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Giant Cell Arteritis - towards a molecular understanding of pathogenesis

Applicant Berger Christoph
Number 173517
Funding scheme Ambizione
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Immunology, Immunopathology
Start/End 01.04.2017 - 31.03.2018
Approved amount 201'807.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Clinical Immunology and Immunopathology

Keywords (4)

Risk Factor; Immunological Target; MHC; Vaskulitis

Lay Summary (German)

Lead
Die Suche nach dem immunologischen Ziel der Abwehrzellen bei einer Autoimmunerkrankung der Arterien.
Lay summary

Bei vielen Autoimmunerkrankungen ist bis Heute ungeklärt, warum die betroffenen Patienten erkranken. Vorgängige Viruserkrankungen können das Immunsystem aktivieren und dazu beitragen, dass es nicht mehr eigen von fremd unterscheiden kann, was eine Abwehrreaktion gegen körpereigene Gewebe auslösen kann.

In unserem Projekt studieren wir eine Autoimmunerkrankung welche die grossen Arterien des Menschen betrifft, die sogenannte Riesenzellarteritis. T Zellen, welche durch spezielle Eiweisse von Viren aktiviert werden können, spielen dabei eine wichtige Rolle. In klinischen Untersuchungen wurde vor kurzem das Varizella Zoster Virus (VZV) als Auslöser der Riesenzellarteritis ins Spiel gebracht. VZV macht bei der Erstinfektion die Windpocken („Wilden Blattern“), bleibt dann im Körper versteckt und kann sich im Alter reaktivieren als Gürtelrose. Wir wollen nun testen, ob die T Zellen in Riesenzellarteritis Patienten Viren erkennen die in der Gefässwand sitzen, oder aber fehlgeleitet sind und körpereigene Eiweisse angreifen. Dazu stimulieren wir die Zellen im Blut mit VZV oder Arterienbestandteilen und untersuchen auch direkt die Zellen welche die Entzündung in der Arterie machen.

Wenn wir krankmachende Zellen identifizieren und charakterisieren können, so kann diese Information genutzt werden um die Diagnose und Behandlung der Patienten zu verbessern.

Direct link to Lay Summary Last update: 03.05.2017

Responsible applicant and co-applicants

Employees

Publications

Publication
Immune system correlates of extensive limb swelling in response to conjugated pneumococcal vaccination
Recher Mike, Hirsiger Julia R., Bigler Marc B., Iff Martin, Lemaître Barbara, Scherer Kathrin, Häusermann Peter, Siegrist Claire-Anne, Berger Christoph T. (2018), Immune system correlates of extensive limb swelling in response to conjugated pneumococcal vaccination, in npj Vaccines, 3(1), 17-17.
Serum neurofilament light chain: a biomarker of neuronal injury in vasculitic neuropathy
Bischof Antje, Manigold Tobias, Barro Christian, Heijnen Ingmar, Berger Christoph T, Derfuss Tobias, Kuhle Jens, Daikeler Thomas (2018), Serum neurofilament light chain: a biomarker of neuronal injury in vasculitic neuropathy, in Annals of the Rheumatic Diseases, 77(7), 1093-1094.
Nano-scale microfluidics to study 3D chemotaxis at the single cell level
Frick Corina, Dettinger Philip, Renkawitz Jörg, Jauch Annaïse, Berger Christoph T., Recher Mike, Schroeder Timm, Mehling Matthias (2018), Nano-scale microfluidics to study 3D chemotaxis at the single cell level, in PLOS ONE, 13(6), e0198330-e0198330.
Computational Strategies for Dissecting the High-Dimensional Complexity of Adaptive Immune Repertoires
Miho Enkelejda, Yermanos Alexander, Weber Cédric R., Berger Christoph T., Reddy Sai T., Greiff Victor (2018), Computational Strategies for Dissecting the High-Dimensional Complexity of Adaptive Immune Repertoires, in Frontiers in Immunology, 9, 224.
Interleukin-6 flags infection in tocilizumab-treated giant cell arteritis
Berger Christoph T, Recher Mike, Daikeler Thomas (2018), Interleukin-6 flags infection in tocilizumab-treated giant cell arteritis, in Rheumatology, 57(1), 196-197.
[ 18 F]FDG positron emission tomography in patients presenting with suspicion of giant cell arteritis—lessons from a vasculitis clinic
Imfeld Stephan, Rottenburger Christof, Schegk Elke, Aschwanden Markus, Juengling Freimut, Staub Daniel, Recher Mike, Kyburz Diego, Berger Christoph T, Daikeler Thomas (2017), [ 18 F]FDG positron emission tomography in patients presenting with suspicion of giant cell arteritis—lessons from a vasculitis clinic, in European Heart Journal - Cardiovascular Imaging, 1.
Calcium pyrophosphate deposition disease: a frequent finding in patients with long-standing erosive gout
Ankli B, Kyburz D, Hirschmann A, Hügle T, Manigold T, Berger CT, Daikeler T (2017), Calcium pyrophosphate deposition disease: a frequent finding in patients with long-standing erosive gout, in Scandinavian Journal of Rheumatology, 47(2), 127-130.

