Abstract:The proposed prediction model identifies eosinophilic asthma without the need for sputum induction. The model forms a noninvasive and externally validated test to assess eosinophilic asthma in patients not on OCS.
“…Another possibility is that eosinophils in the circulation are heterogeneous in their threshold for response to specific stimuli, with the most “activatable” cells continuously extravasating, leaving the least “activatable” cells in the circulation. Indeed, a recent study demonstrated that blood eosinophils from asthmatic subjects displayed little or no change in αM integrin expression in response to formylmethionine‐leucyl‐phenylalanine (fMLF), whereas sputum eosinophils exhibited a robust increase in αM integrin expression after fMLF stimulation .…”
Section: Discussionmentioning
confidence: 99%
“…Indeed, a recent study demonstrated that blood eosinophils from asthmatic subjects displayed little or no change in aM integrin expression in response to formylmethionine-leucyl-phenylalanine (fMLF), whereas sputum eosinophils exhibited a robust increase in aM integrin expression after fMLF stimulation. 42 Along these lines, several studies have suggested the possibility that a small proportion of circulating eosinophils in allergic subjects can be activated in vivo to express the low affinity Fc receptor (FccRIIIa and FccRIIIb) CD16. [43][44][45] In some cases, we did observe a CD16 + "tail" within the CCR3 + blood eosinophil population by FACS.…”
Eosinophilic esophagitis (EoE) is an increasingly recognized allergic disease associated with dysphagia and esophageal fibrosis. We aimed to determine expression patterns of specific eosinophil integrins that promote eosinophilic infiltration of the esophageal epithelium, and to determine how key EoE-related cytokines influence eosinophil activation and survival. Esophageal and peripheral eosinophils were isolated from 20 adult subjects with EoE for immunophenotyping and integrin profiling using multicolor flow cytometry and immunohistochemistry. Expression signatures of eosinophil integrins were further assessed by immunohistochemistry using serial sections of esophageal biopsy specimens. Purified eosinophils were used to assess the effect of EoE-relevant cytokines and recombinant periostin on expression of known eosinophil integrins and eosinophil survival and activation. We found that resting eosinophils express high levels of the β2-pairing integrins αL and αM, and lower levels of α4, α6 and α4β7. The migration of peripheral eosinophils to the esophagus is characterized by the specific induction of αM, and a significant increase in the proportion of αM in high-activity conformation. Periostin, a secreted extracellular matrix protein that is significantly overexpressed in EoE, enhances eosinophil survival, and this effect is mediated by αM interaction. Integrin αM is a specific marker of activated tissue eosinophils in EoE, and promotes eosinophil survival through interactions with periostin. The ability of αMβ2 to mediate eosinophil tissue residency via periostin represents a key mechanism for disease development and a potential therapeutic target in EoE.
“…Another possibility is that eosinophils in the circulation are heterogeneous in their threshold for response to specific stimuli, with the most “activatable” cells continuously extravasating, leaving the least “activatable” cells in the circulation. Indeed, a recent study demonstrated that blood eosinophils from asthmatic subjects displayed little or no change in αM integrin expression in response to formylmethionine‐leucyl‐phenylalanine (fMLF), whereas sputum eosinophils exhibited a robust increase in αM integrin expression after fMLF stimulation .…”
Section: Discussionmentioning
confidence: 99%
“…Indeed, a recent study demonstrated that blood eosinophils from asthmatic subjects displayed little or no change in aM integrin expression in response to formylmethionine-leucyl-phenylalanine (fMLF), whereas sputum eosinophils exhibited a robust increase in aM integrin expression after fMLF stimulation. 42 Along these lines, several studies have suggested the possibility that a small proportion of circulating eosinophils in allergic subjects can be activated in vivo to express the low affinity Fc receptor (FccRIIIa and FccRIIIb) CD16. [43][44][45] In some cases, we did observe a CD16 + "tail" within the CCR3 + blood eosinophil population by FACS.…”
Eosinophilic esophagitis (EoE) is an increasingly recognized allergic disease associated with dysphagia and esophageal fibrosis. We aimed to determine expression patterns of specific eosinophil integrins that promote eosinophilic infiltration of the esophageal epithelium, and to determine how key EoE-related cytokines influence eosinophil activation and survival. Esophageal and peripheral eosinophils were isolated from 20 adult subjects with EoE for immunophenotyping and integrin profiling using multicolor flow cytometry and immunohistochemistry. Expression signatures of eosinophil integrins were further assessed by immunohistochemistry using serial sections of esophageal biopsy specimens. Purified eosinophils were used to assess the effect of EoE-relevant cytokines and recombinant periostin on expression of known eosinophil integrins and eosinophil survival and activation. We found that resting eosinophils express high levels of the β2-pairing integrins αL and αM, and lower levels of α4, α6 and α4β7. The migration of peripheral eosinophils to the esophagus is characterized by the specific induction of αM, and a significant increase in the proportion of αM in high-activity conformation. Periostin, a secreted extracellular matrix protein that is significantly overexpressed in EoE, enhances eosinophil survival, and this effect is mediated by αM interaction. Integrin αM is a specific marker of activated tissue eosinophils in EoE, and promotes eosinophil survival through interactions with periostin. The ability of αMβ2 to mediate eosinophil tissue residency via periostin represents a key mechanism for disease development and a potential therapeutic target in EoE.
