Comparison of pancreatic enzyme abnormalities and protease-activated receptor-2-positive eosinophils in the duodenum of patients with functional dyspepsia-irritable bowel syndrome overlap with functional dyspepsia alone in Asian populations.

BACKGROUND AND AIM: Some patients with functional gastrointestinal disorders exhibit pancreatic dysfunctions and pancreatic enzyme abnormalities. Thus, we aimed to clarify whether significant differences in clinical characteristics, prevalence of pancreatic enzyme abnormalities, duodenal inflammation, and protease-activated receptor 2 (PAR2) expression levels related to hypersensitivity exist between functional dyspepsia (FD) alone and FD-irritable bowel syndrome (IBS) overlap group. METHODS: Ninety-three patients based on the Rome IV criteria, FD alone (n = 44) and FD overlapped with IBS (n = 49) group were enrolled. The patients scored their own clinical symptoms after consuming high-fat meals. Serum trypsin, PLA2, lipase, p-amylase, and elastase-1 levels were measured. PAR2, eotaxin-3, and TRPV4 mRNA levels in duodenum were determined using real-time polymerase chain reaction methods. PRG2- and PAR2 in the duodenum were evaluated using immunostaining. RESULTS: FD score and global GSRS in patients with FD-IBS overlap were significantly higher than FD alone. Although the prevalence of pancreatic enzyme abnormalities in patients with FD alone was significantly (P < 0.01) higher than that in FD-IBS overlap, the ratio of aggravation of clinical symptoms following high-fat intake in patients with FD-IBS overlap was significantly higher (P = 0.007) than that in patients with FD alone. PAR2- and PRG2-double positive cells were localized in the degranulated eosinophils in the duodenum of patients with FD-IBS overlap. The number of PAR2- and PRG2-double positive cells in FD-IBS overlap was significantly (P < 0.01) higher than FD alone. CONCLUSIONS: Pancreatic enzyme abnormalities and PAR2 expression on degranulated eosinophils infiltrations in the duodenum may be associated with the pathophysiology of patients with FD-IBS overlap in Asian populations.

Biomarkers for predicting type 2-high and uncontrolled asthma in real-world practice.

BACKGROUND: Blood eosinophil count (BEC), immunoglobulin (Ig) E, and fractional exhaled nitric oxide (FeNO) are key clinical indicators for identifying type 2 (T2) asthma. OBJECTIVE: To provide optimal cutoff points of T2 markers for assessing T2-high or uncontrolled asthma in real-world practice. METHODS: Various clinical and laboratory parameters were analyzed according to the result of T2 markers (BEC, serum-free IgE, and FeNO) in adults with asthma who had maintained antiasthmatic medications. The cutoff levels for representing uncontrolled asthma were determined using receiver operating characteristic analysis. Blood levels of periostin and eosinophil-derived neurotoxin were measured by enzyme-linked immunosorbent assay. Activation markers of circulating eosinophils (Siglec8+) and neutrophils (CD66+) were analyzed by flow cytometry. RESULTS: Of 133 patients with asthma, 23 (17.3%) had 3 T2 markers (BEC ≥ 300 cells/µL, serum-free IgE ≥ 120 ng/mL, and FeNO ≥ 25 parts per billion) and significantly higher levels of sputum eosinophils, blood eosinophil-derived neurotoxin, and Siglec8+ eosinophils but lower 1-second forced expiratory volume percentage, in addition to a higher rate of uncontrolled status (P < .05 for all). Furthermore, patients with uncontrolled asthma had significantly higher levels of FeNO and BEC with lower 1-second forced expiratory volume percentage (P < .05 for all). The optimal cutoff values for predicting uncontrolled asthma were found to be 22 parts per billion of FeNO levels, 161.4 cells/L of BECs, and 85.9 ng/mL of serum-free IgE levels. CONCLUSION: We suggest the optimal cutoff values of BEC, IgE, and FeNO for classifying T2-high or uncontrolled asthma, which could be applied as candidate biomarkers for targeting patients with asthma who require T2 biologics.