Collaboration

Group / person Country
Types of collaboration
Colin Russell, AMC Amsterdam Netherlands (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Victor Greiff, University Oslo Norway (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
Cell Symposium Human Immunology Poster Escape from the flu vaccine relates to a restricted memory B cell repertoire 22.10.2017 Banff, Canada Berger Christoph; Bigler Marc;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Impfen im Alter - Was? Wann? Wie Warum? German-speaking Switzerland 2017

Awards

Title Year
Medizin Alumni Basel Preis 2017

Associated projects

Number Title Start Funding scheme
148000 Giant Cell Arteritis - towards a molecular understanding of pathogenesis 01.04.2014 Ambizione
192440 Identifying antigenic triggers of T cell-mediated immunopathology in Giant Cell Arteritis 01.03.2021 Project funding (Div. I-III)

Abstract

The adaptive immune system protects us from infections and cancer. T cells and antibodies, which are produced by B cells, recognize specific motifs on proteins, so-called epitopes presented on their surface. Failure of the immune system to distinguishing self from non-self proteins can result in autoimmune disease. An integrative model suggests that this can occur in genetically predisposed subjects on the basis of systemic immune dysregulation supporting subsequent expansion of auto-reactive cells [1]. Auto-immune vasculitis syndromes comprise a spectrum of diseases defined by primary inflammation of blood vessels, with Giant cell arteritis (GCA) being the most frequent form [2]. GCA manifests with constitutional symptoms, headache, and a systemic inflammatory syndrome, and patients are at risk for feared ischemic complications such as vision loss or stroke [2]. Studies on the immunopathology revealed that in GCA, CD4 T cells and macrophages are the key effector cells mediating vascular destruction in inflamed blood vessels [2]. The chain of events leading to GCA, including the immunological target of autoreactive T cells remains, however, unknown. While it is generally assumed that T cells recognize self-proteins from the vessel wall, very recently, a potential link between GCA and the presence of Varicella Zoster virus (VZV) in the arteries has been reported [3-5]. This suggests that VZV might trigger autoimmunity or could be the immunological target itself. A better understanding of the adaptive immune response in GCA has the potential to provide a rational for novel treatment strategies (e.g. addition of antiviral therapy) and/or to uncover individualized disease activity biomarkers (e.g. abundance of antigen specific T cell clones in the blood). To address unmet needs in GCA, we established a prospective cohort at the University Hospital Basel (Basler Riesenzellarteritis Kohorte; BARK) [6-8]. We collect clinical data and biological samples from patients and disease controls, the latter mostly being patients with initially suspected GCA. Taking advantage of this cohort and our expertise in T cell immunology and epitope discovery [9-11] the General Aim of this prolongation proposal is to complete our studies on the expansion of antigen-specific effector T cells in GCA, and their potential use as tool to better diagnose or stratify patients.Specific Aim #1: Screening for- and characterizing pathogenic T cells in GCA. Stimulating peripheral blood T cells using (i) protein fractions extracted from aortic tissue or (ii) VZV antigen, will allow testing whether reactive T cells can be detected in the blood using IFN-? ELISpot and flow cytometry based assays. Antigen specific T cell lines targeting VZV or blood vessel proteins will be generated that can be employed in subsequent antigen characterization assays and be used for T cell receptor (TCR) sequencing. This may provide arguments for a self- or pathogen-derived target epitope and could thereby help unravel the nature of the immune response attacking the arteries.Specific Aim #2: Assessing whether T cell clones in the inflammatory lesions of GCA biopsies share a TCR repertoire, and test their potential as biomarkers. Laser micro-dissection, and a multiplex PCR approach for the analysis of the TCR repertoire in the inflamed artery will be employed to test for the existence of dominant or public T cell clones. This would provide evidence for an antigen specific immune response in GCA. Quantitative PCR will then be used to track GCA-specific T cell clones (as identified in Specific Aim #1 or 2) longitudinally in the peripheral blood. By correlating clonal frequencies with disease activity, their relevance in disease pathogenesis can be assigned, and their value to serve as biomarker for immunosuppressive treatment-stewardship defined.
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