Loss of Interleukin-10 Signaling and Infantile Inflammatory Bowel Disease: Implications for Diagnosis and Therapy
Loss of Interleukin-10 Signaling and Infantile Inflammatory Bowel Disease: Implications for Diagnosis and Therapy
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DOI：
10.1053/j.gastro.2012.04.045
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发表时间：
2012-08-01
期刊：
影响因子：
29.4
通讯作者：
Klein, Christoph
中科院分区：
文献类型：
--
作者：
Kotlarz, Daniel;Beier, Rita;Klein, Christoph
背景与目的：白介素10(IL10)及其受体(IL10R)纯合子功能缺失可导致重症婴幼儿炎症性肠病(IBD)。报道1例IL-10R缺乏症患者接受异基因造血干细胞移植(HSCT)后持续缓解。我们调查了极早发病的IBD患者的异质性，其机制，以及同种异体造血干细胞移植治疗这种疾病的使用。方法：对66例5岁以下早发性IBD患儿进行IL-10、IL-10R1和IL-10R2基因突变分析。患者外周血单个核细胞功能检测(免疫印迹分析和酶联免疫吸附分析)证实IL-10R缺乏。我们评估了标准化异基因造血干细胞移植的治疗效果。结果：采用候选基因测序方法，我们鉴定出16例IL-10或IL-10R缺陷患者：3例存在IL-10突变，5例存在IL-10R1突变，8例存在IL-10R2突变。难治性结肠炎在出生后3个月内全部出现，并与肛周疾病有关(16例患者中有16例)。肠外症状包括毛囊炎(11/16)和关节炎(4/16)。5例患者接受了异基因造血干细胞移植，临床持续缓解，中位随访时间2年。体外实验证实，在所有接受移植的患者中，IL-10R介导的信号重新构建。结论：我们发现极早发病的IBD患者存在IL-10和IL-10R功能突变缺失。提示有肛周疾病的婴幼儿IBD患者应进行IL-10及IL-10R缺乏症的筛查，IL-10R缺乏者接受异基因造血干细胞移植可获得缓解。
BACKGROUND & AIMS: Homozygous loss of function mutations in interleukin-10 (IL10) and interleukin-10 receptors (IL10R) cause severe infantile (very early onset) inflammatory bowel disease (IBD). Allogeneic hematopoietic stem cell transplantation (HSCT) was reported to induce sustained remission in 1 patient with IL-10R deficiency. We investigated heterogeneity among patients with very early onset IBD, its mechanisms, and the use of allogeneic HSCT to treat this disorder. METHODS: We analyzed 66 patients with early onset IBD (younger than 5 years of age) for mutations in the genes encoding IL-10, IL-10R1, and IL-10R2. IL-10R deficiency was confirmed by functional assays on patients' peripheral blood mononuclear cells (immunoblot and enzyme-linked immunosorbent assay analyses). We assessed the therapeutic effects of standardized allogeneic HSCT. RESULTS: Using a candidate gene sequencing approach, we identified 16 patients with IL-10 or IL-10R deficiency: 3 patients had mutations in IL-10, 5 had mutations in IL-10R1, and 8 had mutations in IL-10R2. Refractory colitis became manifest in all patients within the first 3 months of life and was associated with perianal disease (16 of 16 patients). Extraintestinal symptoms included folliculitis (11 of 16) and arthritis (4 of 16). Allogeneic HSCT was performed in 5 patients and induced sustained clinical remission with a median follow-up time of 2 years. In vitro experiments confirmed reconstitution of IL-10R-mediated signaling in all patients who received the transplant. CONCLUSIONS: We identified loss of function mutations in IL-10 and IL-10R in patients with very early onset IBD. These findings indicate that infantile IBD patients with perianal disease should be screened for IL-10 and IL-10R deficiency and that allogeneic HSCT can induce remission in those with IL-10R deficiency.