Eosinophilic Gastritis and Enteritis Are Increased in Families With Eosinophilic Esophagitis.

INTRODUCTION: There are limited data on the familial risk of distal eosinophilic gastrointestinal diseases (EGIDs) in patients with eosinophilic esophagitis (EoE). We analyzed the risk of eosinophilic gastritis/gastroenteritis (EG/EGE) and eosinophilic colitis (EC) as forms of distal EGIDs using International Disease Classification-9/10 codes in subjects with EoE and their relatives. METHODS: The Utah Population Database is a resource that links genealogy information and medical records in Utah. We identified EGIDs in probands and their first-degree (FDRs), second-degree (SDRs), and third-degree (TDRs) relatives in the Utah Population Database. Relative risk and 95% confidence intervals were estimated. All individuals with inflammatory bowel disorder were eliminated to avoid misdiagnosis with EGIDs. RESULTS: We included 8,455 subjects with EoE, 396 with EG/EGE, and 172 with EC. Probands with EoE were at increased risk of EG/EGE and EC. Risks of EG/EGE were increased among FDRs and SDRs of probands with EoE , even without concomitant EoE in the relatives. Increased risk of EG/EGE in FDRs and SDRs was also present for EoE probands without EG/EGE or EC. We observed no isolated familial aggregation of EG/EGE after excluding cases with comorbid EoE. EC probands without EoE were at increased risk of EG/EGE, but no evidence of familial risk of EC was observed. DISCUSSION: The relative risk of EG/EGE is significant among relatives of patients with EoE, suggesting that shared genetic factors exist among these EGIDs. EG/EGE and EC showed limited familial clustering, although sample sizes were small.

Prior hospital-based infection and risk of eosinophilic esophagitis in a Swedish nationwide case-control study.

BACKGROUND AND AIMS: Eosinophilic esophagitis (EoE) is an increasingly common, largely food allergen-driven disease characterized by dysphagia. Prior infections are known to associate with other loss of tolerance diseases such as autoimmunity. We aimed to determine if antecedent infection was associated with later EoE development. METHODS: We performed a case-control study of all patients with biopsy-verified EoE diagnosed between 2000 and 2017 in Sweden (n = 1587) and matched to 5 general population controls (n = 7660). Cases were identified using histopathology codes from the Epidemiology Strengthened by histopathology Reports in Sweden study, a validated cohort of gastrointestinal pathology reports from all 28 pathology centers in Sweden. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals for antecedent infections from patients seen at hospital-based outpatient clinics or inpatients. In secondary analyses, we compared EoE patients with their full siblings to further reduce residual confounding. RESULTS: 564 (35.7%) EoE patients and 1793 (23.4%) matched controls had an earlier record of infection. This corresponded to a 2-fold increased risk of infections in EoE patients (OR 2.01; 95%CI: 1.78-2.27). ORs for earlier gastrointestinal or respiratory infection were 2.73 (n = 128 EoE, 268 control; 95%CI: 2.17-3.41) and 1.89 (n = 305 EoE, 960 control; 95%CI: 1.63-2.20), respectively. Having an EoE diagnosis was linked to a 3.39-fold increased odds of sepsis (n = 14 EoE, 21 control; 95%CI: 1.68-6.65). Individuals with EoE were also more likely to have had an infection compared to their non-EoE siblings (n = 427 EoE, 593 control; OR = 1.57; 95%CI = 1.30-1.89). CONCLUSION: In this nationwide cohort study, prior infection, was associated with subsequent EoE. Risks were particularly high after sepsis, and gastrointestinal or respiratory infections.

Models and Tools for Investigating Eosinophilic Esophagitis at the Bench.

