Gain of function of 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 calcium in skeletal muscle. RYR1 encodes a calcium channel that is predominantly expressed in skeletal muscle sarcoplasmic reticulum where it is involved in releasing the calcium 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 may offer selective immune advantages to their carriers. Furthermore, our results raise the intriguing possibility that pharmacological activation of RyR1 may be exploited for the development of new classes of vaccines and adjuvants.