Systemic innate immune activation in food protein–induced enterocolitis syndrome

Abstract

Background Food protein–induced enterocolitis syndrome (FPIES) is a non–IgE-mediated food allergy of infancy whose pathophysiology is poorly understood. Objectives We set out to identify and phenotype allergen-responsive cells in peripheral blood of a cohort of subjects undergoing supervised food challenge for FPIES. Methods: We profiled antigen-responsive cells in PBMCs by flow cytometry, and examined cells in whole blood obtained before and after challenge by CyTOF mass cytometry and RNAseq. Results Using a CD154-based detection approach, we observed that milk, soy, or rice-responsive T cells, and TNF-α–producing CD154+ T cells, were significantly lower in those with outgrown FPIES compared with those with active FPIES. However, levels were within the normal range and were inconsistent with a role in the pathophysiology of FPIES. Profiling of whole blood by CyTOF demonstrated profound activation of cells of the innate immune system after food challenge, including monocytes, neutrophils, natural killer cells, and eosinophils. Activation was not observed in children with outgrown FPIES. We confirmed this pattern of innate immune activation in a larger cohort by RNAseq. Furthermore, we observed pan–T-cell activation and redistribution from the circulation after a positive food challenge but not in those who had outgrown their FPIES. Conclusions Our data demonstrate a compelling role of systemic innate immune activation in adverse reactions elicited by foods in FPIES. Further investigation is needed to identify the mechanism of antigen specificity of adverse reactions to foods in FPIES.

Food protein‐induced enterocolitis syndrome

“…In addition, an increase of IL‐9 after a positive OFC in FPIES patients was found, while this activation was not observed in children who had outgrown FPIES . IL‐9 has been shown to be essential in intestinal anaphylaxis, suggesting that FPIES could be a variant of intestinal anaphylaxis …”

“…Morita et al reported a T H 2‐skewed cytokines profile from antigen‐restimulated PBMCs in FPIES patients. Thus, the primary role of T cells is being questioned and needs to be elucidated, particularly T cell l role in the unique gastrointestinal manifestations compared to IgE‐mediated allergy . Regulatory T cells (CD4 + CD25 + ) have been incriminated in the mechanism of tolerance acquisition in FPIES, with a potential key role of IL‐10, but these data still need to be confirmed in a larger sample of patients .…”

“…However, major gaps in knowledge remain regarding FPIES pathophysiology. The role of T cells, which are traditionally incriminated in this non‐IgE‐mediated disorder, was questioned, and a major role of mast cells, neutrophils and other innate immune cells was suggested, but needs to be confirmed …”

Food Protein–Induced Enterocolitis Syndrome

“…Pan T-cell activation and redistribution from the bloodstream was noted after a positive OFC, but not in those who had outgrown FPIES [104].…”

“…Further investigation is needed to identify the mechanism of antigen specificity in reactions to foods [104].…”