Eosinophils from A to Z.

Eosinophils are bone marrow-derived granulocytes and are found in low numbers in the peripheral blood of healthy subjects. In type 2 inflammatory diseases, eosinopoiesis in the bone marrow is increased, resulting in a rise in the number of mature eosinophils released in the circulation. From the blood, eosinophils can migrate in multiple tissues and organs under both physiological and pathological conditions. Eosinophils exert their various functions through the synthesis and release of a variety of granule proteins and pro-inflammatory mediators. Despite being present in all species of vertebrates, the functional role of eosinophils is still a matter of debate. Eosinophils may play a role in host defense against various pathogens. In addition, eosinophils have been reported to be involved in tissue homeostasis and exhibit immunomodulatory activities. In this review, we aim to provide a broad overview of eosinophil biology and eosinophilic diseases in a lexicon-style format using keywords starting from A until Z with cross-references to other chapters indicated in italics in the text or specified in parentheses.

Differential role of mucus plugs in asthma: Effects of smoking and association with airway inflammation.

BACKGROUND: The physiological importance of mucus plugs in computed tomography (CT) imaging is being increasingly recognized. However, whether airway inflammation and smoking affect the association between mucus plugs and clinical-physiological outcomes in asthma remains to be elucidated. The objective of this study is to examine how airway inflammation and/or smoking affect the correlation of CT-based mucus plug scores with exacerbation frequency and airflow limitation indices in asthma. METHODS: A total of 168 patients with asthma who underwent chest CT and sputum evaluation were enrolled and classified in eosinophilic asthma (EA; n = 103) and non-eosinophilic asthma (NEA; n = 65) groups based on sputum eosinophil percentage (cut-off: 3%). The mucus plug score was defined as the number of lung segments with mucus plugs seen on CT. RESULTS: More mucus plugs were detected on CT scans in the EA group than in the NEA group, regardless of smoking status. Mucus plug score and exacerbation frequency during one year after enrollment were significantly associated in the EA group but not in the NEA group after adjusting for demographics, blood eosinophil count, and fractional exhaled nitric oxide. Mucus plug score was associated with percentage of predicted forced expiratory volume in 1 s in non-smoking individuals in the EA and NEA group and in smoking individuals in the EA group but not in the NEA group after adjusting for demographics. CONCLUSIONS: The association of mucus plug score with exacerbation frequency and reduced lung function may vary due to airway inflammatory profile and smoking status in asthma.

Eosinophilia in cancer and its regulation by sex hormones.

Gender differences in the functionality of the immune system have been attributed, in part, to direct and indirect effects of sex steroids, especially estrogens, on immune cell repertoire and activity. Notable are studies that have defined roles for estrogens in the regulation of the biology of dendritic cells (DCs), macrophages, T cells and natural killer (NK) cells. Although estrogens can modulate eosinophil function, the mechanisms by which this occurs and how it contributes to the pathobiology of different diseases remains underexplored. Furthermore, although the importance of eosinophils in infection is well established, it remains unclear as to how these innate immune cells, which are present in different tumors, impact the biology of cancer cells and/or response to therapeutics. The observation that eosinophilia influences the efficacy of immune checkpoint blockers (ICBs) is significant considering the role of estrogens as regulators of eosinophil function and recent studies suggesting that response to ICBs is impacted by gender. Thus, in this review, we consider what is known about the roles of estrogen(s) in regulating tissue eosinophilia/eosinophil function and how this influences the pathobiology of breast cancer (in particular). This information provides the context for a discussion of how estrogens/the estrogen receptor (ER) signaling axis can be targeted in eosinophils and how this would be expected to influence the activity of standard-of-care interventions and contemporary immunotherapy regimens in cancer(s).

Solving the Conundrum of Eosinophils in Alloimmunity.

