Basophils express a type 2 cytokine profile on exposure to proteases from helminths and house dust mites

Phillips, Clair; Coward, William R.; Pritchard, David; Hewitt, Colin R. A.

doi:10.1189/jlb.0702356

Cited by 182 publications

(110 citation statements)

References 35 publications

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“…In contrast, other studies rather suggested that ASP treatment leads to partially matured DCs, driving a Th2 cell polarization with IL-4 and IL-5 production (68) and allergic lung inflammation in mice (69). Reasons for these discrepancies are presently unclear but could be due to fungal strain differences or to the impact of ASP on other cells beyond DCs, such as basophils or epithelial cells, which in those experimental systems could contribute to Th2 polarization (70)(71)(72).…”

Section: Discussionmentioning

confidence: 98%

Identification of a New Phenotype of Tolerogenic Human Dendritic Cells Induced by Fungal Proteases from Aspergillus oryzae

Zimmer

Luce

Gaignier

et al. 2011

The Journal of Immunology

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We characterized a new pathway to induce tolerogenic dendritic cells (DCs) following treatment of human monocyte-derived DCs with proteases from the fungus Aspergillus oryzae (ASP). ASP-treated DCs (ASP-DCs) exhibit a CD80−CD83−CD86−Ig-like transcript (ILT)2−ILT3−ILT4+ phenotype, do not secrete cytokines or chemokines, and express tolerogenic markers such as glucocorticoid-induced leucine zipper, NO synthetase-2, retinaldehyde dehydrogenase-1 or retinaldehyde dehydrogenase-2. When cocultured with naive CD4+ T cells, ASP-DCs induce an anergic state that can be reversed by IL-2. Generated T cells mediate a suppressive activity in third-party experiments that is not mediated by soluble factors. A comparison between dexamethasone-treated DCs used as a reference for regulatory T cell-inducing DCs and ASP-DCs reveals two distinct phenotypes. In contrast to dexamethasone, ASP treatment induces glucocorticoid-induced leucine zipper independently of glucocorticoid receptor engagement and leads to NF-κB p65 degradation. Abrogation of protease activities in ASP using specific inhibitors reveals that aspartic acid-containing proteases are key inducers of regulatory genes, whereas serine, cysteine, and metalloproteases contribute to NF-κB p65 degradation. Collectively, those features correspond to a previously unreported anergizing phenotype for human DCs. Such regulatory mechanisms may allow fungi to downregulate host immune responses and provide clues for new approaches to treat proinflammatory disorders.

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Section: Discussionmentioning

confidence: 98%

Identification of a New Phenotype of Tolerogenic Human Dendritic Cells Induced by Fungal Proteases from Aspergillus oryzae

Zimmer

Luce

Gaignier

et al. 2011

The Journal of Immunology

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“…However, since certain allergen and helminth antigens may directly crosslink FcεRI on basophils without the need for specific IgE [34][35][36], these responses may also be enhanced by the presence of TLR ligands at the same time, and TLR activation of basophils may thus contribute to enhanced cytokine production in primary immune responses against helminths as well.…”

Section: Discussionmentioning

confidence: 99%

Activation of human basophils by combined toll‐like receptor‐ and FcεRI‐triggering can promote Th2 skewing of naive T helper cells

