Thymic stromal lymphopoietin–elicited basophil responses promote eosinophilic esophagitis
TL;DR: A new mouse model of EoE-like disease that developed independently of IgE, but was dependent on TSLP and basophils is described, suggesting that the T SLP-basophil axis contributes to the pathogenesis of EeE and could be therapeutically targeted to treat this disease.
Abstract: Eosinophilic esophagitis (EoE) is a food allergy-associated inflammatory disease characterized by esophageal eosinophilia. Current management strategies for EoE are nonspecific, and thus there is a need to identify specific immunological pathways that could be targeted to treat this disease. EoE is associated with polymorphisms in the gene that encodes thymic stromal lymphopoietin (TSLP), a cytokine that promotes allergic inflammation, but how TSLP might contribute to EoE disease pathogenesis has been unclear. Here, we describe a new mouse model of EoE-like disease that developed independently of IgE, but was dependent on TSLP and basophils, as targeting TSLP or basophils during the sensitization phase limited disease. Notably, therapeutic TSLP neutralization or basophil depletion also ameliorated established EoE-like disease. In human subjects with EoE, we observed elevated TSLP expression and exaggerated basophil responses in esophageal biopsies, and a gain-of-function TSLP polymorphism was associated with increased basophil responses in patients with EoE. Together, these data suggest that the TSLP-basophil axis contributes to the pathogenesis of EoE and could be therapeutically targeted to treat this disease.
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TL;DR: It is found that basophils play a crucial role in NH cell-mediated eosinophilic inflammation induced by protease allergens, subsequently leading to protease allergen-induced airway inflammation.
269 citations
Cites background from "Thymic stromal lymphopoietin–elicit..."
...The importance of basophils has been reported in chronic allergic dermatitis, and the food-allergy-associated inflammatory disease, eosinophilic esophagitis (Hill et al., 2012; Noti et al., 2013)....
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TL;DR: Detailed microbiota analysis of a well-characterized cohort of infants with FA showed that dysbiosis of fecal microbiota with several FA-associated key phylotypes may play a pathogenic role in FA.
Abstract: Increasing evidence suggests that perturbations in the intestinal microbiota composition of infants are implicated in the pathogenesis of food allergy (FA), while the actual structure and composition of the intestinal microbiota in human beings with FA remain unclear. Microbial diversity and composition were analyzed with parallel barcoded 454 pyrosequencing targeting the 16S rRNA gene hypervariable V1-V3 regions in the feces of 34 infants with FA (17 IgE mediated and 17 non-IgE mediated) and 45 healthy controls. Here, we showed that several key FA-associated bacterial phylotypes, but not the overall microbiota diversity, significantly changed in infancy fecal microbiota with FA and were associated with the development of FA. The proportion of abundant Bacteroidetes, Proteobacteria, and Actinobacteria phyla were significantly reduced, while the Firmicutes phylum was highly enriched in the FA group (P < 0.05). Abundant Clostridiaceae 1 organisms were prevalent in infants with FA at the family level (P = 0.016). FA-enriched phylotypes negatively correlated with interleukin-10, for example, the genera Enterococcus and Staphylococcus. Despite profound interindividual variability, levels of 20 predominant genera were significantly different between the FA and healthy control groups (P < 0.05). Infants with IgE-mediated FA had increased levels of Clostridium sensu stricto and Anaerobacter and decreased levels of Bacteroides and Clostridium XVIII (P < 0.05). A positive correlation was observed between Clostridium sensu stricto and serum-specific IgE (R = 0.655, P < 0.001). The specific microbiota signature could distinguish infants with IgE-mediated FA from non-IgE-mediated ones. Detailed microbiota analysis of a well-characterized cohort of infants with FA showed that dysbiosis of fecal microbiota with several FA-associated key phylotypes may play a pathogenic role in FA.
265 citations
Cites background from "Thymic stromal lymphopoietin–elicit..."
...The key feature of FA is a T-helper type 2 (Th2)-predominant allergen-specific immune response, with the production of IgE antibodies specific for the food allergen (3)....
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TL;DR: An overview of TSLP, IL-33, and IL-25 and the development of blocking antibodies that target these epithelial cell–derived cytokines is provides an overview of these central regulators of type 2 immunity.
