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Background Immunoglobulin E–mediated food allergy (FA) affects children and adults with variable age of onset. Phenotype and quality of life (QoL) differences between childhood-onset FA (COFA) and adult-onset FA (AOFA) are not known. Objective To identify phenotypic and QoL differences between AOFA and COFA. Methods A cross-sectional study of adults (≥18 years old) seen at Northwestern Memorial HealthCare clinics between 2002 and 2017 with an International Classification of Diseases ninth and tenth revision diagnosis of FA. Subjects completed a FA history survey and a FA QoL questionnaire. FA characteristics and QoL scores were compared between groups. Results Among 294 consented subjects, 202 had a clinical history consistent with labeled immunoglobulin E–mediated FA. The onset of FA symptoms occurred before age 18 years (COFA) in 80 subjects and after age 18 years in 122 (AOFA) subjects. Shellfish reactions were most common in AOFA-labeled subjects (28%), whereas tree nut reactions were the most common in COFA-labeled subjects (55%) compared with other triggers. Hives (68% vs 52%, P = .03), facial swelling (69% vs 50%, P = .009), wheezing (56% vs 29%, P Conclusion There are differences in specific food triggers and symptoms in adult-onset and childhood-onset labeled FA. Adults labeled with childhood-onset FA have reduced QoL.

Eosinophils are important in the pathogenesis of many diseases, including asthma, eosinophilic esophagitis, and eczema. Whereas IL-5 is crucial for supporting mature eosinophils (EoMs), the signals that support earlier eosinophil lineage events are less defined. The IL-33R, ST2, is expressed on several inflammatory cells, including eosinophils, and is best characterized for its role during the initiation of allergic responses in peripheral tissues. Recently, ST2 expression was described on hematopoietic progenitor subsets, where its function remains controversial. Our findings demonstrate that IL-33 is required for basal eosinophil homeostasis, because both IL-33– and ST2-deficient mice exhibited diminished peripheral blood eosinophil numbers at baseline. Exogenous IL-33 administration increased EoMs in both the bone marrow and the periphery in wild-type and IL-33–deficient, but not ST2-deficient, mice. Systemic IL-5 was also increased under this treatment, and blocking IL-5 with a neutralizing Ab ablated the IL-33–induced EoM expansion. The homeostatic hypereosinophilia seen in IL-5–transgenic mice was significantly lower with ST2 deficiency despite similar elevations in systemic IL-5. Finally, in vitro treatment of bone marrow cells with IL-33, but not IL-5, led to specific early expansion of IL-5Rα–expressing precursor cells. In summary, our findings establish a basal defect in eosinophilopoiesis in IL-33– and ST2-deficient mice and a mechanism whereby IL-33 supports EoMs by driving both systemic IL-5 production and the expansion of IL-5Rα–expressing precursor cells.

Background The Centers for Disease Control and Prevention advises that patients with moderate-to-severe asthma belong to a high-risk group that is susceptible to severe COVID-19. However, the association between asthma and COVID-19 has not been well-established. Objective The primary objective was to determine the prevalence of asthma among COVID-19 patients in a major U.S. health system. We assessed the clinical characteristics and comorbidities in asthmatic and non-asthmatic COVID-19 patients. We also determined the risk of hospitalization associated with asthma and/or inhaled corticosteroid use. Methods Medical records of patients with COVID-19 were searched by a computer algorithm (March 1–April 15, 2020), and chart review was used to validate the diagnosis of asthma and medications prescribed for asthma. All patients were PCR-confirmed COVID-19. Demographics and clinical features were characterized. Regression models were used to assess the associations between asthma and corticosteroid use and the risk of COVID-19-related hospitalization. Results Of 1,526 patients identified with COVID-19, 220 (14%) were classified as having asthma. Asthma was not associated with an increased risk of hospitalization (RR of 0.96 [95%CI: 0.77-1.19]) after adjusting for age, sex, gender, and comorbidities. The ongoing use of ICS did not increase the risk of hospitalization in a similar adjusted model (RR of 1.39 [95%CI: 0.90-2.15]). Conclusions Despite a substantial prevalence of asthma in our COVID-19 cohort, asthma was not associated with an increased risk of hospitalization. Similarly, the use of ICS with or without systemic corticosteroids was not associated with COVID-19-related hospitalization., This retrospective study found an asthma prevalence of 14% in a general COVID-19 cohort. A diagnosis of asthma or the use of inhaled corticosteroids was not associated with an increased risk of COVID-19-related hospitalization.

