IL-2 Enhances Gut Homing Potential of Human Naive Regulatory T Cells Early in Life.

Recent evidence suggests early environmental factors are important for gut immune tolerance. Although the role of regulatory T (Treg) cells for gut immune homeostasis is well established, the development and tissue homing characteristics of Treg cells in children have not been studied in detail. In this article, we studied the development and homing characteristics of human peripheral blood Treg cell subsets and potential mechanisms inducing homing molecule expression in healthy children. We found contrasting patterns of circulating Treg cell gut and skin tropism, with abundant ß7 integrin+ Treg cells at birth and increasing cutaneous lymphocyte Ag (CLA+) Treg cells later in life. ß7 integrin+ Treg cells were predominantly naive, suggesting acquisition of Treg cell gut tropism early in development. In vitro, IL-7 enhanced gut homing but reduced skin homing molecule expression in conventional T cells, whereas IL-2 induced a similar effect only in Treg cells. This effect was more pronounced in cord compared with adult blood. Our results suggest that early in life, naive Treg cells may be driven for gut tropism by their increased sensitivity to IL-2-induced ß7 integrin upregulation, implicating a potential role of IL-2 in gut immune tolerance during this critical period of development.

Variants in TRIM22 That Affect NOD2 Signaling Are Associated With Very-Early-Onset Inflammatory Bowel Disease.

BACKGROUND & AIMS: Severe forms of inflammatory bowel disease (IBD) that develop in very young children can be caused by variants in a single gene. We performed whole-exome sequence (WES) analysis to identify genetic factors that might cause granulomatous colitis and severe perianal disease, with recurrent bacterial and viral infections, in an infant of consanguineous parents. METHODS: We performed targeted WES analysis of DNA collected from the patient and her parents. We validated our findings by a similar analysis of DNA from 150 patients with very-early-onset IBD not associated with known genetic factors analyzed in Toronto, Oxford, and Munich. We compared gene expression signatures in inflamed vs noninflamed intestinal and rectal tissues collected from patients with treatment-resistant Crohn's disease who participated in a trial of ustekinumab. We performed functional studies of identified variants in primary cells from patients and cell culture. RESULTS: We identified a homozygous variant in the tripartite motif containing 22 gene (TRIM22) of the patient, as well as in 2 patients with a disease similar phenotype. Functional studies showed that the variant disrupted the ability of TRIM22 to regulate nucleotide binding oligomerization domain containing 2 (NOD2)-dependent activation of interferon-beta signaling and nuclear factor-κB. Computational studies demonstrated a correlation between the TRIM22-NOD2 network and signaling pathways and genetic factors associated very early onset and adult-onset IBD. TRIM22 is also associated with antiviral and mycobacterial effectors and markers of inflammation, such as fecal calprotectin, C-reactive protein, and Crohn's disease activity index scores. CONCLUSIONS: In WES and targeted exome sequence analyses of an infant with severe IBD characterized by granulomatous colitis and severe perianal disease, we identified a homozygous variant of TRIM22 that affects the ability of its product to regulate NOD2. Combined computational and functional studies showed that the TRIM22-NOD2 network regulates antiviral and antibacterial signaling pathways that contribute to inflammation. Further study of this network could lead to new disease markers and therapeutic targets for patients with very early and adult-onset IBD.

IL-10 Potentiates Differentiation of Human Induced Regulatory T Cells via STAT3 and Foxo1.

Foxp3(+) regulatory T cells (Tregs) play essential roles in maintaining the immune balance. Although the majority of Tregs are formed in the thymus, increasing evidence suggests that induced Tregs (iTregs) may be generated in the periphery from naive cells. However, unlike in the murine system, significant controversy exists regarding the suppressive capacity of these iTregs in humans, especially those generated in vitro in the presence of TGF-ß. Although it is well known that IL-10 is an important mediator of Treg suppression, the action of IL-10 on Tregs themselves is less well characterized. In this article, we show that the presence of IL-10, in addition to TGF-ß, leads to increased expansion of Foxp3(+) iTregs with enhanced CTLA-4 expression and suppressive capability, comparable to that of natural Tregs. This process is dependent on IL-10R-mediated STAT3 signaling, as supported by the lack of an IL-10 effect in patients with IL-10R deficiency and dominant-negative STAT3 mutation. Additionally, IL-10-induced inhibition of Akt phosphorylation and subsequent preservation of Foxo1 function are critical. These results highlight a previously unrecognized function of IL-10 in human iTreg generation, with potential therapeutic implications for the treatment of immune diseases, such as autoimmunity and allergy.

Pediatric-to-adult Transition and Medication Adherence in Patients with Inflammatory Bowel Disease.

BACKGROUND: Medication nonadherence is common in inflammatory bowel disease and is associated with poor outcomes. There has been no study on pediatric-to-adult transition as a risk factor for nonadherence in inflammatory bowel disease, which has been demonstrated in other diseases. We aimed to assess whether transitioned (TR) patients have higher nonadherence rates than young adults (YAs) diagnosed in adulthood. METHODS: Consecutive ambulatory subjects were prospectively recruited and completed the validated Medication Adherence Reporting Scale (MARS), with the primary outcome being adherence differences between group age-matched TR and YA groups. Pediatric subjects were taken as the control group. Perceptions of medication-related necessity and concerns were assessed with the Beliefs about Medicines Questionnaire (BMQ). Nonadherers (defined as MARS ≤16) received the Inflammatory Bowel Diseases Pharmacist Adherence Counselling (IPAC) intervention and adherence change was reassessed after 6 months as a secondary outcome. RESULTS: Adherence in TR patients (n = 38, mean age 20.4, 13.2% nonadherent) was noninferior to and numerically better than YAs diagnosed in adulthood (n = 41, mean age 21.2, 24.4%). Nonadherence in the pediatric control group (n = 50, mean age 14.7) was 8.0%. YAs had significantly higher medication-related concerns (14.6 versus 11.9, P = 0.02) than the pediatric group. The IPAC intervention reduced nonadherence rates by 60% (P = 0.004). CONCLUSIONS: TR patients did not have worse adherence than YAs diagnosed in adulthood. Protective factors may include previous treatment in pediatric centers and the salient symptomatology of inflammatory bowel disease, whereas increasing concerns over medications contribute to nonadherence in YAs. Pharmacist-led counselling improves adherence in these patients.