Abstract: The epithelial cell-derived cytokines thymic stromal lymphopoietin (TSLP), IL-33, and IL-25 are central regulators of type 2 immunity, which drives a broad array of allergic responses. Often characterized as "alarmins" that are released by the barrier epithelium in response to external insults, these epithelial cell-derived cytokines were initially thought to act only early in allergic inflammation. Indeed, TSLP can condition dendritic cells to initiate type 2 responses, and IL-33 may influence susceptibility to asthma through its role in establishing the immune environment in the perinatal lungs. However, TSLP, IL-33, and IL-25 all regulate a broad spectrum of innate immune cell populations and are particularly potent in eliciting and activating type 2 innate lymphoid cells (ILC2s) that may act throughout allergic inflammation. Recent data suggest that a TSLP/ILC axis may mediate steroid resistance in asthma. Recent identification of memory Th2 cell subsets that are characterized by high receptor expression for TSLP, IL-33, and IL-25 further supports a role for these cytokines in allergic exacerbations. There is therefore growing interest in developing biologics that target TSLP, IL-33, and IL-25. This Review provides an overview of TSLP, IL-33, and IL-25 and the development of blocking antibodies that target these epithelial cell-derived cytokines.
244 citations
TL;DR: Recent studies that have identified previously unappreciated molecules and pathways that regulate basophil development, activation, and function in the context of allergic inflammation are discussed.
Abstract: Basophils were discovered by Paul Ehrlich in 1879 and represent the least abundant granulocyte population in mammals. The relative rarity of basophils and their phenotypic similarities with mast cells resulted in this cell lineage being historically overlooked, both clinically and experimentally. However, recent studies in human subjects and murine systems have shown that basophils perform nonredundant effector functions and significantly contribute to the development and progression of T H 2 cytokine–mediated inflammation. Although the potential functions of murine and human basophils have provoked some controversy, recent genetic approaches indicate that basophils can migrate into lymphoid tissues and, in some circumstances, cooperate with other immune cells to promote optimal T H 2 cytokine responses in vivo . This article provides a brief historical perspective on basophil-related research and discusses recent studies that have identified previously unappreciated molecules and pathways that regulate basophil development, activation, and function in the context of allergic inflammation. Furthermore, we highlight the unique effector functions of basophils and discuss their contributions to the development and pathogenesis of allergic inflammation in human disease. Finally, we discuss the therapeutic potential of targeting basophils in preventing or alleviating the development and progression of allergic inflammation.
237 citations
TL;DR: It is identified that basophils and ILC2s significantly accumulate in inflamed human and murine skin and form clusters not observed in control skin, and a previously unrecognized role for basophil-derived IL-4 in promoting I LC2 responses during cutaneous inflammation is revealed.
Abstract: Type 2 inflammation underlies allergic diseases such as atopic dermatitis, which is characterized by the accumulation of basophils and group 2 innate lymphoid cells (ILC2s) in inflamed skin lesions Although murine studies have demonstrated that cutaneous basophil and ILC2 responses are dependent on thymic stromal lymphopoietin, whether these cell populations interact to regulate the development of cutaneous type 2 inflammation is poorly defined In this study, we identify that basophils and ILC2s significantly accumulate in inflamed human and murine skin and form clusters not observed in control skin We demonstrate that murine basophil responses precede ILC2 responses and that basophils are the dominant IL-4-enhanced GFP-expressing cell type in inflamed skin Furthermore, basophils and IL-4 were necessary for the optimal accumulation of ILC2s and induction of atopic dermatitis-like disease We show that ILC2s express IL-4Rα and proliferate in an IL-4-dependent manner Additionally, basophil-derived IL-4 was required for cutaneous ILC2 responses in vivo and directly regulated ILC2 proliferation ex vivo Collectively, these data reveal a previously unrecognized role for basophil-derived IL-4 in promoting ILC2 responses during cutaneous inflammation
230 citations
Cites background from "Thymic stromal lymphopoietin–elicit..."
...Treatment of BaS mice with diphtheria toxin results in selective depletion of cutaneous basophils during inflammation (9, 10)....
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...Furthermore, we have shown that TSLP-elicited basophils promote local Th2 cell responses in the context of AD-like disease and promote epicutaneous sensitization to food allergens (9, 10, 41)....
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...Human skin samples were assessed as previously described for flow cytometry, and basophils were defined as CD123FcεRIa cells negative for expression of CD3, CD11c, CD19, CD56, and c-Kit, whereas ILC2s were defined as CD25IL-33R cells negative for expression of lineage (CD3, TCRab, CD5, CD11b, CD11c, CD19, CD56, and FcεRIa) markers (10, 20)....
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References
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TL;DR: OCT as discussed by the authors uses low-coherence interferometry to produce a two-dimensional image of optical scattering from internal tissue microstructures in a way analogous to ultrasonic pulse-echo imaging.
