpe Olle, Burgener Anne-Valérie, Marquardsen Florian, Baldin Fabian, Bigler Marc, Kistner Anne, Jauch Annaise, Bignucolo Olivier, Meyer Benedikt, Meienberg Fabian, Mehling Matthias, Jeker Lukas T, Heijnen Ingmar, Daikeler Thomas D, Gebbers Jan-Olaf, Grimbacher Bodo (2017), Vedolizumab as a successful treatment of CTLA-4-associated autoimmune enterocolitis., in The Journal of allergy and clinical immunology, 139(3), 1043-1046.
A 'Too Negative' ANA Test Predicts Antibody Deficiency.
Recher Mike, Berger Christoph T, Daikeler Thomas, Hess Christoph, Heijnen Ingmar A F M (2016), A 'Too Negative' ANA Test Predicts Antibody Deficiency., in Journal of clinical immunology, 36(4), 374-6.
HLA-C levels impact natural killer cell subset distribution and function.
Sips Magdalena, Liu Qingquan, Draghi Monia, Ghebremichael Musie, Berger Christoph T, Suscovich Todd J, Sun Yongtao, Walker Bruce D, Carrington Mary, Altfeld Marcus, Brouckaert Peter, De Jager Philip L, Alter Galit (2016), HLA-C levels impact natural killer cell subset distribution and function., in Human immunology, 77(12), 1147-1153.
Neglected for too long? - CD8+ Tregs release NOX2-loaded vesicles to inhibit CD4+ T cells.
Berger Christoph T, Hess Christoph (2016), Neglected for too long? - CD8+ Tregs release NOX2-loaded vesicles to inhibit CD4+ T cells., in The Journal of clinical investigation, 126(5), 1646-8.
Diagnosis at your fingertips: splinters and microemboli - is it SLE?
Berger C T, Baldi T, Aschwanden M, Scherer K, Recher M, Hess C, Daikeler T (2015), Diagnosis at your fingertips: splinters and microemboli - is it SLE?, in Lupus, 24(3), 341-2.
Influenza vaccine response profiles are affected by vaccine preparation and preexisting immunity, but not HIV infection.
Berger Christoph T, Greiff Victor, Mehling Matthias, Fritz Stefanie, Meier Marc A, Hoenger Gideon, Conen Anna, Recher Mike, Battegay Manuel, Reddy Sai T, Hess Christoph (2015), Influenza vaccine response profiles are affected by vaccine preparation and preexisting immunity, but not HIV infection., in Human vaccines & immunotherapeutics, 11(2), 391-396.
Neues therapeutisches Ziel für verschiedene Erkrankungen: Immunregulation durch regulatorische T-Zellen
Berger Christoph T., Recher Mike (2015), Neues therapeutisches Ziel für verschiedene Erkrankungen: Immunregulation durch regulatorische T-Zellen, in Schweiz Med Forum, 15(04), 76-81.
Risk factors for pneumocystis pneumonia in giant cell arteritis: a single-centre cohort study.
Berger C T, Greiff V, John S, Koenig K F, Bigler M B, Recher M, Hess C, Daikeler T (2015), Risk factors for pneumocystis pneumonia in giant cell arteritis: a single-centre cohort study., in Clinical and experimental rheumatology, 33(2 Suppl 89), 122-5.
Stress-Induced In Vivo Recruitment of Human Cytotoxic Natural Killer Cells Favors Subsets with Distinct Receptor Profiles and Associates with Increased Epinephrine Levels.
Bigler Marc B, Egli Simon B, Hysek Cédric M, Hoenger Gideon, Schmied Laurent, Baldin Fabian S, Marquardsen Florian A, Recher Mike, Liechti Matthias E, Hess Christoph, Berger Christoph T (2015), Stress-Induced In Vivo Recruitment of Human Cytotoxic Natural Killer Cells Favors Subsets with Distinct Receptor Profiles and Associates with Increased Epinephrine Levels., in PloS one, 10(12), 0145635-0145635.
The ultrasound compression sign to diagnose temporal giant cell arteritis shows an excellent interobserver agreement.
Aschwanden M, Imfeld S, Staub D, Baldi T, Walker U A, Berger C T, Hess C, Daikeler T (2015), The ultrasound compression sign to diagnose temporal giant cell arteritis shows an excellent interobserver agreement., in Clinical and experimental rheumatology, 33(2 Suppl 89), 113-5.
[Better vaccinations - new approaches for targeted immunomodulation in healthy and immunosuppressed].
Balmer Maria L, Berger Christoph T (2014), [Better vaccinations - new approaches for targeted immunomodulation in healthy and immunosuppressed]., in Therapeutische Umschau. Revue thérapeutique, 71(1), 5-15.
Genetic variation in schlafen genes in a patient with a recapitulation of the murine Elektra phenotype.
Recher Mike, Karjalainen-Lindsberg Marja-Liisa, Lindlöf Mikael, Söderlund-Venermo Maria, Lanzi Gaetana, Väisänen Elina, Kumar Arun, Sadeghi Mohammadreza, Berger Christoph T, Alitalo Tiina, Anttila Pekka, Kolehmainen Maija, Franssila Rauli, Chen Tingting, Siitonen Sanna, Delmonte Ottavia M, Walter Jolan E, Pessach Itai, Hess Christoph, Simpson Michael A, Navarini Alexander A, Giliani Silvia, Hedman Klaus, Seppänen Mikko, Notarangelo Luigi D (2014), Genetic variation in schlafen genes in a patient with a recapitulation of the murine Elektra phenotype., in The Journal of allergy and clinical immunology, 133(5), 1462-1465.
Immune screening identifies novel T cell targets encoded by anti-sense reading frames of HIV-1.
Berger Christoph T, Llano Anuska, Carlson Jonathan M, Brumme Zabrina L, Brockman Mark A, Cedeño Samandhy, Harrigan P Richard, Kaufmann Daniel E, Heckerman David, Meyerhans Andreas, Brander Christian, Immune screening identifies novel T cell targets encoded by anti-sense reading frames of HIV-1., in Journal of virology.

