AIE-75 gene : with special reference to the differentiation of mucosal epithelial cells and the regulation of gene expression

AIE-75基因：特别涉及粘膜上皮细胞的分化和基因表达的调控

• 批准号: 14370237
• 负责人: KOBAYASHI Kunihiko
• 金额: $ 9.41万
• 依托单位: HOKKAIDO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370237/
• 关键词: AIE-75; Usher's syndrome; promotor; IPEX; 自己免疫性; AIE-75遺伝子; 遺伝子発現制御; 自己免疫; 難治性下痢; ALE-75; アッシャー症候群; 自己抗原; 転写因子

Autoimmune enteropathy is a rare disease characterized by severe and refracrory diarrhea and the presence of circulating ants-enterocyte autoantibody. We have identified autoimmune enteropathy-related 75 kDa antigen (AIE-75) as a candidate autoantigen in the disease, which distributes to the brush border of both the small intestine and proximal renal tubulus. The distribution of AIE-75 is limited to the apical site of the villi, suggesting that the expression is regulated in cell cycle-or maturation-dependent manners. To approach this, we analyzed cis-element of the promotor region of AIIE-75 gene using luciferase assay, and found that -9 to -63 bases upstream of the transcription initiation site is involved in he negative regulation of the gene expression.The specificity and sensitivity of anti-AJE-75 antibody in autoimmune enteropathy were confirmed in collaboration with other groups. Furthermore, we identified an actin-binding protein, villin, as another autoantigen related to the disease.AIE-75 was found to be a responsible gene for Usher's syndrome type IC which is characterized by deafness and retinopathy. Indeed, AIE-75 was also expressed in both epithelial cells of the inner ear and retina. We found that ALE-75 is involved in the assembly of photoreceptor with cadherin 23 and myosin VII in the retina, but that the expression of AIE-75 is independent of the expression of the both proteins.Some cases of autoimmune enteropathy are inherited in an X-linked manner, named immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) of which cause is the mutation of a forkhead winged helix transcription factor, FOXP3. We found a novel mutation of FOXP3, T1117G, in a mild case of IPEX.

自身免疫性肠病是一种罕见疾病，其特征是严重和难治性腹泻以及循环蚂蚁肠细胞自身抗体的存在。我们已确定自身免疫性肠病相关 75 kDa 抗原 (AIE-75) 作为该疾病的候选自身抗原，分布于小肠和近端肾小管的刷状缘。 AIE-75 的分布仅限于绒毛的顶端部位，表明其表达以细胞周期或成熟依赖性方式受到调节。为了解决这个问题，我们使用荧光素酶测定分析了AIIE-75基因启动子区的顺式元件，发现转录起始位点上游的-9至-63碱基参与了基因表达的负调控。与其他团队合作证实了抗AJE-75抗体在自身免疫性肠病中的特异性和敏感性。此外，我们还发现肌动蛋白结合蛋白villin是另一种与该疾病相关的自身抗原。AIE-75被发现是导致IC型亚瑟氏综合征的基因，该综合征的特征是耳聋和视网膜病变。事实上，AIE-75 在内耳和视网膜的上皮细胞中也表达。我们发现ALE-75参与视网膜中光感受器与钙粘蛋白23和肌球蛋白VII的组装，但AIE-75的表达独立于这两种蛋白的表达。一些自身免疫性肠病以X连锁方式遗传，称为免疫失调、多内分泌病、肠病、X连锁综合征（IPEX），其中 原因是叉头翼螺旋转录因子 FOXP3 的突变。我们在轻度 IPEX 病例中发现了 FOXP3 的新突变 T1117G。

项目成果

Chintalacharuvu et al.: "Cysteine Residues Required for the Attachment of the Light chain in human IgA2"J. Immunol.. 169. 5072-5077 (2002)

Chintalacharuvu 等人：“人 IgA2 中轻链附着所需的半胱氨酸残基”J。

Clintalacharuvu., et al.: "Cysteine Residues Required for the Attachment of the Light chain in human IgA2."J.Immunol.. 169. 5072-5077 (2002)

Clintalacharuvu., et al.：“人 IgA2 中轻链附着所需的半胱氨酸残基。”J.Immunol.. 169. 5072-5077 (2002)

Nieves, DS, et al.: "Dermatologic and Immunologic Findings in the Immune Dysregulation, Polyendorcrinopathy, Enteropathy, X-linked Syndrome."Arch.Dermatol.. (In press).

Nieves, DS 等人：“免疫失调、多内分泌腺病、肠病、X 连锁综合征的皮肤病学和免疫学发现”。Arch.Dermatol..（正在出版）。

Iwata A, et al.: "Cloning and expression tortoise (Trachemys scripta) immunoglobulin Joiningu (J)-chain cDNA."Immunogenetics. 54. 513-519 (2002)

Iwata A 等人：“克隆和表达陆龟 (Trachemys scripta) 免疫球蛋白 Joiningu (J)-链 cDNA。”免疫遗传学。

Kobayashi. I: "Intersitial lung disease associated with juvenile dermatomyositis ; Clinical features and efficacy of cyclosporine A."Rheumatology. 43. 371-374 (2003)

小林。