Eosinophilic esophagitis (EoE) is an increasingly common food allergy disease of the esophagus that received its medical designation code in 2008. Despite this recency, great strides have been made in the understanding of EoE pathophysiology and type 2 immunity through basic and translational scientific investigations conducted at the bench. These advances have been critical to our understanding of disease mechanisms and generating new hypotheses, however, there currently is only one very recently approved FDA-approved therapy for EoE, leaving a great deal to be uncovered for patients with this disease. Here we review some of the innovative methods, models and tools that have contributed to the advances in EoE discovery and suggest future directions of investigation to expand upon this foundation.

Human differentiated eosinophils release IL-13 in response to IL-33 stimulation.

Objective: Eosinophils are hallmarks in allergic type 2 inflammation and are known to release cytotoxic granule proteins that contribute to inflammation. Eosinophils develop in the bone marrow from hematopoietic stem cells and once mature, have a limited lifespan in culture, making them difficult to study ex vivo. IL-33 has increasingly been shown as a key regulator of type 2 inflammation via signaling through its receptor, ST2. The present study was conducted to detail a method of eosinophil differentiation from hematopoietic stem cells and determine the response to IL-33. Methods: CD34+ and CD14+ cells were isolated from donor apheresis cones and differentiated into eosinophils or macrophage controls, respectively. Morphologic, transcriptional and protein analyses were performed to validate this method of eosinophil differentiation. The effect of IL-33 on differentiated eosinophils was assessed using qPCR, immunofluorescence, and multiplex cytokine array. Results: CD34 differentiated eosinophils appear morphologically similar by H&E and express eosinophil peroxidase (EPX) protein as well as the conventional eosinophil transcripts EPX, CLC, and MBP. In addition, differentiated eosinophils expressed both isoforms of the IL-33 receptor, ST2L and sST2 throughout the differentiation process. Transcript levels of both IL-33 receptors were up-regulated by treatment with IL-33 at earlier timepoints in the differentiation. These cells also expressed IL-4 and IL-13 mRNA which were up-regulated by IL-33 as well. Notably, IL-13 expression was significantly higher with IL-33 treatment compared to media control at every timepoint measured. IL-33 significantly increased cellular secretion of IL-13 protein at most timepoints throughout differentiation. IL-8, LIF, CCL1, CCL5, CCL7, and CCL8 were also significantly secreted after IL-33 stimulation. Conclusions: Our findings suggest that CD34 differentiated eosinophils are morphologically and phenotypically similar to peripheral eosinophils. The release of specific cytokines in direct response to IL-33 may contribute to the pathogenesis of type 2 inflammation and facilitates new avenues for studying eosinophils as effector cells in vitro.

cIAP1/2 antagonism eliminates MHC class I-negative tumors through T cell-dependent reprogramming of mononuclear phagocytes.

Loss of major histocompatibility complex (MHC) class I and interferon-γ (IFN-γ) sensing are major causes of primary and acquired resistance to checkpoint blockade immunotherapy. Thus, additional treatment options are needed for tumors that lose expression of MHC class I. The cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1/2) regulate classical and alternative nuclear factor κB (NF-κB) signaling. Induction of noncanonical NF-κB signaling with cIAP1/2 antagonists mimics costimulatory signaling, augmenting antitumor immunity. We show that induction of noncanonical NF-κB signaling induces T cell-dependent immune responses, even in ß2-microglobulin (ß2M)-deficient tumors, demonstrating that direct CD8 T cell recognition of tumor cell-expressed MHC class I is not required. Instead, T cell-produced lymphotoxin reprograms both mouse and human macrophages to be tumoricidal. In wild-type mice, but not mice incapable of antigen-specific T cell responses, cIAP1/2 antagonism reduces tumor burden by increasing phagocytosis of live tumor cells. Efficacy is augmented by combination with CD47 blockade. Thus, activation of noncanonical NF-κB stimulates a T cell-macrophage axis that curtails growth of tumors that are resistant to checkpoint blockade because of loss of MHC class I or IFN-γ sensing. These findings provide a potential mechanism for controlling checkpoint blockade refractory tumors.