A Patient with CTLA-4 Haploinsufficiency Presenting Gastric Cancer
A Patient with CTLA-4 Haploinsufficiency Presenting Gastric Cancer
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DOI：
10.1007/s10875-015-0221-x
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发表时间：
2016-01-01
影响因子：
9.1
通讯作者：
Kobayashi, Masao
中科院分区：
文献类型：
--
作者：
Hayakawa, Seiichi;Okada, Satoshi;Kobayashi, Masao
细胞毒性T淋巴细胞抗原4（CTLA-4）是一种表达于调节性T细胞（T细胞）和活化T细胞上的重要负调节因子。CTLA-4的种系杂合突变导致CTLA-4的单倍不足，从而导致发展为具有不完全遗传的常染色体显性免疫失调综合征。我们在这里报告一个日本患者与这种疾病谁有一个新的杂合单核苷酸插入，76_77insT（p.L28SfsX40），在CTLA 4基因。在CD 3/CD 28刺激后，患者外周血单核细胞显示CD 4（+）FOXP 3（+）细胞中CTLA-4（高）细胞的频率降低。患者出现低丙种球蛋白血症、复发性肺炎、食管念珠菌病、巨细胞病毒阳性慢性胃炎、慢性重度腹泻和1型糖尿病。此外，患者发生多灶性胃癌，组织学上分化差和分化好的腺癌，与慢性萎缩性胃炎和肠上皮化生相关。此前，已报告了23例具有杂合CTLA 4突变的症状性病例。包括本文所述的病例，24例中有3例（12.5%）发生胃癌。值得注意的是，3例患者中有2例表现为与萎缩性胃炎和肠上皮化生相关的多灶性腺癌。CVID患者中也报告了胃癌易感性。这些临床观察表明，胃癌是一种常见的疾病与常染色体显性免疫失调综合征由于CTLA 4突变。
Cytotoxic T-lymphocyte-antigen 4 (CTLA-4) is an essential negative regulator expressed on regulatory T cells (Tregs) and activated T cells. Germline heterozygous mutations in CTLA4 lead to haploinsufficiency of CTLA-4, resulting in the development of an autosomal dominant immune dysregulation syndrome with incomplete penetrance. We report here a Japanese patient with this disorder who has a novel heterozygous single nucleotide insertion, 76_77insT (p. L28SfsX40), in the CTLA4 gene. Peripheral blood mononuclear cells from the patient showed decreased frequency of CTLA-4(high) cells in CD4(+)FOXP3(+) cells following CD3/CD28 stimulation. The patient experienced hypogammaglobulinemia, recurrent pneumonia, esophageal candidiasis, cytomegalovirus-positive chronic gastritis, chronic and severe diarrhea, and type 1 diabetes mellitus. Moreover, the patient developed multifocal gastric cancer, histologically poorly and well-differentiated adenocarcinomas, associated with chronic atrophic gastritis and intestinal metaplasia. Previously, 23 symptomatic cases with heterozygous CTLA4 mutations have been reported. Including the case presented here, 3 of the 24 cases (12.5 %) developed gastric cancer. Notably, 2 of 3 patients presented similarly multifocal adenocarcinomas associated with atrophic gastritis and intestinal metaplasia. Predisposition to gastric cancer has been also reported in CVID patients. These clinical observations suggest that gastric cancer is a disease commonly associated with autosomal dominant immune dysregulation syndrome due to CTLA4 mutation.