A prospective comparative pilot study comparing the urine collection pad with clean catch urine technique in non-toilet-trained children.

INTRODUCTION: There are many different methods for collecting urine from paediatric patients in emergency departments. Therefore, the aims of the study were to: METHODS: The three month study was a prospective non-randomised comparative paediatric pilot study. A purposeful sample of children, requiring a urine microscopy for clinical management, presenting to one district emergency department was enrolled in the study to compare two non-invasive techniques of urine collection. RESULTS: Thirty-three patients were enrolled and satisfactory samples were obtained from 22 patients. The heavy (mixed growth) contamination rate in the UCP group (n=2; 9.1%) versus the CCU group (n=1; 4.5%) was not statistically significant (p=0.50 by Fisher's exact test). The rate of agreement (n=20; 91%) in diagnosing or excluding urinary tract infection between the two groups was high. The median time to urine collection between the two groups (UCP method 30 min; CCU 107.5 min) was statistically significant (p<0.002, Mann-Whitney U test). CONCLUSIONS: This study suggests that UCPs are practicable in Australasian Emergency Departments and may lead to faster diagnosis, disposition and reduced hospital stay.

Raised tacrolimus level and acute renal injury associated with acute gastroenteritis in a child receiving local rectal tacrolimus.

Local rectal application of tacrolimus in distal colitis, pouchitis and perianal Crohn's disease has previously been reported to be both effective and safe. We report a patient treated with per rectum local application of tacrolimus, who developed toxic levels of tacrolimus and acute renal injury during an episode of acute gastroenteritis. This case illustrates that local application of tacrolimus, although usually safe, may be associated with significantly raised tacrolimus levels and acute renal injury during acute gastroenteritis. It is important for physicians to be aware of this association when prescribing local rectal tacrolimus.

Prophylactic gastrectomy in a 16-year-old.

We performed a total gastrectomy in a 16-year-old asymptomatic CDH1 gene mutation carrier in whom two prior gastroscopies with biopsies were normal. The patient's mother died aged 39 years and her aunt died aged 21 years of gastric cancer. A germline CDH1 mutation (associated with hereditary diffuse gastric cancer) was initially identified in her mother at diagnosis and was later identified by predictive testing in this patient. Our patient is the youngest CDH1 carrier to date to have a prophylactic gastrectomy, and is several years below the age at which existing guidelines recommend consideration of gastrectomy. Multiple foci of early-stage carcinoma were found in her gastrectomy specimen. Given the family history of advanced gastric cancer in the late second decade, the unpredictable time course to development of advanced gastric cancer, and the futility of gastroscopic surveillance, we recommend consideration of prophylactic gastrectomy in adolescent asymptomatic CDH1 mutation carriers on an individual basis.

Novel de novo mutations of the interleukin-10 receptor gene lead to infantile onset inflammatory bowel disease.

BACKGROUND AND AIMS: Defects in the interleukin 10 (IL-10) signalling pathway have been shown to cause very early onset inflammatory bowel disease (IBD). We report a patient with severe infantile-onset IBD with a compound heterozygous IL-10 receptor alpha subunit (IL-10RA) mutation, one of which was paternally-inherited and the other occurring de novo. METHODS: Deep sequencing of IL-10, IL-10RA and IL-10 receptor beta subunit (IL-10RB) were performed. Peripheral blood mononuclear cell (PBMC) surface expression of IL-10RA was analysed by flow cytometry. IL-10 signalling pathway was examined by measuring phosphorylated STAT3 in PBMC cultured in the presence of IL-6 or IL-10. RESULT: We identified a missense mutation in exon 4 of IL-10RA (c.583T>C) in one allele and a nonsense mutation in exon 7 of IL-10RA (c.1368G>T) in the other allele. Neither mutation has been reported previously. The patient has functional IL-10RA deficiency despite normal IL-10RA expression. CONCLUSION: This represents the first case report of a de novo mutation of IL-10RA that is associated with very early onset severe IBD. Therefore, IL-10 pathway defect should be considered in patients with infantile-onset IBD even if the parents are non-consanguineous.

Rectal juvenile polyp detected on (99m)Tc-pertechnetate abdominal scintigraphy (Meckel scan).

An 8-year-old boy presented with first episode of rectal bleeding. Initial hemoglobin was 9 g/dL. A Meckel scan showed a hyperemic focus in the lower pelvis. Colonoscopy identified a juvenile polyp with dysplasia in the rectosigmoid region. It is important to carefully evaluate the dynamic flow images in the Meckel scan because pathology other than a Meckel diverticulum may be identified.

Familial multiple lipomatosis with clear autosomal dominant inheritance and onset in early adolescence.

Familial multiple lipomatosis is rare. Several modes of inheritance have been proposed but no conclusive evidence shown, although some families have suggested autosomal dominant inheritance. The authors describe a family with multiple lipomatosis showing clear autosomal dominant inheritance, and no mutations within the NF1, SPRED1 or Cowden disease (PTEN) genes. Familial autosomal dominant lipomatosis is a rare but distinct entity.