CD4+ cells are required for chronic eosinophilic lung inflammation but not airway remodeling

Doherty, Taylor; Soroosh, Pejman; Broide, David H.; Croft, Michael

doi:10.1152/ajplung.90543.2008

Cited by 45 publications

(37 citation statements)

References 42 publications

(46 reference statements)

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“…In strong contrast, Rag1 −/− mice that lack T and B cells fail to develop significant airway inflammation and hyperresponsiveness upon exposure to Aspergillus [20]. In allergic airway inflammation driven by OVA in mice, antibody-mediated depletion of CD4 + T cells prevented acute inflammation, although airway remodeling remained unaffected [21]. In mouse models of airway inflammation based on the physiologically relevant HDM allergen, Th2 cells are critical and act in close collaboration with IL-21 producing T cells [22].…”

Section: Introductionmentioning

confidence: 93%

T cells are necessary for ILC2 activation in house dust mite‐induced allergic airway inflammation in mice

Bruijn

Tindemans

et al. 2016

Eur J Immunol

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Allergic asthma is a chronic inflammation of the airways mediated by an adaptive type 2 immune response. Upon allergen exposure, group 2 innate lymphoid cells (ILC2s) can be rapidly activated and represent an early innate source of IL-5 and IL-13. Here, we used a house dust mite (HDM)-driven asthma mouse model to study the induction of ILC2s in allergic airway inflammation. In BALF, lungs, and lymph nodes, ILC2 activation is critically dependent on prior sensitization with HDM. Importantly, T cells are required for ILC2 induction, whereby T-cell activation precedes ILC2 induction. During HDM-driven allergic airway inflammation the accumulation of ILC2s in BALF is IL-33 independent, although infiltrating ILC2s produce less cytokines in Il33 −/− mice. Transfer of in vitro polarized OVA-specific OT-II Th2 cells alone or in combination with Th17 cells followed by OVA and HDM challenge is not sufficient to induce ILC2, despite significant eosinophilic inflammation and T-cell activation. In this asthma model, ILC2s are therefore not an early source of Th2 cytokines, but rather contribute to type 2 inflammation in which Th2 cells play a key role. Taken together, ILC2 induction in HDM-mediated allergic airway inflammation in mice critically depends on activation of T cells.Keywords: Allergy · Asthma · Group 2 innate lymphoid cells (ILC2s) · House dust mite · Th2 cellsAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionAsthma is a heterogeneous disease involving chronic inflammation of the airways and is characterized by episodes of coughing, wheezing, and shortness of breath. Multiple genetic predispositions and environmental factors contribute to asthma development and it is estimated that ß300 million people are affected worldwide. The asthma syndrome is divided into distinct disease entities with specific mechanisms, which have been called asthma endotypes [1,2]. The most prevalent endotype is allergic asthma, showing a strong association between exacerbations and repeated Correspondence: Dr. Rudi W. Hendriks e-mail: r.hendriks@erasmusmc.nl exposure to allergens such as pollen, fungi, or house dust mite (HDM). Allergic asthma is thought to be a classic Th2-mediated disease in which the signature effector cytokines IL-4, IL-5, and IL-13 are key orchestrators of persistent inflammation, airway hyperresponsiveness and remodeling, smooth muscle cell hyperplasia, mucous cell metaplasia, and increased angiogenesis (reviewed in [2,3]).Although production of IL-5 and IL-13 by a non-T/non-B lymphocyte population in response to IL-25 was first reported by Fort et al. [4], only recently these cells were accurately characterized and defined as a novel cell population that is negative for classic hematopoietic lineage markers and expresses Sca-1, CD117 (c-kit), CD25 (IL-2Rα), CD127 (IL-7Rα), and T1/ST2 (IL-33R) [5][6][7]. These innate cells are currently referred to as group 2 innate lymphoid cells (ILC2s) and were found to produce IL-13, which is [24]. Ho...