Abstract: A technique called optical coherence tomography (OCT) has been developed for noninvasive cross-sectional imaging in biological systems. OCT uses low-coherence interferometry to produce a two-dimensional image of optical scattering from internal tissue microstructures in a way that is analogous to ultrasonic pulse-echo imaging. OCT has longitudinal and lateral spatial resolutions of a few micrometers and can detect reflected signals as small as approximately 10(-10) of the incident optical power. Tomographic imaging is demonstrated in vitro in the peripapillary area of the retina and in the coronary artery, two clinically relevant examples that are representative of transparent and turbid media, respectively.
11,568 citations
TL;DR: It is shown that human thymic stromal lymphopoietin (TSLP) potently activated CD11c+ dendritic cells (DCs) and induced production of the TH2-attracting chemokines TARC (thymus and activation-regulated chemokine) and MDC (macrophage-derivedChemokine; CCL22).
Abstract: Whether epithelial cells play a role in triggering the immune cascade leading to T helper 2 (T(H)2)-type allergic inflammation is not known. We show here that human thymic stromal lymphopoietin (TSLP) potently activated CD11c(+) dendritic cells (DCs) and induced production of the T(H)2-attracting chemokines TARC (thymus and activation-regulated chemokine; also known as CCL17) and MDC (macrophage-derived chemokine; CCL22). TSLP-activated DCs primed naive T(H) cells to produce the proallergic cytokines interleukin 4 (IL-4), IL-5, IL-13 and tumor necrosis factor-alpha, while down-regulating IL-10 and interferon-gamma. TSLP was highly expressed by epithelial cells, especially keratinocytes from patients with atopic dermatitis. TSLP expression was associated with Langerhans cell migration and activation in situ. These findings shed new light on the function of human TSLP and the role played by epithelial cells and DCs in initiating allergic inflammation.
1,980 citations
TL;DR: A new conceptual definition is proposed highlighting that EoE represents a chronic, immune/antigen-mediated disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation.
Abstract: Eosinophilic esophagitis (EoE) is a clinicopathologic condition of increasing recognition and prevalence. In 2007, a consensus recommendation provided clinical and histopathologic guidance for the diagnosis and treatment of EoE; however, only a minority of physicians use the 2007 guidelines, which require fulfillment of both histologic and clinical features. Since 2007, the number of EoE publications has doubled, providing new disease insight. Accordingly, a panel of 33 physicians with expertise in pediatric and adult allergy/immunology, gastroenterology, and pathology conducted a systematic review of the EoE literature (since September 2006) using electronic databases. Based on the literature review and expertise of the panel, information and recommendations were provided in each of the following areas of EoE: diagnostics, genetics, allergy testing, therapeutics, and disease complications. Because accumulating animal and human data have provided evidence that EoE appears to be an antigen-driven immunologic process that involves multiple pathogenic pathways, a new conceptual definition is proposed highlighting that EoE represents a chronic, immune/antigen-mediated disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. The diagnostic guidelines continue to define EoE as an isolated chronic disorder of the esophagus diagnosed by the need of both clinical and pathologic features. Patients commonly have high rates of concurrent allergic diatheses, especially food sensitization, compared with the general population. Proved therapeutic options include chronic dietary elimination, topical corticosteroids, and esophageal dilation. Important additions since 2007 include genetic underpinnings that implicate EoE susceptibility caused by polymorphisms in the thymic stromal lymphopoietin protein gene and the description of a new potential disease phenotype, proton pump inhibitor-responsive esophageal eosinophila. Further advances and controversies regarding diagnostic methods, surrogate disease markers, allergy testing, and treatment approaches are discussed.
1,675 citations
TL;DR: Patients receiving reslizumab showed significantly greater reductions in sputum eosinophils, improvements in airway function, and a trend toward greater asthma control than those receiving placebo.
Abstract: Rationale: Eosinophilic asthma is a phenotype of asthma characterized by the persistence of eosinophils in the airways. IL-5 is involved in the activation and survival of eosinophils.Objectives: To evaluate the effect of the antibody to IL-5, reslizumab, in patients with eosinophilic asthma that is poorly controlled with high-dose inhaled corticosteroid.Methods: Patients were randomly assigned to receive infusions of reslizumab at 3.0 mg/kg (n = 53) or placebo (n = 53) at baseline and at Weeks 4, 8, and 12, with stratification by baseline Asthma Control Questionnaire (ACQ) score less than or equal to 2 or greater than 2. The primary efficacy measure was the difference between the reslizumab and placebo groups in the change in ACQ score from baseline to end of therapy (Week 15 or early withdrawal).Measurements and Main Results: Mean changes from baseline to end of therapy in ACQ score were –0.7 in the reslizumab group and –0.3 in the placebo group (P = 0.054) and in FEV1 were 0.18 and –0.08 L, respectively...
669 citations