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The type 2 immune response is associated with helminth infections and allergic inflammation where antibody production of the IgG1 and IgE isotypes can elicit protective or proinflammatory functions. Studies over the past few years revealed important new insights regarding the regulatory mechanisms orchestrating the humoral type 2 immune response. This includes investigations on B-cell extrinsic signals, such IL-4 and IL-21, derived from different T-helper cell subsets or discovery of new follicular helper T cells with regulatory or IgE-promoting activities. In addition, studies on B-cell intrinsic factors required for germinal center formation and class switch recombination, including the transcription factors STAT3, STAT6, and BCL-6, led to a better understanding of these processes in type 2 immune responses. Here, we review the current understanding of mechanisms controlling humoral type 2 immunity in vivo including the generation of IgE-producing plasma cells and the memory IgE response., (© 2020 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

Parasitic worms (helminths) developed various immunoregulatory mechanisms to counteract the immune system of their host. The increasing identification and characterization of helminth-derived factors with strong immune modulatory activity provides novel insights into immune escape strategies of helminths. Such factors might be good targets to enhance anti-helminthic immune responses. In addition, immunosuppressive helminth-derived factors could be useful to develop new therapeutic strategies for treatment of chronic inflammatory conditions. This review will take an in depth look at the effects of immunomodulatory molecules produced by different helminths with a focus on schistosomes and mouse models of hookworm infections., (Copyright © 2020 Wiedemann and Voehringer.)

Eicosanoids are key mediators of type-2 inflammation, e.g., in allergy and asthma. Helminth products have been suggested as remedies against inflammatory diseases, but their effects on eicosanoids are unknown. Here, we show that larval products of the helminth Heligmosomoides polygyrus bakeri ( HpbE ), known to modulate type-2 responses, trigger a broad anti-inflammatory eicosanoid shift by suppressing the 5-lipoxygenase pathway, but inducing the cyclooxygenase (COX) pathway. In human macrophages and granulocytes, the HpbE -driven induction of the COX pathway resulted in the production of anti-inflammatory mediators [e.g., prostaglandin E 2 (PGE 2 ) and IL-10] and suppressed chemotaxis. HpbE also abrogated the chemotaxis of granulocytes from patients suffering from aspirin-exacerbated respiratory disease (AERD), a severe type-2 inflammatory condition. Intranasal treatment with HpbE extract attenuated allergic airway inflammation in mice, and intranasal transfer of HpbE -conditioned macrophages led to reduced airway eosinophilia in a COX/PGE 2 -dependent fashion. The induction of regulatory mediators in macrophages depended on p38 mitogen-activated protein kinase (MAPK), hypoxia-inducible factor-1α (HIF-1α), and Hpb glutamate dehydrogenase (GDH), which we identify as a major immunoregulatory protein in HpbE Hpb GDH activity was required for anti-inflammatory effects of HpbE in macrophages, and local administration of recombinant Hpb GDH to the airways abrogated allergic airway inflammation in mice. Thus, a metabolic enzyme present in helminth larvae can suppress type-2 inflammation by inducing an anti-inflammatory eicosanoid switch, which has important implications for the therapy of allergy and asthma., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Basophils are a major source of IL-4 and IL-13, two key cytokines that orchestrate expulsion of gastrointestinal nematodes in different mouse models. Based on recent reports, this review discusses potential roles of basophils and other cells during early and late phases of the immune response against parasitic worms., (Copyright © 2011 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.)

Protective immunity against gastrointestinal and tissue dwelling helminths is coordinated by interaction of different effector cells of the innate and adaptive immune system. Helminths induce a strong type 2 immune response which is characterized by high levels of IgE and increased numbers of Th2 cells, eosinophils, mast cells and basophils. Basophils are rapidly mobilized after helminth infection and can be efficiently recruited into lymphoid and peripheral tissues where they execute their effector functions. Recent work demonstrated that basophils contribute to initiation and execution of type 2 immunity. This review discusses the potential role of basophils for protective immunity against helminths.