Background Previous studies found conflicting results about whether hidradenitis suppurativa (HS) is associated with depression or anxiety. Objectives To determine the relationship of HS with depression and anxiety. Methods A systematic review was performed of published observational studies in MEDLINE, PubMed, Embase, Global Resource for Eczema Trials (GREAT), Latin American and Caribbean Health Sciences Literature (LILACS), Cochrane, Scopus, and PsychInfo that analyzed depression or anxiety in HS. Two reviewers performed title/abstract review and data extraction. Meta-analysis was performed with random-effects weighting. Results Thirty-eight studies met inclusion criteria; 27 had sufficient data for meta-analysis. The prevalences of depression (26.5% vs 6.6%) and anxiety (18.1% vs 7.1%) were higher in persons with versus without HS. Patients with HS had higher odds of depression in 12 of 13 studies and pooled analysis (odds ratio, 2.54; 95% confidence interval, 2.15-3.01), and anxiety in 6 of 6 studies and pooled analysis (odds ratio, 2.00; 95% confidence interval, 1.66-2.42). Similar results were found in sensitivity analyses for different methods of HS diagnosis (physician diagnosed and chart review) and control groups (healthy and dermatologic control individuals). HS was associated with higher antidepressant and anxiolytic use and with suicidality, but not mean depression and anxiety scale scores. Limitations Individual-level data were unavailable. Conclusions Patients with HS have higher odds of depression, anxiety, and suicidality.

Sialic acid-binding Ig-like lectin 8 (Siglec-8) is expressed on the surface of human eosinophils, mast cells, and basophils&mdash, cells that participate in allergic and other diseases. Ligation of Siglec-8 by specific glycan ligands or antibodies triggers eosinophil death and inhibits mast cell degranulation, consequences that could be leveraged as treatment. However, Siglec-8 is not expressed in murine and most other species, thus limiting preclinical studies in vivo. Based on a ROSA26 knock-in vector, a construct was generated that contains the CAG promoter, a LoxP-floxed-Neo-STOP fragment, and full-length Siglec-8 cDNA. Through homologous recombination, this Siglec-8 construct was targeted into the mouse genome of C57BL/6 embryonic stem (ES) cells, and chimeric mice carrying the ROSA26-Siglec-8 gene were generated. After cross-breeding to mast cell-selective Cre-recombinase transgenic lines (CPA3-Cre, and Mcpt5-Cre), the expression of Siglec-8 in different cell types was determined by RT-PCR and flow cytometry. Peritoneal mast cells (dual Fc&epsilon, RI+ and c-Kit+) showed the strongest levels of surface Siglec-8 expression by multicolor flow cytometry compared to expression levels on tissue-derived mast cells. Siglec-8 was seen on a small percentage of peritoneal basophils, but not other leukocytes from CPA3-Siglec-8 mice. Siglec-8 mRNA and surface protein were also detected on bone marrow-derived mast cells. Transgenic expression of Siglec-8 in mice did not affect endogenous numbers of mast cells when quantified from multiple tissues. Thus, we generated two novel mouse strains, in which human Siglec-8 is selectively expressed on mast cells. These mice may enable the study of Siglec-8 biology in mast cells and its therapeutic targeting in vivo.

Background T cells and cancer cells utilize glycolysis for proliferation. The hexokinase (1–4) family of enzymes catalyze the first step of glycolysis. Hexokinase 2 (HK2) is one of the most highly upregulated metabolic enzymes in both cancer and activated T cells. HK2 is required for the development and/or growth of cancer in several cancer models, but the necessity of HK2 in T cells is not fully understood. The clinical applicability of HK2 inhibition in cancer may be significantly limited by any potential negative effects of HK2 inhibition on T cells. Therefore, we investigated the necessity of HK2 for T cell function. In order to identify additional therapeutic cancer targets, we performed RNA-seq to compare in vivo proliferating T cells to T cell leukemia. Methods HK2 was genetically ablated in mouse T cells using a floxed Hk2 allele crossed to CD4-Cre. CD4+ and CD8+ cells from mice were characterized metabolically and tested in vitro. T cell function in vivo was tested in a mouse model of colitis, Th2-mediated lung inflammation, and viral infection. Treg function was tested by crossing Hk2-floxed mice to FoxP3-Cre mice. Hematopoietic function was tested by deleting HK2 from bone marrow with Vav1-iCre. RNA-seq was used to compare T cells proliferating in response to virus with primary T-ALL leukemia induced with mutant Notch1 expression. Results We unexpectedly report that HK2 is largely dispensable for in vitro T cell activation, proliferation, and differentiation. Loss of HK2 does not impair in vivo viral immunity and causes only a small impairment in the development of pathological inflammation. HK2 is not required for Treg function or hematopoiesis in vivo. One hundred sixty-seven metabolic genes were identified as being differentially expressed between T cells and leukemia. Conclusions HK2 is a highly upregulated enzyme in cancer and in T cells. The requirement for HK2 in various cancer models has been described previously. Our finding that T cells are able to withstand the loss of HK2 indicates that HK2 may be a promising candidate for cancer therapy. Furthermore, we identify several other potential metabolic targets in T-ALL leukemia that could spare T cell function. Electronic supplementary material The online version of this article (10.1186/s40170-018-0184-5) contains supplementary material, which is available to authorized users.

