STIM1 and STIM2 protein deficiency in T lymphocytes underlies development of the exocrine gland autoimmune disease, Sjögren's syndrome

Abstract

Primary Sjögren's Syndrome (pSS) is an autoimmune disease involving salivary and other exocrine glands that leads to progressive lymphocytic infiltration into the gland, tissue damage, and secretory defects. The mechanism underlying this disease remains poorly understood. Here we report that mice with T-cell–targeted deletion of Stromal Interaction Molecule (STIM) 1 and STIM2 [double-knockout (DKO)] mice develop spontaneous and severe pSS-like autoimmune disease, displaying major hallmarks of the disease. In DKO mice, diffuse lymphocytic infiltration was seen in submandibular glands, a major target of pSS, by age 6 wk, progressing to severe inflammation by age 12 wk. Sjögren's syndrome-specific autoantibodies (SSA/Ro and SSB/La) were detected in the serum, and progressive salivary gland destruction and loss of fluid secretion were also seen. Importantly, we report that peripheral blood mononuclear cells as well as lymphocytic infiltrates in submandibular glands from patients with pSS demonstrated significant reductions in STIM1 and STIM2 proteins. Store-operated calcium entry was also reduced in peripheral blood mononuclear cells from pSS patients compared with those from healthy controls. Thus, deficiency of STIM1 and STIM2 proteins in T cells, and consequent defects in Ca 2+ signaling, are associated with salivary gland autoimmunopathy in DKO mice and pSS patients. These data reveal a previously unreported link between STIM1 and STIM2 proteins and pSS.

Aquaporin gene therapy corrects Sjögren’s syndrome phenotype in mice

“…Knockout mice for AQP5, NKCC1, IP3R types 2 and 3, matriptase, and the M3 and M1 muscarinic receptors are all reported to have a decrease in saliva flow (28)(29)(30)(31)(32). The interplay between the epithelia and the immune system adds a further layer of complexity because T-cell knockouts of IP3K, STIM1/STIM2, and ID3 and overexpression of IL-12, BAFF, and sTNFR1 are all also reported to induce loss of gland function and may initiate it by different pathways (33)(34)(35)(36)(37)(38). We report an association between elevated BMP6 protein expression and AQP5 expression, but changes in any of these other factors triggered by environmental stimuli could account for the loss of gland activity in the patients with normal BMP6 expression.…”

STIM1 and STIM2 Proteins Differently Regulate Endogenous Store-operated Channels in HEK293 Cells

“…(15, 19 -22). Disruption of STIM2-mediated signaling contributes to a broad spectrum of diseases, including immune and autoimmune disorders, cancer, ischemia, and neurodegeneration (15,(23)(24)(25)(26)(27)(28)(29)(30)(31)(32) CRAC channels are the first described and best studied storeoperated channels (33). However, it is only in a few cell types (mainly in the immune system) that store-operated calcium currents are mediated by CRAC channels alone.…”

Trpc1

“…Trpc1-null mice show reduced secretion of salivary fluid, a function that is consistent with its role as a store-operated channel . These findings are supported by the identification of loss-of-function mutations in STIM1, associated with Sjogren's syndrome (Cheng et al 2012), characterized by reduced salivary gland secretion. Guided by the potential role of TRPC1 as a receptor-and/or mechanically activated channel, a possible role of TRPC1 in cardiac hypertrophy was examined (Seth et al 2009).…”

“…These data are supported by experiments in Trpc1-null mice where agonist-induced store-operated entry channels and salivary gland fluid secretion are both suppressed in salivary gland cells derived from these mice ). Further, naturally occurring mutations in STIM1 in humans lead to Sjogren's syndrome, an autoimmune disease characterized by exocrine gland defects (Cheng et al 2012). …”