LAUSR

Gain-of-function mutations in gene encoding ryanodine receptor type 1 (RyR1), an endo/sarcoplasmic reticulum Ca2+ release channel, are linked to a variety of skeletal muscular disorders. Other tissues, including cells of the immune system, have been shown to express RyR1. A previous study demonstrated enhanced immune responses in mice with gain-of-function RyR1 mutation (Vukcevic et al., 2013, J Cell Sci, 126: 3485-92). Here we report that after induction of an experimental autoimmune encephalomyelitis (EAE), a T cell-mediated autoimmune disease, the mice carrying gain-of-function RyR1 R163C mutation (R163C mice) displayed an earlier disease onset and augmentation of neurological symptoms compared with wild-type (WT) mice. In vitro studies revealed that splenocytes from the R163C mice have altered Ca2+ signaling compared with those from WT mice, which was revealed by challenging the cells with different concentrations of extracellular Ca2+ and Ca2+ mobilizing agent thapsigargin. No differences were found in the relative abundances of immune cell subtypes in spleens and lymph nodes from R163C and WT mice prior to the onset of the EAE. Nevertheless, immunostaining of the lumbar spinal cord sections after the onset of the clinical symptoms, revealed the larger pro-inflammatory infiltrate and axonal damage in the R163C mice compared with the WT mice, indicating that R163C mutation may affect immune cell trafficking to the CNS. These data indicate that altered Ca2+ handling in R163C mice immune cells may enhance these cells autoimmune responses and that gain-of-function mutations in RYR1 may represent a previously unknown risk factor for autoimmune diseases.