Food allergy affects around 10% of the population. As the prevalence of food allergy continues to increase, disproportionately in children, new therapies for food allergy are being investigated. While there are no approved treatments for food allergy, immunotherapy facilitates significant desensitization and protection from accidental exposure. Nevertheless, current immunotherapies do not entirely nor permanently eliminate sensitivity to the food allergen. Since the rates of sustained unresponsiveness are significantly lower than desensitization, future therapies that enhance the rates of long-term tolerance in patients will catalyze progress in this field over the next 5–10 years.

Mast cells and basophils are developmentally related cells whose activation is a hallmark of allergy. Functionally, mast cells and basophils overlap in their ability to produce several mediators, including histamine and granule proteases, but studies have increasingly demonstrated nonredundant roles. To characterize the transcriptional heterogeneity of mast cells and basophils upon their activation, we performed large-scale comparative microarrays of murine bone marrow–derived mast cells and bone marrow–derived basophils (BMBs) at rest, upon an adaptive-type activation (IgE cross-linking), or upon an innate-type activation (IL-33 stimulation). Hierarchical clustering demonstrated that bone marrow–derived mast cells and BMBs shared specific activation-associated transcriptional signatures but differed in other signatures both between cell type and between activation mode. In bone marrow–derived mast cells, IgE cross-linking upregulated 785 genes, including Egr2, Ccl1, and Fxyd6, whereas IL-33 stimulation induced 823 genes, including Ccl1, Egr2, and Il1b. Focused bioinformatics pathway analysis demonstrated that IgE activation aligned with processes such as oxidative phosphorylation, angiogenesis, and the p53 pathway. The IL-33–activated transcriptome was enriched in genes commonly altered by NF-κB in response to TNF, by IL-6 via STAT3, and in response to IFN-γ. Furthermore, BMBs activated via IgE cross-linking selectively induced immune response genes Ccl1, Il3, and Il2 compared with IL-33–stimulated BMBs. Principal-component analysis revealed key cell- and activation-specific clustering. Overall, our data demonstrate that mast cells and basophils have cell- and activation-specific transcriptional responses and suggest that context-specific gene networks and pathways may shape how the immune system responds to allergens and innate cytokines.

Mast cells (MC) and basophils (BΦ) are key effector cells in allergy that are developmentally related. Functionally, they both release mediators like histamine and granule proteases. However, studies also suggest that MC and BΦ have non-redundant roles in allergic diseases. Their ability to respond to IL-33—an epithelium-derived cytokine that helps initiate allergic inflammation—is not well understood. To fully characterize the transcriptional responses and heterogeneity of MC and BΦ, we performed large-scale comparative microarrays of bone marrow-derived mast cells (BMMCs) and basophils (BMBs) either at rest, upon IgE activation, or upon IL-33 activation. Hierarchical clustering demonstrated that BMMCs had activation-specific transcriptional signatures. IgE-crosslinking upregulated 1803 unique genes including Ccl7, Fxyd6, and Cd33; while IL-33 stimulation induced 1918 genes including Il1b, Cd72, and Tnfaip2. Focused bioinformatics pathway analysis demonstrated IgE-activation aligned with pathways relating to complement activation and CD137 signaling, while IL-33 initiated responses in the NF-κB and IL-10 signaling pathways. Furthermore, BMBs activated via IgE-crosslinking induced type 2 immune response genes like Il2, Il4, Ccl17 and Il13 which were surprisingly absent in IL-33 stimulated BMBs. Further analysis revealed cell-specific transcriptional signatures with 4360 genes that were significant in BMBs but not in BMMCs after IgE activation, and 1645 after IL-33 stimulation. Here we show that MC and BΦ have cell-specific and activation-specific transcriptional responses, and our data suggest novel gene networks and pathways that may shape how the immune system responds to allergens and innate cytokines.