US children is in line with data from the single-center population-based birth cohorts from Israel and Spain, reporting cumulative incidence of 0.34% and 0.7%, respectively. 4,5 Our study provides the first-ever estimate of FPIES prevalence in adults. To date, only several small case series of adult patients were published. 2 Our report has several limitations. The survey was not developed to estimate FPIES prevalence, and details of the trigger foods and symptoms are lacking. Although the survey asked about physician-diagnosed FPIES, specific case definition was not provided; we have no information about the diagnostic criteria used, and whether oral food challenges were performed to confirm diagnosis. Therefore, it is possible that FPIES diagnosis was used incorrectly because of the poor familiarity of the physicians with FPIES and led to underestimation or overestimation of true FPIES prevalence. This cross-sectional study captures patients reporting lifetime FPIES; therefore, we do not know which patients may or may not have outgrown FPIES and whether there is any difference in those who do and those who do not outgrow. These data suggest that FPIES affects nearly 1 million people in the United States, and the FPIES prevalence estimates are consistent with reports from Spain and Israel and not greatly different from the Australian estimates. Our data indicate the need for further epidemiologic studies to better characterize the population-level burden of FPIES in the United States.

A hallmark of humoral immune responses is the production of antibodies. This process involves a complex cascade of molecular and cellular interactions, including recognition of specific antigen by the B cell receptor (BCR), which triggers activation of B cells and differentiation into plasma cells (PCs). Although activation of the small GTPase Rac has been implicated in BCR-mediated antigen recognition, its precise role in humoral immunity and the upstream regulator remain elusive. DOCK2 is a Rac-specific guanine nucleotide exchange factor predominantly expressed in hematopoietic cells. We found that BCR-mediated Rac activation was almost completely lost in DOCK2-deficient B cells, resulting in defects in B cell spreading over the target cell-membrane and sustained growth of BCR microclusters at the interface. When wild-type B cells were stimulated in vitro with anti-IgM F(ab′)2 antibody in the presence of IL-4 and IL-5, they differentiated efficiently into PCs. However, BCR-mediated PC differentiation was severely impaired in the case of DOCK2-deficient B cells. Similar results were obtained in vivo when DOCK2-deficient B cells expressing a defined BCR specificity were adoptively transferred into mice and challenged with the cognate antigen. In addition, by generating the conditional knockout mice, we found that DOCK2 expression in B-cell lineage is required to mount antigen-specific IgG antibody. These results highlight important role of the DOCK2–Rac axis in PC differentiation and IgG antibody responses.

Intestinal microfold cells (M cells) in Peyer's patches are a special subset of epithelial cells that initiate mucosal immune responses through uptake of luminal antigens. Although the cytokine receptor activator of nuclear factor-kB ligand (RANKL) expressed on mesenchymal cells triggers differentiation into M cells, other environmental cues remain unknown. Here, we show that the metastasis-promoting protein S100A4 is required for development of mature M cells. S100A4-producing cells are a heterogenous cell population including lysozymeexpressing dendritic cells and group 3 innate lymphoid cells. We found that in the absence of DOCK8, a Cdc42 activator critical for interstitial leukocyte migration, S100A4-producing cells are reduced in the subepithelial dome, resulting in a maturation defect of M cells. While S100A4 promotes differentiation into mature M cells in organoid culture, genetic inactivation of S100a4 prevents the development of mature M cells in mice. Thus, S100A4 is a key environmental cue that regulates M cell differentiation in collaboration with RANKL.

Background: IL-31 is a major pruritogen associated with atopic dermatitis (AD). Although a specific antibody for IL-31 receptor has been shown to alleviate pruritus in patients with AD, therapeutic approaches to inhibition of IL-31 production remain unexploited. IL-31 production by T H cells critically depends on the transcription factor EPAS1, which mediates IL31 promoter activation in collaboration with SP1.

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