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Background Eosinophilic esophagitis (EoE) is an atopic disease characterized by eosinophilic inflammation in which dietary antigens (in particular, milk) play a major role. EoE is most likely a mixed IgE and non-IgE food-mediated reaction in which overexpression of Th2 cytokines, particularly IL-13, play a major role; however, the cells responsible for IL-13 overexpression remain elusive. Th2-cytokines are secreted following the ligation of invariant natural killer T cell receptors to sphingolipids (SLs). Sphingolipids (SLs) are presented via the CD1d molecule on the INKTs surface. Cow's milk-derived SL has been shown to activate iNKTs from children with IgE-mediated food allergies to milk (FA-MA) to produce Th2 cytokines. The role of iNKTs and milk-SL in EoE pathogenesis is currently unknown. Objective The aim of this study was to investigate the role of iNKTs and milk-SL in EoE. Methods Peripheral blood mononuclear cells (PBMCs) from 10 children with active EoE (EoE-A), 10 children with controlled EoE (EoE-C) and 16 healthy controls (non-EoE) were measured ex vivo and then incubated with α-galactosylceramide (αGal) and milk-SL. INKTs from peripheral blood (PB) and oesophageal biopsies were studied. Results EoE-A children had significantly fewer peripheral blood iNKTs with a greater Th2-response to αGal and milk-SM compared with iNKTs of EoE-C and non-EoE children. Additionally, EoE-A children had increased iNKT levels in oesophageal biopsies compared with EoE-C children. Conclusion Milk-SLs are able to activate peripheral blood iNKTs in EoE-A children to produce Th2 cytokines. Additionally, iNKT levels are higher at the site of active oesophageal eosinophilic inflammation. Clinical Relevance This study suggests that sphingolipids (SLs) contained in milk may drive the development of EoE by promoting an iNKT-cell-mediated Th2-type cytokine response that facilitates eosinophil-mediated allergic inflammation. [ABSTRACT FROM AUTHOR]

Background: Dyskeratosis Congenita (DKC) is a syndrome characterized by immunodeficiency, bone marrow failure, somatic abnormalities, and cancer predisposition resulting from defective telomere maintenance. The immunologic features of DKC remain under diagnosed and under treated despite the fact that immunodeficiency is a major cause of premature mortality in DKC. Methods: This study undertook a retrospective review of 7 DKC patients diagnosed at the Children's Hospital of Philadelphia. In parallel, we reviewed previously reported immunologic findings in DKC patients. Results: Immunologic abnormalities (lymphopenia, low B-cell numbers, hypogammaglobulinemia, and decreased T-cell function) were the most frequent laboratory findings at initial presentation, preceding the development of significant anemia or thrombocytopenia. Recurrent sinopulmonary or opportunistic infections were present in 6/7 patients. Infant-onset patients had more severe immunologic and somatic features (particularly severe enteropathy). Conclusion: In DKC, development of immunologic abnormalities can precede bone marrow failure, highlighting the importance of proper immunodeficiency management to minimize morbidity and premature mortality in this disease. [ABSTRACT FROM AUTHOR]

OBJECTIVES: CHARGE (coloboma, heart defect, atresia choanae, retarded growth and development, genital hypoplasia, ear anomalies/deafness) syndrome and chromosome 22q11.2 deletion syndrome are known to have significant clinical overlap including cardiac anomalies, ear abnormalities, hearing loss, developmental delay, renal abnormalities, and cleft palate. Immunodeficiency has been well documented in 22q11.2 deletion, but there has been limited recognition of this potentially serious complication in CHARGE syndrome. The goals of our study were to identify clinical features unique to CHARGE syndrome or 22q11.2 deletion and to describe the spectrum of immunodeficiency found in patients with CHARGE syndrome. METHODS: This study included 25 children diagnosed with CHARGE syndrome with positive CHD7 mutations through the Children's Hospital of Philadelphia genetics program. Clinical features and laboratory findings were reviewed retrospectively. We compared our findings to data available for a large cohort of patients with 22q11.2 deletion syndrome followed in our clinical genetics program. RESULTS: Features found more commonly in CHARGE syndrome included coloboma, choanal atresia, facial nerve palsy, tracheoesophageal fistula, and genital hypoplasia in boys. A high incidence of marked hypocalcemia was observed in our study group (72%). We found a spectrum of cell-mediated immunodeficiency in our study group, which ranged from lymphopenia (60%) to severe combined immunodeficiency (8%). Defects in humoral immunity were documented in 4 patients and included severe hypogammaglobulinemia with decreased T-cell numbers, transient hypogammaglobulinemia during infancy, and immunoglobulin A deficiency. CONCLUSIONS: The presence of coloboma, choanal atresia, facial nerve palsy, tracheoesophageal fistula, or genital hypoplasia in boys should alert the clinician to the possibility of CHARGE syndrome rather than the 22q11.2 deletion. Molecular testing for CHD7 mutations may help to confirm the diagnosis. In this study, significant hypocalcemia and lymphopenia occurred more frequently in patients with CHARGE syndrome than in those with 22q11.2 deletion syndrome. Early inclusion of immunologists to the multidisciplinary care team (as with 22q11.2 deletion) may be of great benefit to affected patients. [ABSTRACT FROM AUTHOR]