{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T05:00:37Z","timestamp":1785128437419,"version":"3.55.0"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Ryanodine receptor 1 (RyR1) is a key intracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    release channel primarily expressed in skeletal muscle, but also in some immune cells. Gain-of-function RYR1 mutations are the most common cause of the pharmacogenetic disorder malignant hyperthermia susceptibility. Compatibly, mice knocked in for gain of function\n                    <jats:italic>Ryr1<\/jats:italic>\n                    mutations develop malignant hyperthermia but also show subtle changes in their immune function, supporting a potential but yet to be explored effect of RyR1 mutations on the human immune system. Healthy controls and subjects classified as Malignant Hyperthermia Susceptible were enrolled in an anonymized allergy questionnaire study. PBMC and Epstein Barr virus immortalized B cells from the two cohorts were characterized for surface markers by flow cytometry and for calcium homeostasis using the intracellular calcium indicator Fluo-4. Serum samples were investigated for circulating cytokines by ELISA and Ig quantification was carried out by a clinical laboratory. Malignant hyperthermia susceptible individuals report a higher frequency of allergies, show changes in circulating immunoglobulin and cytokine levels and their circulating B cells exhibit a pre-activated state, with increased surface expression of the co-stimulatory molecules CD86 and CD40. Stimulation of EBV-immortalized B lymphocytes with the RyR1 agonist caffeine results in a tetracaine-sensitive increased surface expression of CD86, which was more pronounced in cells from malignant hyperthermia susceptible individuals. Our results support a functional role of RyR1 in B-lymphocyte Ca\n                    <jats:sup>2+<\/jats:sup>\n                    signaling and show that in humans the presence of gain of function\n                    <jats:italic>RYR1<\/jats:italic>\n                    mutations leads to the pre-activation of B cells.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1876709","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T04:25:51Z","timestamp":1785126351000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["RYR1 mutations linked to malignant hyperthermia susceptibility are associated with phenotypic changes in human B-lymphocytes"],"prefix":"10.3389","volume":"17","author":[{"given":"Huiying","family":"Li","sequence":"first","affiliation":[{"name":"Department of Biomedicine and Neurology, Basel University Hospital","place":["Basel, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela V.","family":"Andrade","sequence":"additional","affiliation":[{"name":"Brazilian Malignant Hyperthermia Unit. Department of Anesthesiology, Pain and Intensive Care, University Federal of S\u00e3o Paulo","place":["S\u00e3o Paulo, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irem Huriye","family":"Ceren","sequence":"additional","affiliation":[{"name":"Department of Biomedicine and Neurology, Basel University Hospital","place":["Basel, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis","family":"Ruiz","sequence":"additional","affiliation":[{"name":"Department of Biomedicine and Neurology, Basel University Hospital","place":["Basel, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aline I.","family":"Silva","sequence":"additional","affiliation":[{"name":"Brazilian Malignant Hyperthermia Unit. Department of Anesthesiology, Pain and Intensive Care, University Federal of S\u00e3o Paulo","place":["S\u00e3o Paulo, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murilo F.","family":"Farias","sequence":"additional","affiliation":[{"name":"Brazilian Malignant Hyperthermia Unit. Department of Anesthesiology, Pain and Intensive Care, University Federal of S\u00e3o Paulo","place":["S\u00e3o Paulo, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thalles S.","family":"Zorzeto","sequence":"additional","affiliation":[{"name":"Brazilian Malignant Hyperthermia Unit. Department of Anesthesiology, Pain and Intensive Care, University Federal of S\u00e3o Paulo","place":["S\u00e3o Paulo, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariz","family":"Vainzof","sequence":"additional","affiliation":[{"name":"Human Genome and Stem Cells Research Center, Institute of Biosciences, University of S\u00e3o Paulo","place":["S\u00e3o Paulo, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Zorzato","sequence":"additional","affiliation":[{"name":"Department of Biomedicine and Neurology, Basel University Hospital","place":["Basel, Switzerland"]},{"name":"Department of Life Science and Biotechnology, University of Ferrara","place":["Ferrara, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helga C. A.","family":"Silva","sequence":"additional","affiliation":[{"name":"Brazilian Malignant Hyperthermia Unit. 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