生物谷報(bào)道：在以色列Beth Israel Deaconess Medical Center（BIDMC ）的研究人員揭示,，一組鈣離子通道在引發(fā)炎癥反應(yīng)中起到至關(guān)重要的作用,。這不僅解開了長期以來氣喘和過敏癥狀的分子奧秘，同時(shí)也發(fā)現(xiàn)了肥大細(xì)胞的重要功能,。他們的研究結(jié)果刊登在2008年1月發(fā)行的《自然·免疫學(xué)》（Nature Immunology）上。
據(jù)該項(xiàng)研究第一作者,、BIDMC病理部和哈佛醫(yī)學(xué)院的研究人員Monika Vig博士說,，在全身的組織中都發(fā)現(xiàn)免疫細(xì)胞組，但人們曾經(jīng)認(rèn)為肥大細(xì)胞只在過敏性反應(yīng)中起作用,。肥大細(xì)胞在胚囊中貯存炎性細(xì)胞因子及化合物（包括組織胺和肝素）,，形成 “顆粒”,。當(dāng)肥大細(xì)胞遇到一種過敏原（比如說花粉）這些“顆粒”降解，'釋放出其內(nèi)容物而引發(fā)過敏性反應(yīng),。
不過,，近幾年，科學(xué)家已經(jīng)發(fā)現(xiàn)了肥大細(xì)胞的眾多其他角色,，暗示了他們是一些生物反應(yīng)的關(guān)鍵因素,，而且還與從多發(fā)性硬化癥和類風(fēng)濕關(guān)節(jié)炎到癌癥和動脈粥樣硬化等疾病有關(guān)。
為了使肥大細(xì)胞行使功能,，它們需要一個(gè)生物信號--具體來說,，就是需要鈣離子。鈣離子進(jìn)出細(xì)胞的方式是通過離子通道,，即CRAC流（calcium-release-activated calcium,，激活鈣釋放的鈣）。去年,，包括Vig在內(nèi)的幾個(gè)研究小組,，鑒定了CRACM1為編碼這個(gè)鈣離子通道的確切基因。
她解釋說,，“隨著鑒定這一長期以來難以捉摸的基因,，我們能夠構(gòu)造一個(gè)敲除CRACM1基因的小鼠，希望這些動物可用來證明,，它們對通常導(dǎo)致嚴(yán)重的過敏反應(yīng)的各種刺激不敏感”,。進(jìn)一步實(shí)驗(yàn)表明，由于肥大細(xì)胞CRACM1基因被敲除,，因此當(dāng)它們接觸到過敏原,，無法觸發(fā)過敏性反應(yīng)。
哈佛醫(yī)學(xué)院的資深作者,、病理學(xué)教授Jean-Pierre Kinet說,，這些發(fā)現(xiàn)提供了遺傳證據(jù)，顯示CRAC通道是肥大細(xì)胞活化所必需的,。這個(gè)結(jié)果證明了如下概念：CRAC通道的抑制劑應(yīng)能對肥大細(xì)胞相關(guān)疾病,，包括氣喘，過敏性疾病起作用 ,。
Vig還說 ,，因?yàn)榉蚀蠹?xì)胞也與其他幾個(gè)損害人健康的疾病（包括多發(fā)性硬化,，類風(fēng)濕關(guān)節(jié)炎及癌癥）有關(guān)系,，因此將來CRAC通道的抑制劑，能用于減緩疾病的發(fā)展以及減輕疾病的癥狀,。
生物谷推薦英文原文：
Nature Immunology 9, 89 - 96 (2007)
Published online: 2 December 2007 | doi:10.1038/ni1550
Defective mast cell effector functions in mice lacking the CRACM1 pore subunit of store-operated calcium release–activated calcium channels
Monika Vig1, Wayne I DeHaven2, Gary S Bird2, James M Billingsley1, Huiyun Wang1, Patricia E Rao3, Amy B Hutchings3, Marie-Hélène Jouvin1, James W Putney2 & Jean-Pierre Kinet1
Abstract
CRACM1 (also called Orai1) constitutes the pore subunit of store-operated calcium release–activated calcium channels. A point mutation in the gene encoding CRACM1 is associated with severe combined immunodeficiency disease in humans. Here we generated CRACM1-deficient mice in which -galactosidase activity 'reported' CRACM1 expression. CRACM1-deficient mice were smaller in size. Mast cells derived from CRACM1-deficient mice showed grossly defective degranulation and cytokine secretion, and the allergic reactions elicited in vivo were inhibited in CRACM1-deficient mice. We detected robust CRACM1 expression in skeletal muscles and some regions of the brain, heart and kidney but not in the lymphoid regions of thymus and spleen. In contrast, we found CRACM2 expression to be much higher in mouse T cells. In agreement with those findings, the store-operated calcium influx and development and proliferation of CRACM1-deficient T cells was unaffected. Thus, CRACM1 is crucial in mouse mast cell effector function, but mouse T cell calcium release–activated calcium channels are functional in the absence of CRACM1.
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, USA.
Synta Pharmaceuticals, Lexington, Massachusetts 02421, USA.
Correspondence to: Monika Vig1 e-mail: [email protected]
