LRBA突变,BEACH结构域蛋白,导致人类严重的免疫缺陷。根据生化分析,LRBA在许多组织和器官中表达,但是对它的细胞和亚细胞定位知之甚少,以及它在免疫系统之外的缺乏表型。通过LacZ组织化学对Lrba基因陷阱小鼠的研究,我们对许多组织中的LRBA表达进行了全面调查,在许多如果不是所有的上皮中检测到它,在外分泌和内分泌细胞中,和神经元亚群。外分泌和内分泌胰腺的免疫荧光显微镜,唾液腺,和肠段,证实了这些细胞表达模式,并提供了有关LRBA蛋白亚细胞定位的信息。免疫电子显微镜显示,在神经元和内分泌细胞中,共同表达LRBA及其最接近的亲戚,神经海滩,这两种蛋白质都表现出与内膜互补的部分关联,而不是重叠,亚细胞分布。人类LRBA缺乏症的突出表现,如炎症性肠病或内分泌疾病,被认为主要是由于免疫失调。然而,因为基本上所有受影响的组织也表达LRBA,LRBA缺乏可能会增强其脆弱性并导致其发病机制。
Mutations in LRBA, a BEACH domain protein, cause severe immune deficiency in humans. LRBA is expressed in many tissues and organs according to biochemical analysis, but little is known about its cellular and subcellular localization, and its deficiency phenotype outside the immune system. By LacZ histochemistry of Lrba gene-trap mice, we performed a comprehensive survey of LRBA expression in numerous tissues, detecting it in many if not all epithelia, in exocrine and endocrine cells, and in subpopulations of neurons. Immunofluorescence microscopy of the exocrine and endocrine pancreas, salivary glands, and intestinal segments, confirmed these patterns of cellular expression and provided information on the subcellular localizations of the LRBA protein. Immuno-electron microscopy demonstrated that in neurons and endocrine cells, which co-express LRBA and its closest relative, neurobeachin, both proteins display partial association with endomembranes in complementary, rather than overlapping, subcellular distributions. Prominent manifestations of human LRBA deficiency, such as inflammatory bowel disease or endocrinopathies, are believed to be primarily due to immune dysregulation. However, as essentially all affected tissues also express LRBA, it is possible that LRBA deficiency enhances their vulnerability and contributes to the pathogenesis.