An estimated quarter of the human world population is infected with gastrointestinal helminths causing major socioeconomic problems in endemic countries. A better understanding of humoral immune responses against helminths is urgently needed to develop effective vaccination strategies. Here, we used a fate mapping (FM) approach to mark germinal center (GC) B cells and their developmental fates by induced expression of a fluorescent protein during infection of mice with the helminth Nippostrongylus brasiliensis. We could show that FM+ cells persist weeks after clearance of the primary infection mainly as CD80+CD73+PD-L2+ memory B cells. A secondary infection elicited expansion of helminth-specific memory B cells and plasma cells (PCs). Adoptive transfers and analysis of somatic mutations in immunoglobulin genes further revealed that FM+ B cells rapidly convert to PCs rather than participating again in a GC reaction. These results provide new insights in the population dynamics of the humoral immune response against helminths. [ABSTRACT FROM AUTHOR]

The transcription factor STAT6 regulates gene expression in response to IL‐4 and IL‐13. To further investigate how activated STAT6 modulates B cells development and function in vivo, we characterized mice that express a constitutively active version specifically in B cells. CD19Cre_STAT6vt mice show spontaneous phosphorylation and nuclear translocation of STAT6 in B cells. About 80 genes were more than twofold up‐ or downregulated in splenic B cells from CD19Cre_STAT6vt as compared to control mice. B cell development, tissue localization, and populations of follicular and marginal zone B cells, B1 B cells, GC B cells, and plasma cells (PCs) appeared to be normal. However, the number of IgE+ and IgG1+ GC B cells and PCs as well as serum IgE and IgG1 levels were increased in CD19Cre_STAT6vt mice. Infection with Lymphocytic choriomeningitis virus associated with high levels of TNF and IFN‐γ did not prevent the development of a significantly increased IgE and IgG1 response against the virus in CD19Cre_STAT6vt mice. These results suggest that prolonged STAT6 activation during chronic allergic inflammation may result in IgE responses during subsequent viral or bacterial infection that could further stimulate mast cell activation even in the absence of the initial allergic response. [ABSTRACT FROM AUTHOR]

Infection of mice with the gastrointestinal helminth Nippostrongylus brasiliensis elicits profound local proliferation and accumulation of type 2 innate lymphoid cells (ILC2s) in the lung. The regulation of ILC2 proliferation and accumulation in the lung is poorly understood. Using T cell‐specific IL‐4/IL‐13‐deficient mice, we demonstrate that IL‐4/IL‐13 secretion from Th2 cells promotes proliferation and expansion of the ILC2 population in the lung of N. brasiliensis‐infected mice. Competitive mixed BM chimeras containing normal and STAT6‐deficient ILC2s further indicated that ILC2s have to respond directly to IL‐4/IL‐13 for this effect while STAT6 is not required for IL‐13 production in ILC2s. In addition, expression of a constitutively active form of STAT6 in ILC2s was sufficient to promote their proliferation in uninfected mice. The expression of MHC class II in ILC2s appeared to be enhanced by STAT6 signaling supporting the concept that Th2 cells and ILC2s can communicate in an antigen‐dependent manner resulting in a Th2‐regulated accumulation of ILC2s in the lung during an acute type 2 immune response. Based on our observations, targeting the STAT6 pathway in ILC2s could help to develop new treatments to dampen ILC2 proliferation in the lung and thereby ameliorate ILC2‐mediated allergic inflammation. [ABSTRACT FROM AUTHOR]

