Navigating diagnostic options for inborn errors of immunity in children: a case-based illustration.

PURPOSE OF REVIEW: In recent years, there has been a dramatic increase in the number of recognized inborn errors of immunity (IEI), many of which present in childhood. This review discusses diagnostic approaches for some of the more common presentations of IEI in childhood. RECENT FINDINGS: Implementation of newborn screening (NBS) using the T cell receptor excision circle (TREC) assay has led to the timely identification of patients with severe combined immunodeficiency (SCID) as well as both syndromic and nonsyndromic forms of T cell lymphopenia, including DiGeorge syndrome. Improvements in the availability of immunophenotyping assays, genetic testing and advanced diagnostic techniques such as the artificial thymic organoid system can improve diagnostic clarity and impact management plans. Diagnostic improvements in humoral immunodeficiency include development of novel assays to quantify and functionally evaluate polysaccharide vaccine response. SUMMARY: IEI represent a rapidly growing field, particularly in paediatrics. Use of state-of-the-art diagnostic testing can facilitate rapid identification of IEI, hopefully allowing for initiation of prompt treatment and improved patient outcomes.

Omeprazole inhibits IgE-mediated mast cell activation and allergic inflammation induced by ingested allergen in mice.

BACKGROUND: Patients with eosinophilic esophagitis have increased numbers of mucosal mast cells. Administration of the proton pump inhibitor omeprazole can reduce both esophageal mast cell and eosinophil numbers and attenuate type 2 inflammation in these subjects. OBJECTIVE: Given that maintenance of an acidic environment within granules is important for mast cell homeostasis, we sought to evaluate the effects of omeprazole on mast cell functions including development, IgE:FcεRI-mediated activation, and responses to food allergen. METHODS: Mast cell degranulation, cytokine secretion, and early signaling events in the FcεRI pathway, including protein kinase phosphorylation and Ca2+ flux, were measured after IgE crosslinking in murine bone marrow-derived mast cells and human cord blood-derived mast cells. The effects of omeprazole on these responses were investigated as was its impact on mast cell-dependent anaphylaxis and food allergy phenotypes in vivo. RESULTS: Murine and human mast cells treated with omeprazole exhibited diminished degranulation and release of cytokines and histamine in response to allergen. In murine mast cells, phosphorylation of protein kinases, ERK and SYK, was decreased. Differentiation of mast cells from bone marrow progenitors was also inhibited. IgE-mediated passive anaphylaxis was blunted in mice treated with omeprazole as was allergen-induced mast cell expansion and mast cell activation in the intestine in a model of food allergy. CONCLUSIONS: Our findings suggest that omeprazole targets pathways important for the differentiation and activation of murine mast cells and for the manifestations of food allergy and anaphylaxis.