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Section: Introductionmentioning

confidence: 93%

T cells are necessary for ILC2 activation in house dust mite‐induced allergic airway inflammation in mice

Bruijn

Tindemans

et al. 2016

Eur J Immunol

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“…50 The timing of CD4 depletion may be critical, as depletion after allergen sensitization protected from eosinophilic inflammation, but had no effect on tissue remodelling. 51 In other models, eosinophils appear to be required for airway remodelling, with reduced matrix and collagen deposition observed in eosinophil-deficient mice after an 8-week OVAchallenge chronic model. 52 The infiltration and activation of T H 17 cells, which express IL-17A, can also promote tissue remodelling in chronic models, independent of T H 2 cells.…”

Section: Chronic Inflammation and Tissue Remodellingmentioning

confidence: 98%

Mouse models of severe asthma: Understanding the mechanisms of steroid resistance, tissue remodelling and disease exacerbation

et al. 2017

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Severe asthma has significant disease burden and results in high healthcare costs. While existing therapies are effective for the majority of asthma patients, treatments for individuals with severe asthma are often ineffective. Mouse models are useful to identify mechanisms underlying disease pathogenesis and for the preclinical assessment of new therapies. In fact, existing mouse models have contributed significantly to our understanding of allergic/eosinophilic phenotypes of asthma and facilitated the development of novel targeted therapies (e.g. anti-IL-5 and anti-IgE). These therapies are effective in relevant subsets of severe asthma patients. Unfortunately, non-allergic/noneosinophilic asthma, steroid resistance and disease exacerbation remain areas of unmet clinical need. No mouse model encompasses all features of severe asthma. However, mouse models can provide insight into pathogenic pathways that are relevant to severe asthma. In this review, as examples, we highlight models relevant to understanding steroid resistance, chronic tissue remodelling and disease exacerbation. Although these models highlight the complexity of the immune pathways that may underlie severe asthma, they also provide insight into new potential therapeutic approaches.

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“…Sections were stained with H&E and periodic acid-Schiff (PAS) and analyzed by light microscopy (340). We randomly selected five sections stained with H&E per lung and scored peribronchial inflammatory cell infiltration, as described previously (23). The population of PASstained goblet cells per total epithelial cells was calculated by using hybrid cell count BZ-H2C software (KEYENCE, Osaka, Japan).…”

Section: Allergic Airway Inflammationmentioning

confidence: 99%

Involvement of CD300a Phosphatidylserine Immunoreceptor in Aluminum Salt Adjuvant–Induced Th2 Responses

Miki

Nakahashi-Oda

Sumida

et al. 2015

The Journal of Immunology

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Aluminum salt (alum) has been widely used for vaccinations as an adjuvant. Alum not only enhances immunogenicity but also induces Th2 cell immune responses. However, the mechanisms of how alum enhances Th2 cell immune responses have been controversial. In an experimental allergic airway inflammation model, in which alum in conjunction with OVA Ag was i.p. injected for immunization, we found that apoptotic cells and inflammatory dendritic cells (iDC) expressing CD300a, an inhibitory immunoreceptor for phosphatidylserine (PS), significantly increased in number in the peritoneal cavity after the immunization. In contrast, apoptotic cells and iDCs were scarcely observed in the peritoneal cavity after injection of OVA alone. In CD300a-deficient mice, eosinophil infiltration in bronchoalveolar lavage fluid, serum IgE levels, and airway hyperreactivity were significantly decreased after immunization with alum plus OVA compared with wild-type mice. In vitro, iDCs purified from CD300a-deficient mice after the immunization induced significantly less IL-4 production from OT-II naive CD4+ T cells after coculture with OVA Ag. CD300a expressed on iDCs bound PS on apoptotic cells in the peritoneal cavity after injection of OVA plus alum. Blocking CD300a interaction with PS by injection of a neutralizing anti-CD300a Ab resulted in inhibition of the development of allergic airway inflammation. These results suggest that CD300a is involved in alum-induced Th2 skewing.

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CD4+ cells are required for chronic eosinophilic lung inflammation but not airway remodeling

Abstract: Doherty TA, Soroosh P, Broide DH, Croft M. CD4ϩ cells are required for chronic eosinophilic lung inflammation but not airway remodeling.

Cited by 45 publications

References 42 publications

T cells are necessary for ILC2 activation in house dust mite‐induced allergic airway inflammation in mice

T cells are necessary for ILC2 activation in house dust mite‐induced allergic airway inflammation in mice

Mouse models of severe asthma: Understanding the mechanisms of steroid resistance, tissue remodelling and disease exacerbation

Involvement of CD300a Phosphatidylserine Immunoreceptor in Aluminum Salt Adjuvant–Induced Th2 Responses

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