Eosinophils are bone-marrow-derived granulocytes known for their ability to facilitate clearance of parasitic infections and their association with asthma and other inflammatory diseases. The purpose of this review is to discuss the currently available human observational and animal experimental data linking eosinophils to the immunologic response in solid organ transplantation. First, we present observational human studies that demonstrate a link between transplantation and eosinophils yet were unable to define the exact role of this cell population. Next, we describe published experimental models and demonstrate a defined mechanistic role of eosinophils in downregulating the alloimmune response to murine lung transplants. The overall summary of this data suggests that further studies are needed to define the role of eosinophils in multiple solid organ allografts and points to the possibility of manipulating this cell population to improve graft survival.

2021 year in review: Spotlight on eosinophils.

This review highlights recent advances in the understanding of eosinophils and eosinophilic diseases, particularly eosinophilic gastrointestinal diseases during the last year. The increasing incidence of diseases marked by eosinophilia has been documented and highlighted the need to understand eosinophil biology and eosinophilic contributions to disease. Significant insight into the nature of eosinophilic diseases has been achieved using next-generation sequencing technologies, proteomic analysis, and machine learning to analyze tissue biopsies. These technologies have elucidated mechanistic underpinnings of eosinophilic inflammation, delineated patient endotypes, and identified patient responses to therapeutic intervention. Importantly, recent clinical studies using mAbs that interfere with type 2 cytokine signaling or deplete eosinophils point to multiple and complex roles of eosinophils in tissues. Several studies identified distinct activation features of eosinophils in different tissues and disease states. The confluence of these studies supports a new paradigm of tissue-resident eosinophils that have pro- and anti-inflammatory immunomodulatory roles in allergic disease. Improved understanding of unique eosinophil activation states is now poised to identify novel therapeutic targets for eosinophilic diseases.

Role of Eosinophils in Intestinal Inflammation and Fibrosis in Inflammatory Bowel Disease: An Overlooked Villain?

Eosinophils are leukocytes which reside in the gastrointestinal tract under homeostatic conditions, except for the esophagus which is normally devoid of eosinophils. Research on eosinophils has primarily focused on anti-helminth responses and type 2 immune disorders. In contrast, the search for a role of eosinophils in chronic intestinal inflammation and fibrosis has been limited. With a shift in research focus from adaptive to innate immunity and the fact that the eosinophilic granules are filled with inflammatory mediators, eosinophils are becoming a point of interest in inflammatory bowel diseases. In the current review we summarize eosinophil characteristics and recruitment as well as the current knowledge on presence, inflammatory and pro-fibrotic functions of eosinophils in inflammatory bowel disease and other chronic inflammatory conditions, and we identify research gaps which should be covered in the future.

Eosinophils mediate SIgA production triggered by TLR2 and TLR4 to control Ascaris suum infection in mice.

Human ascariasis is the most prevalent but neglected tropical disease in the world, affecting approximately 450 million people. The initial phase of Ascaris infection is marked by larval migration from the host's organs, causing mechanical injuries followed by an intense local inflammatory response, which is characterized mainly by neutrophil and eosinophil infiltration, especially in the lungs. During the pulmonary phase, the lesions induced by larval migration and excessive immune responses contribute to tissue remodeling marked by fibrosis and lung dysfunction. In this study, we investigated the relationship between SIgA levels and eosinophils. We found that TLR2 and TLR4 signaling induces eosinophils and promotes SIgA production during Ascaris suum infection. Therefore, control of parasite burden during the pulmonary phase of ascariasis involves eosinophil influx and subsequent promotion of SIgA levels. In addition, we also demonstrate that eosinophils also participate in the process of tissue remodeling after lung injury caused by larval migration, contributing to pulmonary fibrosis and dysfunction in re-infected mice. In conclusion, we postulate that eosinophils play a central role in mediating host innate and humoral immune responses by controlling parasite burden, tissue inflammation, and remodeling during Ascaris suum infection. Furthermore, we suggest that the use of probiotics can induce eosinophilia and SIgA production and contribute to controlling parasite burden and morbidity of helminthic diseases with pulmonary cycles.

