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.

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.

Immune cells have been implicated in interstitial lung diseases (ILDs), although their phenotypes and effector mechanisms remain poorly understood. To better understand these cells, we conducted an exploratory mass cytometry analysis of immune cell subsets in bronchoalveolar lavage fluid (BALF) from patients with idiopathic pulmonary fibrosis (IPF), connective-tissue disease (CTD)-related ILD, and sarcoidosis, using two panels including 64 markers. Among myeloid cells, we observed the expansion of CD14+ CD36hi CD84hiCCR2– monocyte populations in IPF. These CD14+ CD36hi CD84hi CCR2– subsets were also increased in ILDs with a progressive phenotype, particularly in a case of acute exacerbation (AEx) of IPF. Analysis of B cells revealed the presence of cells at various stages of differentiation in BALF, with a higher percentage of IgG memory B cells in CTD-ILDs and a trend toward more FCRL5+ B cells. These FCRL5+ B cells were also present in the patient with AEx-IPF and sarcoidosis with advanced lung lesions. Among T cells, we found increased levels of IL-2R+ TIGIT+ LAG3+ CD4+ T cells in IPF, increased levels of CXCR3+ CD226+ CD4+ T cells in sarcoidosis, and increased levels of PD1+ TIGIT+ CD57+ CD8+ T cells in CTD-ILDs. Together, these findings underscore the diverse immunopathogenesis of ILDs.

No abstract

Immune cells have been implicated in interstitial lung diseases (ILDs), although their phenotypes and effector mechanisms remain poorly understood. To better understand these cells, we conducted an exploratory mass cytometry analysis of immune cell subsets in bronchoalveolar lavage fluid (BALF) from patients with idiopathic pulmonary fibrosis (IPF), connective-tissue disease (CTD)-related ILD, and sarcoidosis, using two panels including 64 markers. Among myeloid cells, we observed the expansion of CD14+CD36hiCD84himonocyte populations in IPF. These CD14+CD36hiCD84hisubsets were also increased in ILDs with a progressive phenotype, particularly in a case of acute exacerbation (AEx) of IPF. Analysis of B cells revealed the presence of cells at various stages of differentiation in BALF, with a higher percentage of IgG memory B cells in CTD-ILDs and a trend toward more FCRL5+B cells. These FCRL5+B cells were also present in the patient with AEx-IPF and sarcoidosis with advanced lung lesions. Among T cells, we found increased levels of IL-2R+TIGIT+LAG3+CD4+T cells in IPF, increased levels of CXCR3+CD226+CD4+T cells in sarcoidosis, and increased levels of PD1+TIGIT+CD57+CD8+T cells in CTD-ILDs. Together, these findings underscore the diverse immunopathogenesis of ILDs.