Objective
IBD is a group of complex, systemic disorders associated with intestinal inflammation and extraintestinal manifestations. Recent studies revealed Mendelian forms of IBD, which contributed significantly to our understanding of disease pathogenesis and the heritability of IBD.
Design
We performed exome sequencing in a family with Crohn’s disease (CD) and severe autoimmunity, analysed immune cell phenotype and function in affected and non-affected individuals, and performed in silico and in vitro analyses of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) structure and function.
Results
A novel missense variant was identified in CTLA4 encoding CTLA-4, a coinhibitory protein expressed by T cells and required for regulation of T cell activation. The residue affected by the mutation, CTLA-4 Tyr60, is evolutionarily highly conserved, and the identified Y60C variant is predicted to affect protein folding and structural stability and demonstrated to cause impaired CTLA-4 dimerisation and CD80 binding. Intestinal inflammation and autoimmunity in carriers of CTLA-4 Y60C exhibit incomplete penetrance with a spectrum of clinical presentations ranging from asymptomatic carrier status to fatal autoimmunity and intestinal inflammation. In a clinically affected CTLA-4 Y60C carrier, T cell proliferation was increased in vitro and associated with an increased ratio of memory to naive T cells in vivo, consistent with impaired regulation of T cell activation.
Conclusions
Our results support the concept that variants in CTLA4 provide the basis for a novel Mendelian form of early-onset CD associated with systemic autoimmunity. Incomplete penetrance of autoimmunity further indicates the presence of other genetic and/or environmental modifiers.
Duodenal involvement in pediatric CD is frequently patchy and may show variable severity even within a single biopsy fragment. Variability cannot be predicted by clinical characteristics. Multiple endoscopic biopsies, including the duodenal bulb, should be obtained in suspected pediatric CD cases to maximize diagnostic yield.
Objective
Our objective was to determine the rate of mucosal recovery in pediatric patients with celiac disease on a gluten free diet. We also sought to determine whether IgA tissue transglutaminase (tTG) correlates with mucosal damage at the time of a repeat endoscopy with duodenal biopsy in these patients.
Methods
We performed a retrospective chart review of one-hundred and three pediatric patients, under 21 years of age, with a diagnosis of celiac disease defined as Marsh 3 histology, and who underwent a repeat endoscopy with duodenal biopsy at least twelve months after initiating a gluten free diet.
Results
We found that 19% of pediatric patients treated with a gluten free diet had persistent enteropathy. At the time of the repeat biopsy, tTG was elevated in 43% of cases with persistent enteropathy and 32% of cases in which there was mucosal recovery. Overall the positive predictive value of the autoantibody tissue transglutaminase was 25% and the negative predictive value was 83% in patients on a gluten free diet for a median of 2.4 years.
Conclusions
Nearly one in five children with celiac disease in our population had persistent enteropathy despite maintaining a gluten free diet and IgA tTG was not an accurate marker of mucosal recovery. Neither the presence of symptoms nor positive serology were predictive of a patient’s histology at the time of repeat biopsy. These findings suggest a revisitation of monitoring and management criteria of celiac disease in childhood.
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