et al. 2013

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Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionBasophils are circulating granulocytes that can migrate to tissues when inflammation or other triggers are present locally. Activation of basophils through crosslinking of FcεRI via antigen-specific IgE causes the release of granule contents (histamine, proteoglycans), lipid-derived mediators (leukotrienes), and cytokines. Due to their potent activation via IgE-bound antigens and their production of T helper 2 (Th2) type cytokines such as IL-4 and IL-13, Correspondence: Jolien Suurmond e-mail: j.suurmond@lumc.nl basophils are often considered important innate effector cells in IgE-mediated immune responses. Besides activation through IgE, several other pathways have been described to activate basophils, including activation through complement receptors and toll-like receptors (TLR). Although information about TLR protein expression and the response of basophils to TLR ligands is scarce, human basophils express mRNA of several TLRs, and protein of TLR-2 and -4. However, the functional response of basophils to ligation of most TLRs is unknown [1][2][3][4].Basophil responses to TLR ligands may be important, as it is not understood how pathogens and allergens may lead to induction of Th2 responses. As TLR ligation of dendritic cells most often induces type 1 responses through production of IL-12, it is not understood whether and how Th2 cells can be induced via TLR. Since basophils are a known early source of IL-4 and other cytokines associated with Th2 responses, they have been proposed to play a prominent role in the induction of such responses [8]. In mice, it was suggested that basophils play a crucial role in responses against Th2-associated helminth parasites and in protease allergens [9][10][11]. Basophils were proposed to function as APCs in these studies and were also shown to be present in LNs in models of allergy and helminth infection [12][13][14]. However, the function of basophils as APCs during the priming phase of Th2 responses in mice has been challenged by others [13,15,16], and human basophils could not present antigens to CD4 + T cells [17,18]. Therefore, it seems unlikely that human basophils function as APCs. However, by providing an early IL-4 signal that facilitates Th2 skewing after T-cell activation by APCs, basophils could play an important role in skewing of Th2 responses as accessory cells. Indeed, in a mouse model for papain-induced Th2 responses, both DCs and basophils were important for Th2 skewing [19].Since several allergens and helminth parasites can activate TLRs [20][21][22], it would be of high importance to know whether human basophils can be activated via TLR triggering, and if so, which cytokines are released. Until now, little information on these aspects is available for human basophils. Furthermore, as allergic responses and helminth infections may induce IgE responses [23], it would be important to know whether these pathways would interact and prom...

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“…In vitro stimulation of human basophils with Der p 1 induces IL-4 expression (23), and Sokol et al (14) reported that the Th2 differentiation induced by papain in mice is mediated by IL-4 derived from papainstimulated basophils. However, Tang et al (17) proposed a reactive oxygen species-mediated model of papain-induced Th2 immune responses, in which basophils act as an amplifier rather than an initiator, and Hammad et al (24) reported that the true initiator of the HDM-induced Th2 response is not basophils, but inflammatory dendritic cells.…”

mentioning

confidence: 99%

IL-33–Mediated Innate Response and Adaptive Immune Cells Contribute to Maximum Responses of Protease Allergen–Induced Allergic Airway Inflammation

Kamijo

Takeda

Tokura

et al. 2013

The Journal of Immunology

153

164

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How the innate and adaptive immune systems cooperate in the natural history of allergic diseases has been largely unknown. Plant-derived allergen, papain, and mite allergens, Der f 1 and Der p 1, belong to the same family of cysteine proteases. We examined the role of protease allergens in the induction of Ab production and airway inflammation after repeated intranasal administration without adjuvants and that in basophil/mast cell stimulation in vitro. Papain induced papain-specific IgE/IgG1 and lung eosinophilia. Der f 1 induced Der f 1–specific IgG1 and eosinophilia. Although papain-, Der f 1–, and Der p 1–stimulated basophils expressed allergy-inducing cytokines, including IL-4 in vitro, basophil-depleting Ab and mast cell deficiency did not suppress the papain-induced in vivo responses. Protease inhibitor–treated allergens and a catalytic site mutant did not induce the responses. These results indicate that protease activity is essential to Ab production and eosinophilia in vivo and basophil activation in vitro. IL-33–deficient mice lacked eosinophilia and had reduced papain-specific IgE/IgG1. Coadministration of OVA with papain induced OVA-specific IgE/IgG1, which was reduced in IL-33–deficient mice. We demonstrated IL-33 release, subsequent IL-33–dependent IL-5/IL-13 release, and activation of T1/ST2-expressing lineage−CD25+CD44+ innate lymphoid cells in the lung after papain inhalation, suggesting the contribution of the IL-33–type 2 innate lymphoid cell–IL-5/IL-13 axis to the papain-induced airway eosinophilia. Rag2-deficient mice, which lack adaptive immune cells, showed significant, but less severe, eosinophilia. Collectively, these results suggest cooperation of adaptive immune cells and IL-33–responsive innate cells in protease-dependent allergic airway inflammation.

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Basophils express a type 2 cytokine profile on exposure to proteases from helminths and house dust mites

Cited by 182 publications

References 35 publications

Identification of a New Phenotype of Tolerogenic Human Dendritic Cells Induced by Fungal Proteases from Aspergillus oryzae

Identification of a New Phenotype of Tolerogenic Human Dendritic Cells Induced by Fungal Proteases from Aspergillus oryzae

Activation of human basophils by combined toll‐like receptor‐ and FcεRI‐triggering can promote Th2 skewing of naive T helper cells

IL-33–Mediated Innate Response and Adaptive Immune Cells Contribute to Maximum Responses of Protease Allergen–Induced Allergic Airway Inflammation

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