Infections with helminth parasites are controlled by a concerted action of innate and adaptive effector cells in the frame of a type 2 immune response. Basophils are innate effector cells that may also contribute to the initiation and amplification of adaptive immune responses. Here, we use constitutively basophil-deficient Mcpt8-Cre mice to analyze the impact of basophils during initiation and execution of the protective type 2 responses to both, a primary infection and a challenge infection of immune mice with the helminth parasite Strongyloides ratti. Basophil numbers expanded during parasite infection in blood and mesenteric lymph nodes. Basophil deficiency significantly elevated intestinal parasite numbers and fecal release of eggs and larvae during a primary infection. However, basophils were neither required for the initiation of a S. ratti-specific cellular and humoral type 2 immune response nor for the efficient protection against a challenge infection. Production of Th2 cytokines, IgG1 and IgE as well as mast cell activation were not reduced in basophil-deficient Mcpt8-Cre mice compared to basophil-competent Mcpt8-WT littermates. In addition, a challenge infection of immune basophil-deficient and WT mice resulted in a comparable reduction of tissue migrating larvae, parasites in the intestine and fecal release of eggs and L1 compared to mice infected for the first time. We have shown previously that S. ratti infection induced expansion of Foxp3+ regulatory T cells that interfered with efficient parasite expulsion. Here we show that depletion of regulatory T cells reduced intestinal parasite burden also in absence of basophils. Thus basophils were not targeted specifically by S. ratti-mediated immune evasive mechanisms. Our collective data rather suggests that basophils are non-redundant innate effector cells during murine Strongyloides infections that contribute to the early control of intestinal parasite burden. [ABSTRACT FROM AUTHOR]

Type 2 innate lymphoid cells (ILC2s) are a major source of cytokines, which are also produced by Th2 cells and several cell types of the innate immune system. Work over the past few years indicates that ILC2s play a central role in regulating type 2 immune responses against allergens and helminths. ILC2s can interact with a variety of cells types of the innate and adaptive immune system by cell-cell contacts or by communication via soluble factors. In this review, we provide an overview about recent advances in our understanding how ILC2s orchestrate type 2 immune responses with focus on direct interactions between ILC2s and other cells of the immune system. [ABSTRACT FROM AUTHOR]

IgE-mediated activation of mast cells and basophils contributes to protective immunity against helminths but also causes allergic responses. The development and persistence of IgE responses are poorly understood, which is in part due to the low number of IgE-producing cells. Here, we used next generation sequencing to uncover a striking overlap between the IgE and IgG1 repertoires in helminth-infected or OVA/alum-immunized wild-type BALB/c mice. The memory IgE response after secondary infection induced a strong increase of IgE+ plasma cells in spleen and lymph nodes. In contrast, germinal center B cells did not increase during secondary infection. Unexpectedly, the memory IgE response was lost in mice where the extracellular part of IgG1 had been replaced with IgE sequences. Adoptive transfer studies revealed that IgG1+ B cells were required and sufficient to constitute the memory IgE response in recipient mice. T cell-derived IL-4/IL-13 was required for the memory IgE response but not for expansion of B cells from memory mice. Together, our results reveal a close relationship between the IgE and IgG1 repertoires in vivo and demonstrate that the memory IgE response is mainly conserved at the level of memory IgG1+ B cells. Therefore, targeting the generation and survival of allergen-specific IgG1+ B cells could lead to development of new therapeutic strategies to treat chronic allergic disorders. [ABSTRACT FROM AUTHOR]

Allergic and parasitic worm immunity is characterized by infiltration of tissues with interleukin (IL)-4- and IL-13-expressing cells, including T-helper-2 cells, eosinophils and basophils. Tissue macrophages assume a distinct phenotype, designated alternatively activated macrophages. Relatively little is known about the factors that trigger these host responses. Chitin, a widespread environmental biopolymer of N-acetyl-β-d-glucosamine, provides structural rigidity to fungi, crustaceans, helminths and insects. Here, we show that chitin induces the accumulation in tissue of IL-4-expressing innate immune cells, including eosinophils and basophils, when given to mice. Tissue infiltration was unaffected by the absence of Toll-like-receptor-mediated lipopolysaccharide recognition but did not occur if the injected chitin was pre-treated with the IL-4- and IL-13-inducible mammalian chitinase, AMCase, or if the chitin was injected into mice that overexpressed AMCase. Chitin mediated alternative macrophage activation in vivo and the production of leukotriene B4, which was required for optimal immune cell recruitment. Chitin is a recognition element for tissue infiltration by innate cells implicated in allergic and helminth immunity and this process can be negatively regulated by a vertebrate chitinase. [ABSTRACT FROM AUTHOR]