Transcriptional Regulation of the Human IL5RA Gene through Alternative Promoter Usage during Eosinophil Development.

Regulation of the IL-5 receptor alpha (IL5RA) gene is complicated, with two known promoters (P1 and P2) driving transcription, and two known isoforms (transmembrane and soluble) dichotomously affecting the signaling potential of the protein products. Here, we sought to determine the patterns of P1 and P2 promoter usage and transcription factor occupancy during primary human eosinophil development from CD34+ hematopoietic stem cell progenitors. We found that during eosinophilopoiesis, both promoters were active but subject to distinct temporal regulation, coincident with combinatorial interactions of transcription factors, including GATA-1, PU.1, and C/EBP family members. P1 displayed a relatively constant level of activity throughout eosinophil development, while P2 activity peaked early and waned thereafter. The soluble IL-5Rα mRNA peaked early and showed the greatest magnitude fold-induction, while the signaling-competent transmembrane isoform peaked moderately. Two human eosinophilic cell lines whose relative use of P1 and P2 were similar to eosinophils differentiated in culture were used to functionally test putative transcription factor binding sites. Transcription factor occupancy was then validated in primary cultures by ChIP. We conclude that IL-5-dependent generation of eosinophils from CD34+ precursors involves complex and dynamic activity including both promoters, several interacting transcription factors, and both signaling and antagonistic protein products.

Ding Chuan Tang Attenuates Airway Inflammation and Eosinophil Infiltration in Ovalbumin-Sensitized Asthmatic Mice.

Asthma is a T helper 2 (Th2) cell-associated chronic inflammatory diseases characterized with airway obstruction, increased mucus production, and eosinophil infiltration. Conventional medications for asthma treatment cannot fully control the symptoms, and potential side effects are also the concerns. Thus, complement or alternative medicine (CAM) became a new option for asthma management. Ding Chuan Tang (DCT) is a traditional Chinese herbal decoction applied mainly for patients with coughing, wheezing, chest tightness, and asthma. Previously, DCT has been proved to improve children airway hyperresponsiveness (AHR) in a randomized and double-blind clinical trial. However, the mechanisms of how DCT alleviates AHR remain unclear. Since asthmatic features such as eosinophil infiltration, IgE production, and mucus accumulation are relative with Th2 responses, we hypothesized that DCT may attenuate asthma symptoms through regulating Th2 cells. Ovalbumin (OVA) was used as a stimulant to sensitize BALB/c mice to establish an asthmatic model. AHR was detected one day before sacrifice. BALF and serum were collected for immune cell counting and antibody analysis. Splenocytes were cultured with OVA in order to determine Th2 cytokine production. Lung tissues were collected for histological and gene expression analyses. Our data reveal that DCT can attenuate AHR and eosinophil accumulation in the 30-day sensitization asthmatic model. Histological results demonstrated that DCT can reduce cell infiltration and mucus production in peribronchial and perivascular site. In OVA-stimulated splenocyte cultures, a significant reduction of IL-5 and IL-13 in DCT-treated mice suggests that DCT may alleviate Th2 responses. In conclusion, the current study demonstrates that DCT has the potential to suppress allergic responses through the reduction of mucus production, eosinophil infiltration, and Th2 activity in asthma.

Eosinophils Suppress the Migration of T Cells Into the Brain of Plasmodium berghei-Infected Ifnar1-/- Mice and Protect Them From Experimental Cerebral Malaria.