Collaboration

Group / person Country
Types of collaboration
Cardiff Institute of Infection & Immunity Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Institute for Rheumatology, Immunology and Allergology Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
La Jolla Institute for Allergy & Immunology United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Institut für Pathologie Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
D-BSSE ETH Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Poster at the NK 2016, Tenormina Italy October 2nd-5th 2016 Poster Interferon lambda 3 (IFN-λ3) enhances NK cell cytotoxicity against tumor cell lines 02.10.2016 Tenormina, Italy Bigler Marc;
10th Vaccine Meeting Talk given at a conference Seasonal influenza vaccination induces cross-binding antibody responses in healthy subjects and HIV-infected individuals 04.09.2016 Amsterdam, Netherlands Berger Christoph;
Medart Basel Talk given at a conference Meet the Expert - Differentialdiagnose der Vaskulitiden 24.06.2016 Basel, Switzerland Berger Christoph;
Swiss Society for Internal Medicine Meeting Talk given at a conference Influenza vaccination induces cross-strain reactive antibody responses 09.05.2016 Basel, Switzerland Berger Christoph;
18th Course AIU Grindelwald Talk given at a conference Giant Cell Arteritis - A practical Approach 06.02.2016 Grindelwald, Switzerland Berger Christoph;
Symposium d'Immunologie et d'Allergologie, Hopital Universitaires de Geneve Talk given at a conference Immunopathogenesis of Giant Cell Arteritis 28.04.2015 Genf, Switzerland Berger Christoph;
Swiss Society for Allergology and Immunology (SSAI) 2015 Conference Poster Stress-induced in vivo recruitment of human cytotoxic Natural Killer cells is epinephrine-mediated and requires distinct receptor profiles 05.03.2015 Basel, Switzerland Bigler Marc; Berger Christoph;
Vasculitis and ANCA-Workshop 2015 Poster Risk factors for pneumocystis jirovecii pneumonia in giant cell arteritis - a single centre cohort study 21.02.2015 London, Great Britain and Northern Ireland Berger Christoph; Bigler Marc;


Awards

Title Year
Co-Preisträger SAKK Amgen Research Award 2015

Associated projects

Number Title Start Funding scheme
173517 Giant Cell Arteritis - towards a molecular understanding of pathogenesis 01.04.2017 Ambizione

Abstract

Failure of the immune system to discriminate self from non-self can result in autoimmune disease. An integrative model suggests that the balance between auto-reactive T cells and so-called regulatory T cells (Tregs) dictates the likelihood to develop autoimmunity. We aim to test this hypothesis in patients with Giant cell arteritis (GCA), an autoimmune disease of the blood vessels. Both, IL-17 producing Th17 cells -that represent the prototype of auto-reactive effector T cells- and Tregs, have been linked to GCA pathogenesis. We will investigate, whether dysregulated Treg function contributes to disease pathogenesis, e.g. via insufficient suppression of auto-aggressive T-cells or by inducing a Th17 promoting cytokine milieu.Following antigenic stimulation, T effector cells expand clonally. T cell receptor (TCR) sequencing can be used to assess the clonal T cell repertoire. In chronic infections, certain cancers and autoimmune diseases, T cell clones have been identified that occur frequently and are shared between different patients affected with the same disease (‘public T cell clones’). Little is known about the TCR repertoire in GCA. We hypothesize that clonally expanded T cells detect common vascular self-antigens in GCA, which should be reflected in a narrow TCR repertoire and the presence of public TCR. To test this hypothesis, we aim to define the TCR repertoire at the site of autoimmune inflammation in GCA, taking advantage of laser capture microdissection of infiltrating T cells, combined with an unbiased PCR approach. Using computational epitope prediction tools, the target antigen will then be further characterized. As a clinical application, identification of disease-specific TCR clonotypes in inflamed tissue would permit to track and characterize them in the peripheral blood, opening the possibility for highly specific biomarker-research.
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