Analysis of a child with Very early onset inflammatory bowel disease due to compound heterozygous variants of IL10RA and DUOX2 genes / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis of a child with Very early onset inflammatory bowel disease (VEOIBD).@*METHODS@#A female child who had presented at the Children's Hospital of Fudan University on May 23, 2018 due to occurrence of diarrhea and fever 6 days after birth was selected as the study subject. Clinical data of the child was collected. Family-based whole-exome sequencing (WES) was carried out. Candidate variant was verified by Sanger sequencing and PCR of the patient and her parents.@*RESULTS@#The child had developed the symptoms 6 days after birth, with main manifestations including diarrhea, fever, failure to thrive, rectovestibular fistula and hypothyroidism. An enterostomy was performed at the age of 3.5 months due to severe intestinal adhesion and obstruction. Based on her clinical manifestations, colonoscopic finding, and results of biopsies, she was diagnosed with VEOIBD in conjunct with congenital hypothyroidism. Replacement treatment of levothyroxine was given since one month of age. Family-based WES revealed that the child has harbored compound heterozygous variants of the DUOX2 gene, namely c.2654G>T (p.R885L) and c.505C>T (p.R169W), in addition with a heterozygous c.301C>T (p.R101W) variant of the IL10RA gene. Re-analysis of the WES data revealed that the patient also had a 333 bp deletion spanning exon 1 of the IL10RA gene (Chr11: 117857034_117857366).@*CONCLUSION@#For patients with VEOIBD, genetic testing is recommended. Presence of additional DUOX2 gene variants might have exacerbated the clinical symptoms in this patient. Above finding has facilitated genetic counseling and prenatal diagnosis for this family, and raised clinicians' awareness of this rare disease.

The role of zinc ifnger protein A20 in immune regulation of dendritic cells and in the pathogenesis of inlfammatory bowel disease / 临床儿科杂志

Ubiquitin plays a vital role in both protein degradation and many kinds of cellular functions, such as DNA damage repair, cell cycle regulation, cell growth and immune system function.Ubiquitin modiifed enzyme zinc ifnger protein A20 is considered to be an important gateway for the regulation of immune and inlfammatory responses, which is a key negative regulator in NF-κB signaling pathway. Dendritic cell (DC) is a full-time antigen presenting cell that identifies inflammatory response or pathogenic microorganism by multiple receptors, and is a key moderator for immunity homeostasis. Researches in recent years showed that A20 plays an important role in regulating the function of DC, which may take part in the occurrence and development of inlfammatory bowel disease. In this article, the regulation of A20 in the immunoregulation of DC and its function on the pathogenesis of inlfammatory bowel disease were reviewed.

Efficacy of thalidomide on trinitrobenzene sulfonate-induced colitis in young rats and its mechanism / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Thalidomide could relieve clinical symptoms and intestinal mucosal lesions effectively in children with refractory inflammatory bowel disease (IBD) from the pre-clinical study. This study aimed to observe the therapeutic effect of thalidomide by the established animal model of IBD model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in Sprague-Dawley (SD) rats and to investigate the possible mechanism of action.</p><p><b>METHODS</b>A total of 82 SD rats of about 4-5 weeks were randomly divided into three groups: the control group (25 rats), TNBS-treated group (29 rats), and thalidomide treatment group (28 rats). Daily activities were recorded. At least eight rats from each group were killed on the 4th, 7th, and 14th days. Morphological and histological changes in the colon were individually assessed. Serum was collected and the levels of TNF-α and interleukins (IL-1β and IL-10) were assayed by ELISA method. The expression of colonic mucosal nuclear factor (NF)-κB was assayed with the immunohistochemical method.</p><p><b>RESULTS</b>(1) In the control group, diarrhea and rectal bleeding recovered rapidly and no death was recorded. In the TNBS-treated group, diarrhea and rectal bleeding persisted for a longer time. The mortality rate was 10.34% during the observation period. In the thalidomide treatment group, diarrhea and rectal bleeding persisted for a significantly shorter time than the TNBS-treated group (P < 0.01). The rats of this group also exhibited faster weight gain on day 7 compared with the TNBS-treated group but still lower than that of the control group. The mortality rate of the thalidomide treatment group was 3.57%. (2) Macroscopic and microscopic scores of the thalidomide-treated group were significantly lower than those of the TNBS model group on the 14th day (P < 0.01). These results suggested faster and better colonic recovery in the thalidomide-treated group. (3) NF-κB expression in the colonic mucosa of the control group was lower than in the others, mainly distributed in the cytoplasm. A large amount of intra-nuclear and cytoplasm staining was observed (more prominently intra-nuclear) in the TNBS model group and the thalidomide treatment group. On the 7th and 14th days, intra-nuclear NF-κB-containing cells in the thalidomide treatment group were still significantly lower than those in the TNBS model group (P < 0.01). (4) In the control group, the cellular inflammatory factors (TNF-α, IL-1β, and IL-10) were expressed at a low level while in the other two groups they were already expressed at a significantly higher level on day 4. On day 7 the expressions of TNF-α and IL-1β in the thalidomide treatment group were lower than in the TNBS model group. On day 14, the expressions of TNF-α and IL-1β in the thalidomide treatment group were significantly lower than in the TNBS model group (P < 0.05). On day 4, the IL-10 levels of the thalidomide treatment group became significantly elevated. The levels gradually decreased but still remained at a higher level. In the TNBS model group, the IL-10 expression peaked later than in the thalidomide treatment group.</p><p><b>CONCLUSIONS</b>Thalidomide was effective in the management of TNBS-induced colitis in young rats. This may be due to the suppression and down-regulation of NF-κB and the expression of the downstream inflammatory mediators (TNF-α and IL-1β). There is also indication that the expression of the anti-inflammatory cytokine (IL-10) is concomitantly up-regulated as well.</p>