title: Gain of function in the immune system caused by a ryanodine receptor 1 mutation.
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.
authors.affiliation: Departments of Anaesthesia and Biomedicine, Basel University Hospital, Hebelstrasse 20, 4031 Basel, Switzerland.
authors.forename: Mirko
authors.initials: M
authors.lastname: Vukcevic
authors.forename: Francesco
authors.initials: F
authors.lastname: Zorzato
authors.forename: Simone
authors.initials: S
authors.lastname: Keck
authors.forename: Dimitrios A
authors.initials: DA
authors.lastname: Tsakiris
authors.forename: Jennifer
authors.initials: J
authors.lastname: Keiser
authors.forename: Rick M
authors.initials: RM
authors.lastname: Maizels
authors.forename: Susan
authors.initials: S
authors.lastname: Treves
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D007136:Immunoglobulins / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009351:Nematospiroides dubius / Q000276:immunology; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics* / Q000276:immunology*; D017206:Strongylida Infections / Q000097:blood / Q000276:immunology
chemical_list: D007136:Immunoglobulins; D019837:Ryanodine Receptor Calcium Release Channel
keywords: Dendritic cell; Immune system; RyR1; Ryanodine receptor