The Editors' Choice

      Striking allergic/TH2 cause in proton pump inhibitor–responsive esophageal eosinophilia and eosinophilic esophagitis

      Diagnosis of eosinophilic esophagitis (EoE), per consensus recommendations, requires clinical symptoms, more than15 eosinophils/high-power microscopic field, and a failed proton pump inhibitor (PPI) trial. However, 30% to 50% of patients with esophageal eosinophilia respond to PPI monotherapy despite their EoE-like clinical features. This new clinical entity, referred to as PPI-responsive esophageal eosinophilia (PPI-REE), poses a diagnostic dilemma. Using the recently validated “EoE diagnostic panel” comprising 94 EoE-associated genes, Wen et al (p 187) comparatively characterized the molecular signatures of PPI-REE and EoE. Their novel findings demonstrate that untreated PPI-REE has an allergic/TH2 signature that largely overlaps with the EoE transcriptome. Moreover, PPI monotherapy alone was sufficient to normalize PPI-REE's EoE-like signature, including mast cell genes and markers of impaired barrier function. The authors propose that a cluster of genes might predict whether a patient with esophageal eosinophilia will respond to a PPI, which could alter current clinical paradigms and practice. With its striking EoE-like allergic/TH2 cause, PPI-REE should be re-evaluated as an allergic subentity of EoE, with antiallergic treatment considered in addition to PPIs. These interesting and transformative findings call for future genome-wide comparison and large-scale validation of the predictive genes of PPI responsiveness identified by the authors.

      Fresh milk keeps infections at bay

      As they report in this issue, Loss et al (p 56) used a large European cohort to investigate whether consumption of cow's milk during the first year of life exerts protective effects comparable with those of breast-feeding. Among children who were fed fresh unprocessed cow's milk, the incidence of rhinitis episodes (see Figure: adjusted odds ratio, 0.71; 95% CI, 0.54-0.94), respiratory tract infections, fever, and otitis was found to be significantly lower than in the group whose milk ration consisted of a commercially processed ultra–heat-treated milk. The effect was diminished if this milk was heated at home before consumption. The authors hypothesize that this effect is related to heat-sensitive components in native cow's milk, such as whey proteins or beneficial microorganisms. However, they emphasize that consumption of untreated cow's milk remains a health risk because of potential contamination with harmful bacteria. The authors argue that a novel microbiologically safe yet minimally processed milk might be of major public health relevance for respiratory tract infections and possibly for subsequent development of asthma. A prevention strategy based on a safe and well-accepted food that is part of everyday nutrition might succeed without profound changes in lifestyle.
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      Association of milk consumption and rhinitis (adjusted odds ratios are given with 95% CIs). UHT, Ultra–heat-treated.

      Gut immune reconstitution in patients with immune dysregulation–polyendocrinopathy–enteropathy–X-linked syndrome after hematopoietic stem cell transplantation

      Immune dysregulation–polyendocrinopathy–enteropathy–X-linked (IPEX) syndrome is an inherited syndrome of early-onset systemic autoimmunity and the prototype of immune dysregulatory disorders. The only effective cure is hematopoietic stem cell transplantation (HSCT). Gambineri et al (p 260) describe gut immune reconstitution in a patient with IPEX syndrome who continued to have gastrointestinal symptoms after HSCT. Gut function and tolerance of enteral nutrition progressively improved in parallel with increased forkhead box protein 3 (FOXP3) expression within the gut mucosa (see Figure) and the appearance of donor CD4+CD31α4/β7high gut-homing lymphocytes. Furthermore, cells of donor origin were mostly present in the periphery rather than in the gut early after transplantation, possibly explaining poor gut function. The increase in donor chimerism within gut-homing lymphocytes was associated with later progressive increase in FOXP3 cells within the small bowel, possibly suggesting that a preferential homing of donor regulatory T cells to the gut is associated with disease recovery. This is the first study of gut immune reconstitution in a patient affected with an inherited disorder of immune tolerance, and it can be considered a unique case study that sheds light on the role of the intestine in reconstituting the immune system after HSCT.
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      Increase in FOXP3 expression in the examined total small bowel mucosal and submucosal tissue at different times after transplantation.

      The basophil activation test estimates severity and threshold of allergic reactions to peanut

      Patients with peanut allergy often react to small amounts of the allergen, and the subsequent symptoms can be life-threatening. Currently, the method of choice to determine the severity and threshold dose at which patients react is the oral food challenge (OFC), which consists of administering (in a hospital) peanut to patients known to be allergic. The basophil activation test (BAT) is a novel test that looks at whether basophils, which are blood cells involved in allergic reactions, react to peanut in a test tube. Santos et al (p 179) assessed the utility of the BAT in identifying patients with severe allergic reactions to peanut and patients who react to small amounts of the allergen. BATs were performed in 52 children who reacted to peanut on the same day as the OFC. Patients with severe reactions had a higher proportion of activated basophils in the BAT than patients with milder symptoms (see Figure). The dose of peanut protein to which the basophils reacted in the BAT was associated with the dose at which patients reacted on OFCs. The information provided by the BAT should be interpreted in light of the presence of other risk factors and can help identify high-risk patients who require closer monitoring and intensified education.
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      The BAT identifies severe reactors and patients with low threshold to peanut.

      Genetic ancestry matters in asthma susceptibility

      Among children in the United States, the extremes of asthma prevalence and mortality are represented by Hispanic/Latino populations, with Puerto Ricans having the highest and Mexicans the lowest values. Although environmental factors are important, Puerto Ricans and Mexicans vary greatly in their genetic ancestry, which can also contribute to asthma disparities. Pino-Yanes et al (p 228) present results from the largest, most comprehensive study of genetic ancestry, asthma susceptibility, and lung function in Latinos to date. The authors examined 5493 Latino children with and without asthma from 3 independent studies in which genetic ancestry was estimated by using genotypes at hundreds of thousands of polymorphic sites scattered throughout the genome. The authors demonstrate that disparities in asthma prevalence and lung function among Latinos can be partially explained by differences in genetic ancestry independent of early-life exposures and socioeconomic status. These findings are clinically relevant because the current method for predicting lung function in Puerto Ricans relies on spirometric reference equations derived from Mexicans or whites. Therefore Puerto Ricans will benefit from the development of population-specific reference equations. Finally, the authors' results demonstrate that not just environmental but also genetic differences between diverse Latino populations play an important role in asthma susceptibility and differences in lung function.

      Novel atopic dermatitis genes identified through laser capture microdissection

      Atopic dermatitis (AD) is a common skin disease characterized by TH2 and TH22 activation and barrier abnormalities. The relative contributions of the AD epidermis and dermis to the disease phenotype are unknown. Esaki et al (p 153) used laser capture microdissection to separate epidermal and dermal tissues from patients with AD and control subjects. This study defined the individual epidermal and dermal AD phenotypes and identified novel immune and barrier AD genes. These included IL34, a regulatory cytokine previously unrecognized in skin diseases, as well as a few tight junction genes (CLDN4 and CLDN8). The authors also related key AD immune genes as primarily epidermal (MMP12 or PI3) or dermal (IL22, CTLA4, or CCR7) and linked their expressions to possible cellular sources. These data create a new disease model that takes into account the relative effect of individual skin tissues in creating the AD phenotype. This approach can be applied to future studies aiming to dissect the individual contributions of barrier responses and immune activation to different AD phenotypes or various therapeutic responses.
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      Heat map shows clear genomic separation in the epidermis and dermis, with signal dilution in bulk tissues.