Allergic inflammation is driven by IgE-producing plasma cells (PCs), which are required for IgE-mediated activation of mast cells and basophils. Repeated antigen encounter elicits a memory IgE response with elevated serum IgE titers and accumulation of IgE-producing PCs. However, the cellular compartment and molecular signals that underlie the immunologic memory of IgE responses remain unclear. With this study we aimed at clarifying whether inactivation of the cytoplasmic immunoglobulin tail tyrosine (ITT) motif in transmembrane IgE (mIgE) impairs the memory IgE response in mice. We generated mice with an inactivated mIgE-ITT motif and analyzed serum IgE levels as well as the generation of IgE-producing germinal center B cells and PCs subsequent to primary and secondary infection with helminths. In vitro cultures were used to study the mIgE-ITT–controlled expression of mIgE on the surface of PCs. Systemic mast cell activation was determined by serum Mcpt1 ELISA in response to ovalbumin challenge. mIgE-ITT–mutant mice showed an impaired memory IgE response subsequent to helminth infection. Furthermore, sensitization and challenge of mIgE-ITT–mutant mice with ovalbumin resulted in diminished serum IgE titers and reduced mast cell activation. The mIgE-ITT motif was required for optimal cell surface expression of mIgE B-cell antigen receptors but not for intracellular IgE expression in PCs. These results indicate that the mIgE B-cell antigen receptor plays a critical role in establishing or maintaining the population of IgE-producing PCs during memory IgE responses. [ABSTRACT FROM AUTHOR]

[Display omitted] • Heligmosmoides polygyrus secretes acetate during its L3 stage and as an adult worm. • Increased acetate is beneficial for Heligmosomoides polygyrus during infection. • Acetate increases permeability in murine intestinal organoids. • Acetate disorganizes tight junction protein Claudin 7 in murine intestinal organoids. • Permeability increasing effects of acetate are FFAR2-dependent. Approximately 2 billion people worldwide and a significant part of the domestic livestock are infected with soil-transmitted helminths, of which many establish chronic infections causing substantial economic and welfare burdens. Beside intensive research on helminth-triggered mucosal and systemic immune responses, the local mechanism that enables infective larvae to cross the intestinal epithelial barrier and invade mucosal tissue remains poorly addressed. Here, we show that Heligmosomoides polygyrus infective L3s secrete acetate and that acetate potentially facilitates paracellular epithelial tissue invasion by changed epithelial tight junction claudin expression. In vitro, impedance-based real-time epithelial cell line barrier measurements together with ex vivo functional permeability assays in intestinal organoid cultures revealed that acetate decreased intercellular barrier function via the G-protein coupled free fatty acid receptor 2 (FFAR2, GPR43). In vivo validation experiments in FFAR2−/− mice showed lower H. polygyrus burdens, whereas oral acetate-treated C57BL/6 wild type mice showed higher burdens. These data suggest that locally secreted acetate – as a metabolic product of the energy metabolism of H. polygyrus L3s – provides a significant advantage to the parasite in crossing the intestinal epithelial barrier and invading mucosal tissues. This is the first and a rate-limiting step for helminths to establish chronic infections in their hosts and if modulated could have profound consequences for their life cycle. [ABSTRACT FROM AUTHOR]

Summary: Basophils are associated with T helper 2 (Th2) cell-polarized immune responses such as allergic disorders or helminth infections. To directly address the role of basophils for type 2 immunity, we generated transgenic mice with constitutive and selective deletion of basophils. Differentiation and accumulation of Th2 cells, induction of eosinophilia, and increase in serum IgE or IgG1 induced by allergens or by infection with the helminth Nippostrongylus brasiliensis appeared to be basophil independent. Further, basophils were not required for passive IgE- or IgG1-mediated systemic anaphylaxis. However, basophils were essential for IgE-meditated chronic allergic dermatitis and for protection against secondary infection with N. brasiliensis. These results demonstrate that basophils play an important role for protective immunity against helminths and orchestrate chronic allergic inflammation, whereas primary Th2 cell responses can operate efficiently in the absence of this cell type. [ABSTRACT FROM AUTHOR]