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Gain of function in the immune system caused by a ryanodine receptor 1 mutation

Vukcevic, M. and Zorzato, F. and Keck, S. and Tsakiris, D. A. and Keiser, J. and Maizels, R. M. and Treves, S.. (2013) Gain of function in the immune system caused by a ryanodine receptor 1 mutation. Journal of cell science, 126 (15). pp. 3485-3492.

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Official URL: http://edoc.unibas.ch/dok/A6165164

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Abstract

Mutations in RYR1, the gene encoding ryanodine receptor 1, are linked to a variety of neuromuscular disorders including malignant hyperthermia (MH), a pharmacogenetic hypermetabolic disease caused by dysregulation of Ca(2+) in skeletal muscle. RYR1 encodes a Ca(2+) channel that is predominantly expressed in skeletal muscle sarcoplasmic reticulum, where it is involved in releasing the Ca(2+) necessary for muscle contraction. Other tissues, however, including cells of the immune system, have been shown to express ryanodine receptor 1; in dendritic cells its activation leads to increased surface expression of major histocompatibility complex II molecules and provides synergistic signals leading to cell maturation. In the present study, we investigated the impact of an MH mutation on the immune system by studying the RYR1Y522S knock-in mouse. Our results show that there are subtle but significant differences both in resting 'non-challenged' mice as well as in mice treated with antigenic stimuli, in particular the knock-in mice: (i) have dendritic cells that are more efficient at stimulating T cell proliferation, (ii) have higher levels of natural IgG1 and IgE antibodies, and (iii) are faster and more efficient at mounting a specific immune response in the early phases of immunization. We suggest that some gain-of-function MH-linked RYR1 mutations might offer selective immune advantages to their carriers. Furthermore, our results raise the intriguing possibility that pharmacological activation of RyR1 might be exploited for the development of new classes of vaccines and adjuvants.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin
03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Perioperative Patient Safety (Girard/Treves)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Helminth Drug Development (Keiser)
UniBasel Contributors:Zorzato, Francesco and Vukcevic, Mirko and Tsakiris, Dimitrios A. and Keiser, Jennifer and Treves, Susan
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Company of Biologists
ISSN:0021-9533
e-ISSN:1477-9137
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:11 May 2017 08:49
Deposited On:25 Oct 2013 08:33

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