“…High percentage of sputum eosinophils in asthmatic patients was found to be associated with low or no upregulation of α M integrin or activation of FcγRII (CD32) on blood eosinophils in response to formylmethionine-leucyl-phenylalanine (fMLF) in vitro , whereas low sputum eosinophil count was associated with great α M upregulation and CD32 activation in response to fMLF (72). These results indicate that the responsiveness of circulating eosinophils to a chemoattractant is lower in subjects with high sputum eosinophilia.…”
Section: Downregulation In Severe Asthma or After Antigen Challengementioning
Asthma is frequently characterized by eosinophil-rich airway inflammation. Airway eosinophilia is associated with asthma exacerbations and likely plays a part in airway remodeling. Eosinophil recruitment from the bloodstream depends on circulating eosinophils becoming activated, which leads to eosinophil arrest on activated endothelium, extravasation, and continued movement through the bronchial tissue by interaction with the extracellular matrix (ECM). Circulating eosinophils can exist at different activation levels, which include non-activated or pre-activated (sensitized or “primed”). Further, the bloodstream may lack pre-activated cells, due to such eosinophils having arrested on endothelium or extravasated into tissue. Increased expression, and in some instances, decreased expression of cell-surface proteins, including CD44, CD45, CD45R0, CD48, CD137, neuropeptide S receptor, cytokine receptors, Fc receptors, and integrins (receptors mediating cell adhesion and migration by interacting with ligands on other cells or in the ECM), and activated states of integrins or Fc receptors on blood eosinophils have been reported to correlate with aspects of asthma. A subset of these proteins has been reported to respond to intervention, e.g., with anti-interleukin (IL)-5. How these surface proteins and the activation state of the eosinophil respond to other interventions, e.g., with anti-IL-4 receptor alpha or anti-IL-13, is unknown. Eosinophil surface proteins suggested to be biomarkers of activation, particularly integrins, and reports on correlations between eosinophil activation and aspects of asthma are described in this review. Intermediate activation of beta1 and beta2 integrins on circulating eosinophils correlates with decreased pulmonary function, airway inflammation, or airway lumen eosinophils in non-severe asthma. The correlation does not appear in severe asthma, likely due to a higher degree of extravasation of pre-activated eosinophils in more severe disease. Bronchoalveolar lavage (BAL) eosinophils have highly activated integrins and other changes in surface proteins compared to blood eosinophils. The activation state of eosinophils in lung tissue, although likely very important in asthma, is largely unknown. However, some recent articles, mainly on mice but partly on human cells, indicate that tissue eosinophils may have a surface phenotype(s) different from that of sputum or BAL eosinophils.
“…Thus, costs related to comorbidities and the impact of biologics on these factors will be key. The development of biomarkers, prediction models, the design of trials comparing different biologics and the implementation of strategies to investigate the safety, function, and efficacy in children, the elderly, and pregnant women represent additional crucial challenges that need to be answered in the near future.Gaps in the treatment of allergic disease with biologics How to predict treatment response?Will new biologics help to promote tolerance induction?How to define precision medicine approaches to treat severe and complex atopic phenotypes?Long‐term side effects of biologics?Safety and efficacy of biologics in childhood, in pregnancy, and in elderly?Novel biomarkers and sets of biomarkers will be needed.Treatment algorithms and guidelines for biologics usage are needed.…”
Section: Unmet Needs and Future Research Areas In Treatment Of Allergmentioning
confidence: 99%
“…193,194 Thus, costs related to comorbidities 195 and the impact of biologics on these factors will be key. The development of biomarkers, prediction models, 5,196 the design of trials comparing different biologics and the implementation of strategies to investigate the safety, function, and efficacy in children, the elderly, and pregnant women represent additional crucial challenges that need to be answered in the near future.…”
This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
AbstractThe specialties of allergy and clinical immunology have entered the era of precision medicine with the stratification of diseases into distinct disease subsets, specific diagnoses, and targeted treatment options, including biologicals and small molecules.This article reviews recent developments in research and patient care and future trends in the discipline. The section on basic mechanisms of allergic diseases summarizes the current status and defines research needs in structural biology, type 2 inflammation, immune tolerance, neuroimmune mechanisms, role of the microbiome and diet, environmental factors, and respiratory viral infections. In the section on diagnostic challenges, clinical trials, precision medicine and immune monitoring
Zuzana Diamanthttps://orcid.org/0000-0003-0133-0100Thomas Eiwegger https://orcid.org/0000-0002-2914-7829Wytske J. Fokkens https://orcid.org/0000-0003-4852-229X
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