Cerebral malaria is a potentially lethal disease, which is caused by excessive inflammatory responses to Plasmodium parasites. Here we use a newly developed transgenic Plasmodium berghei ANKA (PbAAma1OVA) parasite that can be used to study parasite-specific T cell responses. Our present study demonstrates that Ifnar1-/- mice, which lack type I interferon receptor-dependent signaling, are protected from experimental cerebral malaria (ECM) when infected with this novel parasite. Although CD8+ T cell responses generated in the spleen are essential for the development of ECM, we measured comparable parasite-specific cytotoxic T cell responses in ECM-protected Ifnar1-/- mice and wild type mice suffering from ECM. Importantly, CD8+ T cells were increased in the spleens of ECM-protected Ifnar1-/- mice and the blood-brain-barrier remained intact. This was associated with elevated splenic levels of CCL5, a T cell and eosinophil chemotactic chemokine, which was mainly produced by eosinophils, and an increase in eosinophil numbers. Depletion of eosinophils enhanced CD8+ T cell infiltration into the brain and increased ECM induction in PbAAma1OVA-infected Ifnar1-/- mice. However, eosinophil-depletion did not reduce the CD8+ T cell population in the spleen or reduce splenic CCL5 concentrations. Our study demonstrates that eosinophils impact CD8+ T cell migration and proliferation during PbAAma1OVA-infection in Ifnar1-/- mice and thereby are contributing to the protection from ECM.

Eosinophils are part of the granulocyte response in tuberculosis and promote host resistance in mice.

Host resistance to Mycobacterium tuberculosis (Mtb) infection requires the activities of multiple leukocyte subsets, yet the roles of the different innate effector cells during tuberculosis are incompletely understood. Here we uncover an unexpected association between eosinophils and Mtb infection. In humans, eosinophils are decreased in the blood but enriched in resected human tuberculosis lung lesions and autopsy granulomas. An influx of eosinophils is also evident in infected zebrafish, mice, and nonhuman primate granulomas, where they are functionally activated and degranulate. Importantly, using complementary genetic models of eosinophil deficiency, we demonstrate that in mice, eosinophils are required for optimal pulmonary bacterial control and host survival after Mtb infection. Collectively, our findings uncover an unexpected recruitment of eosinophils to the infected lung tissue and a protective role for these cells in the control of Mtb infection in mice.

Detrimental role of IL-33/ST2 pathway sustaining a chronic eosinophil-dependent Th2 inflammatory response, tissue damage and parasite burden during Toxocara canis infection in mice.

Toxocariasis is a neglected disease that affects people around the world. Humans become infected by accidental ingestion of eggs containing Toxocara canis infective larvae, which upon reaching the intestine, hatch, penetrate the mucosa and migrate to various tissues such as liver, lungs and brain. Studies have indicated that Th2 response is the main immune defense mechanism against toxocariasis, however, there are still few studies related to this response, mainly the IL-33/ST2 pathway. Some studies have reported an increase in IL-33 during helminth infections, including T. canis. By binding to its ST2 receptor, IL-33 stimulating the Th2 polarized immune cell and cytokine responses. Thus, we aimed to investigate the role of the IL-33/ST2 pathway in the context of T. canis larval migration and the immunological and pathophysiological aspects of the infection in the liver, lungs and brain from Wild-Type (WT) BALB/c background and genetically deficient mice for the ST2 receptor (ST2-/-). The most important findings revealed that the IL-33/ST2 pathway is involved in eosinophilia, hepatic and cerebral parasitic burden, and induces the formation of granulomas related to tissue damage and pulmonary dysfunction. However, ST2-/- mice, the immune response was skewed to Th1/Th17 type than Th2, that enhanced the control of parasite burden related to IgG2a levels, tissue macrophages infiltration and reduced lung dysfunction. Collectively, our results demonstrate that the Th2 immune response triggered by IL-33/ST2 pathway mediates susceptibility to T. canis, related to parasitic burden, eosinophilia and granuloma formation in which consequently contributes to tissue inflammation and injury.

Dynamic Decrease in Eosinophil After Intravenous Thrombolysis Predicts Poor Prognosis of Acute Ischemic Stroke: A Longitudinal Study.

