The Calcium Sensors STIM1 and STIM2 Control B Cell Regulatory Function through Interleukin-10 Production

Matsumoto, Masanori; Fujii, Yoko; Baba, Akemi; Hara, Masaki; Kurosaki, Tomohiro; Baba, Yoshifumi

doi:10.1016/j.immuni.2011.03.016

Cited by 236 publications

(306 citation statements)

References 43 publications

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“…However, a recent report of an STIM1-deficient patient suggested that intrinsic defects in other immune cell populations, such as natural killer cells, natural killer T cells, and B cells, could also contribute to the complex clinical phenotype seen in patients with STIM1 deficiency (40). This is consistent with studies in mice showing that B-cell knockdown of STIM1 and STIM2 led to exacerbation of experimental autoimmune encephalomyelitis, suggesting STIM-dependent SOC influx as a key signal for B-cell regulatory function required to limit autoimmunity (41). Thus, far, STIM2 defects or mutations have not been reported in any clinical conditions.…”

Section: Reduction Of Stim1 and Stim2 Expression In Pbmcs From Psssupporting

confidence: 73%

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

Cheng¹,

Alevizos

Liu³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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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.

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Section: Reduction Of Stim1 and Stim2 Expression In Pbmcs From Psssupporting

confidence: 73%

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

Cheng¹,

Alevizos

Liu³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…In contrast, STIM1/Orai1-dependent SOCe is required for T and B cell activation (61), and mutations in STIM1 result in immunodeficiency and autoimmune syndromes (62). Recently, a type 1 diabetic mouse model study reported that downregulation of STIM1 and SERCA3 in coronary ECs enhanced the ER Ca 2+ leak and store depletion (27).…”

Section: Discussionmentioning

confidence: 99%

Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation

Gandhirajan¹,

Meng²,

et al. 2013

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During sepsis, acute lung injury (ALI) results from activation of innate immune cells and endothelial cells by endotoxins, leading to systemic inflammation through proinflammatory cytokine overproduction, oxidative stress, and intracellular Ca 2+ overload. Despite considerable investigation, the underlying molecular mechanism(s) leading to LPS-induced ALI remain elusive. To determine whether stromal interaction molecule 1-dependent (STIM1-dependent) signaling drives endothelial dysfunction in response to LPS, we investigated oxidative and STIM1 signaling of EC-specific Stim1-knockout mice. Here we report that LPSmediated Ca 2+ oscillations are ablated in ECs deficient in Nox2, Stim1, and type II inositol triphosphate receptor (Itpr2). LPS-induced nuclear factor of activated T cells (NFAT) nuclear accumulation was abrogated by either antioxidant supplementation or Ca 2+ chelation. Moreover, ECs lacking either Nox2 or Stim1 failed to trigger store-operated Ca 2+ entry (SOCe) and NFAT nuclear accumulation. LPS-induced vascular permeability changes were reduced in EC-specific Stim1 -/-mice, despite elevation of systemic cytokine levels. Additionally, inhibition of STIM1 signaling prevented receptor-interacting protein 3-dependent (RIP3-dependent) EC death. Remarkably, BTP2, a small-molecule calcium release-activated calcium (CRAC) channel blocker administered after insult, halted LPS-induced vascular leakage and pulmonary edema. These results indicate that ROS-driven Ca 2+ signaling promotes vascular barrier dysfunction and that the SOCe machinery may provide crucial therapeutic targets to limit sepsis-induced ALI.

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“…BCR ligation induces TIM-1 expression on B cells [41,42], and TIM-1 ligation appears to enhance BCR signaling since it increases antibody production both in vitro and in vivo [43]. The importance of BCR-related signals is further highlighted by the observation that the stromal interaction molecules 1 (STIM1) and 2 (STIM2) are required for B cell IL-10 production [44]. Remarkably, B cells lacking both stromal interaction molecule proteins failed to produce IL-10 after BCR stimulation in the presence of PMA and ionomycin for 5 hours [44].…”

Section: Biology Of B10 Cellsmentioning

confidence: 99%

“…The importance of BCR-related signals is further highlighted by the observation that the stromal interaction molecules 1 (STIM1) and 2 (STIM2) are required for B cell IL-10 production [44]. Remarkably, B cells lacking both stromal interaction molecule proteins failed to produce IL-10 after BCR stimulation in the presence of PMA and ionomycin for 5 hours [44]. All of the above indicate that BCR-related signals are particularly important in B10 cell development.…”

Section: Biology Of B10 Cellsmentioning

confidence: 99%

IL-10-producing regulatory B cells (B10 cells) in autoimmune disease

2013

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B cell abnormalities contribute to the development and progress of autoimmune disease. Traditionally, the role of B cells in autoimmune disease was thought to be predominantly limited to the production of autoantibodies. Nevertheless, in addition to autoantibody production, B cells have other functions potentially relevant to autoimmunity. Such functions include antigen presentation to and activation of T cells, expression of co-stimulatory molecules and cytokine production. Recently, the ability of B cells to negatively regulate cellular immune responses and inflammation has been described and the concept of regulatory B cells has emerged. A variety of cytokines produced by regulatory B cell subsets have been reported, with IL-10 being the most studied. In this review, this specific IL-10-producing subset of regulatory B cells has been labeled B10 cells to highlight that the regulatory function of these rare B cells is mediated by IL-10, and to distinguish them from other B cell subsets that regulate immune responses through different mechanisms. B10 cells are a functionally defined subset currently identified only by their competency to produce and secrete IL-10 following appropriate stimulation. Although B10 cells share surface markers with other previously defined B cell subsets, currently there is no cell surface or intracellular phenotypic marker or set of markers unique to B10 cells. The recent discovery of an effective way to expand B10 cells ex vivo opens new horizons in the potential therapeutic applications of this rare B cell subset. This review highlights the current knowledge on B10 cells and discusses their potential as novel therapeutic agents in autoimmunity.

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The Calcium Sensors STIM1 and STIM2 Control B Cell Regulatory Function through Interleukin-10 Production

Cited by 236 publications

References 43 publications

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

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

Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation

IL-10-producing regulatory B cells (B10 cells) in autoimmune disease

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