Background and Purpose: Blood eosinophil counts are thought to be associated with atherosclerosis in acute ischemic stroke (AIS) and AIS severity. We aimed to investigate 1): the temporal profile of eosinophil in AIS patients treated with recombinant tissue plasminogen activator (r-tPA); 2): The association between dynamic eosinophil and 3-month outcomes in different AIS etiologies; 3): incremental predictive ability of dynamic eosinophil adding to conventional model; and 4): the longitudinal change of neutrophil-to-lymphocyte ratio (NLR) and compared its prognostic value with eosinophils. Methods: A total of 623 AIS patients with intravenous thrombolysis in two hospitals were included. Blood samples were obtained on admission, within 24 h after an intravenous thrombolysis and on the seventh day. A multivariate logistic regression model with restricted cubic spline was performed to explore the association between dynamic eosinophil and a 3-month poor outcome. C-statistic, net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were adopted to explore the incremental predictive ability. Results: Percent change in eosinophil counts after intravenous thrombolysis was median -25.00% (IQR -68.25%-+14.29%). Decrease in eosinophil >75% after intravenous thrombolysis was associated with 2.585 times risk for poor outcome and 13.836 times risk for death. However, the association were weak for patients outside of cardioembolic stroke. Adding eosinophil changes to a conventional model improved the discriminatory ability of poor outcome (NRI = 53.3%; IDI = 2.2%) and death (NRI = 101.0%; IDI = 6.9%). Conclusions: Dynamic decrease in eosinophil after intravenous thrombolysis predicts a 3-month poor outcome and death in AIS patients with r-tPA treatment and improved the predictive ability of conventional model. However, this result needs to be interpreted carefully in non-cardioembolic AIS patients.

The JAK1/2 inhibitor baricitinib suppresses eosinophil effector function and restricts allergen-induced airway eosinophilia.

BACKGROUND: Eosinophilic asthma is increasingly recognized as one of the most severe and difficult-to-treat asthma subtypes. The JAK/STAT pathway is the principal signaling mechanism for a variety of cytokines and growth factors involved in asthma. However, the direct effect of JAK inhibitors on eosinophil effector function has not been addressed thus far. OBJECTIVE: Here we compared the effects of the JAK1/2 inhibitor baricitinib and the JAK3 inhibitor tofacitinib on eosinophil effector function in vitro and in vivo. METHODS: Differentiation of murine bone marrow-derived eosinophils. Migratory responsiveness, respiratory burst, phagocytosis and apoptosis of human peripheral blood eosinophils were assessed in vitro. In vivo effects were investigated in a mouse model of acute house dust mite-induced airway inflammation in BALB/c mice. RESULTS: Baricitinib more potently induced apoptosis and inhibited eosinophil chemotaxis and respiratory burst, while baricitinib and tofacitinib similarly affected eosinophil differentiation and phagocytosis. Of the JAK inhibitors, oral application of baricitinib more potently prevented lung eosinophilia in mice following allergen challenge. However, both JAK inhibitors neither affected airway resistance nor compliance. CONCLUSION: Our data suggest that the JAK1/2 inhibitor baricitinib is even more potent than the JAK3 inhibitor tofacitinib in suppressing eosinophil effector function. Thus, targeting the JAK1/2 pathway represents a promising therapeutic strategy for eosinophilic inflammation as observed in severe eosinophilic asthma.

Emerging Evidence for Pleiotropism of Eosinophils.

Eosinophils are complex granulocytes with the capacity to react upon diverse stimuli due to their numerous and variable surface receptors, which allows them to respond in very different manners. Traditionally believed to be only part of parasitic and allergic/asthmatic immune responses, as scientific studies arise, the paradigm about these cells is continuously changing, adding layers of complexity to their roles in homeostasis and disease. Developing principally in the bone marrow by the action of IL-5 and granulocyte macrophage colony-stimulating factor GM-CSF, eosinophils migrate from the blood to very different organs, performing multiple functions in tissue homeostasis as in the gastrointestinal tract, thymus, uterus, mammary glands, liver, and skeletal muscle. In organs such as the lungs and gastrointestinal tract, eosinophils are able to act as immune regulatory cells and also to perform direct actions against parasites, and bacteria, where novel mechanisms of immune defense as extracellular DNA traps are key factors. Besides, eosinophils, are of importance in an effective response against viral pathogens by their nuclease enzymatic activity and have been lately described as involved in severe acute respiratory syndrome coronavirus SARS-CoV-2 immunity. The pleiotropic role of eosinophils is sustained because eosinophils can be also detrimental to human physiology, for example, in diseases like allergies, asthma, and eosinophilic esophagitis, where exosomes can be significant pathophysiologic units. These eosinophilic pathologies, require specific treatments by eosinophils control, such as new monoclonal antibodies like mepolizumab, reslizumab, and benralizumab. In this review, we describe the roles of eosinophils as effectors and regulatory cells and their involvement in pathological disorders and treatment.

Neutrophils self-limit swarming to contain bacterial growth in vivo.

Neutrophils communicate with each other to form swarms in infected organs. Coordination of this population response is critical for the elimination of bacteria and fungi. Using transgenic mice, we found that neutrophils have evolved an intrinsic mechanism to self-limit swarming and avoid uncontrolled aggregation during inflammation. G protein-coupled receptor (GPCR) desensitization acts as a negative feedback control to stop migration of neutrophils when they sense high concentrations of self-secreted attractants that initially amplify swarming. Interference with this process allows neutrophils to scan larger tissue areas for microbes. Unexpectedly, this does not benefit bacterial clearance as containment of proliferating bacteria by neutrophil clusters becomes impeded. Our data reveal how autosignaling stops self-organized swarming behavior and how the finely tuned balance of neutrophil chemotaxis and arrest counteracts bacterial escape.

Bidirectional crosstalk between eosinophils and esophageal epithelial cells regulates inflammatory and remodeling processes.

Eosinophils accumulate adjacent to epithelial cells in the mucosa of patients with eosinophilic esophagitis (EoE), yet the bidirectional communication between these cells is not well understood. Herein, we investigated the crosstalk between human eosinophils and esophageal epithelial cells. We report that blood-derived eosinophils have prolonged survival when cocultured with epithelial cells; 96 ± 1% and 30 ± 6% viability was observed after 7 and 14 days of coculture, respectively, compared with 1 ± 0% and 0 ± 0% of monoculture. In the presence of IL-13 and epithelial cells, eosinophils had greater survival (68 ± 1%) at 14 days compared with cocultures lacking IL-13. Prolonged eosinophil viability did not require cellular contact and was observed when eosinophils were cultured in conditioned media from esophageal epithelial cells; neutralizing GM-CSF attenuated eosinophil survival. The majority of eosinophil transcripts (58%) were dysregulated in cocultured eosinophils compared with freshly isolated cells. Analysis of epithelial cell transcripts indicated that exposure to eosinophils induced differential expression of a subset of genes that were part of the EoE esophageal transcriptome. Collectively, these results uncover a network of crosstalk between eosinophils and esophageal epithelial cells involving epithelial mediated eosinophil survival and reciprocal changes in cellular transcripts, events likely to occur in EoE.

Immune Cells and Immunotherapy for Cardiac Injury and Repair.

Cardiac injury remains a major cause of morbidity and mortality worldwide. Despite significant advances, a full understanding of why the heart fails to fully recover function after acute injury, and why progressive heart failure frequently ensues, remains elusive. No therapeutics, short of heart transplantation, have emerged to reliably halt or reverse the inexorable progression of heart failure in the majority of patients once it has become clinically evident. To date, most pharmacological interventions have focused on modifying hemodynamics (reducing afterload, controlling blood pressure and blood volume) or on modifying cardiac myocyte function. However, important contributions of the immune system to normal cardiac function and the response to injury have recently emerged as exciting areas of investigation. Therapeutic interventions aimed at harnessing the power of immune cells hold promise for new treatment avenues for cardiac disease. Here, we review the immune response to heart injury, its contribution to cardiac fibrosis, and the potential of immune modifying therapies to affect cardiac repair.