The IL-17 cytokine family and their role in allergic inflammation

Allergic diseases and asthma has long been hypothesized as the results of the dysregulation of type 2 immune responses to environmental allergens. Recent progresses in characterizing the proinflammatory IL-17 cytokine family have added additional layer of complexity on the regulation of allergic inflammation. The delineation of IL-17-producing CD4+ T cell subset (Th17) has led to the revision of Th1/Th2 paradigm and impacts our perspectives on the basis of chronic tissue inflammation. In addition, the distinctive expression patterns and biological activities of individual IL-17 cytokine member may play different roles in the regulation of the pathogenesis of allergic diseases. Understanding the cellular source and targeting cells of IL-17 cytokine family member will provide the basis to elucidate the cellular mechanism underlying allergic inflammation and improve our therapeutic approaches for allergy.     

Functions of thymic stromal lymphopoietin in immunity and disease

Thymic stromal lymphopoietin (TSLP) is an interleukin 7-like cytokine expressed mainly by epithelial cells. Current studies provide compelling evidence that TSLP is capable of activating dendritic cells to promote T helper (Th) 2 immune responses. TSLP has also been shown to directly promote Th2 differentiation of na?ve CD4(+) T cell and activate natural killer T cells, basophils and other innate immune cells at the initial stage of inflammation. In addition, TSLP affects B cell maturation and activation and can also influence regulatory T (Treg) cell differentiation and development. TSLP-induced Th2 responses are associated with the pathogenesis of allergic inflammatory diseases, including atopic dermatitis, asthma, and rhinitis. Based on recent findings in humans and mouse models, TSLP might also be involved in the pathogenesis of inflammatory bowel disease and progression of cancer. In this review, we will summarize our current understanding of the biology of TSLP and highlight the important issues for future investigations.     

Reprogramming cholesterol metabolism in macrophages and its role in host defense against cholesterol-dependent cytolysins

Cholesterol is a critical lipid for all mammalian cells, ensuring proper membrane integrity, fluidity, and biochemical function. Accumulating evidence indicates that macrophages rapidly and profoundly reprogram their cholesterol metabolism in response to activation signals to support host defense processes. However, our understanding of the molecular details underlying how and why cholesterol homeostasis is specifically reshaped during immune responses remains less well understood. This review discusses our current knowledge of cellular cholesterol homeostatic machinery and introduces emerging concepts regarding how plasma membrane cholesterol is partitioned into distinct pools. We then discuss how proinflammatory signals can markedly reshape the cholesterol metabolism of macrophages, with a focus on the differences between MyD88-dependent pattern recognition receptors and the interferon signaling pathway. We also discuss recent work investigating the capacity of these proinflammatory signals to selectively reshape plasma membrane cholesterol homeostasis. We examine how these changes in plasma membrane cholesterol metabolism influence sensitivity to a set of microbial pore-forming toxins known as cholesterol-dependent cytolysins that specifically target cholesterol for their effector functions. We also discuss whether lipid metabolic reprogramming can be leveraged for therapy to mitigate tissue damage mediated by cholesterol-dependent cytolysins in necrotizing fasciitis and other related infections. We expect that advancing our understanding of the crosstalk between metabolism and innate immunity will help explain how inflammation underlies metabolic diseases and highlight pathways that could be targeted to normalize metabolic homeostasis in disease states.     

Allergen uptake and presentation by dendritic cells

Allergic diseases such as atopic dermatitis, rhinitis and asthma are thought to result from a dysregulated immune response to commonly encountered antigens in genetically predisposed individuals. This response leads to chronic eosinophil-rich allergic inflammation and is controlled by Th2 lymphocytes. The first step in the allergic immune response is the uptake and presentation of allergen by professional antigen presenting cells such as dendritic cells, macrophages and B lymphocytes. Immature dendritic cells reside in the epithelia of the skin, upper and lower airways and gut and have the potential to sense foreign antigens and non-specific inflammatory tissue damage. Following recognition and uptake of Ag, mature dendritic cells migrate to the T-cell rich area of draining lymph nodes, display an array of Ag-derived peptides on the surface of major histocompatibility complex molecules and acquire the cellular specialization to select and activate naive Ag-specific T cells. By the nature of the signals they provide to naive T cells, mature dendritic cells are critical for polarizing Th0 helper cells into either Th1 or Th2 effector cells and for inducing long-lived memory Th cells. This article reviews recent information implying dendritic cells in the pathogenesis of allergic disease.     

The Th1/Th2 paradigm in ocular allergy

PURPOSE OF REVIEW: The paradigm that diseases are either Th1 mediated or Th2 mediated has recently been challenged in a number of classical ocular diseases. The objective of this article is to highlight the importance of understanding the exact mechanisms of Th1 and Th2 cells in the pathology of ocular allergy. RECENT FINDINGS: Current research of Th1 and Th2 cytokines in an animal model of ocular allergy demonstrates the intricate complex regulation by both subsets of cytokines of the disease process. Th2 prone BALB/c wild type mice sensitized and topically challenged with short ragweed for seven consecutive days (multi-hit) developed a sustained, chronic conjunctival inflammation. Significantly, IFN-gamma knockout mice in the multi-hit antigen challenge model had a reduced conjunctival cellular infiltrate. Evaluation of adhesion molecules that actively regulate cellular infiltration into the conjunctiva revealed a lack of vascular cell adhesion molecule-1 in multi-hit antigen challenged IFN-gamma knockout mice. SUMMARY: Recent ocular allergy studies question the Th1/Th2 paradigm. These studies encourage further understanding of the intricate interactions of Th1 and Th2 cytokines in ocular inflammatory disease. The following components of Th1 and Th2 cells in the development of chronic inflammation associated with allergic conjunctivitis will be discussed: T helper subsets Th1 and Th2 in ocular inflammation, activation of T cells in the lymph node, and the role of IFN-gamma as the endothelium gatekeeper in the pathology of Th2-mediated allergic conjunctivitis.     

Cooperation of adapter molecules in proximal signaling cascades during allergic inflammation

Summary:  Activation of mast cells through their high-affinity immunoglobulin E receptor (FcεRI) plays an important role in allergic disorders. Other mast cell-activating stimuli, such as Toll-like receptor (TLR) ligands, synergize with FcεRI to enhance allergic inflammation. Thus, there is much interest in understanding how signaling occurs downstream of these receptors. One key event for FcεRI-mediated mast cell activation is the inducible formation of multimolecular proximal signaling complexes. These complexes are nucleated by adapter proteins, scaffolds that localize various signaling molecules through their multiple molecule-binding domains. Here we review recent findings in proximal signaling cascades with an emphasis on how adapter molecules cooperate with each other to generate an optimal signal in mast cells, and we discuss how signals crosstalk between FcεRI and TLRs in enhancing mast cell activation. Deciphering the molecular mechanisms leading to mast cell activation will hopefully bring new ideas for the development of novel therapeutics to control allergic diseases.     

Translational Mini‐Review Series on Th17 Cells: Function and regulation of human T helper 17 cells in health and disease

T helper (Th) cell have a central role in modulating immune responses. While Th1 and Th2 cells have long been known to regulate cellular and humoral immunity, Th17 cells have been identified only recently as a Th lineage that regulates inflammation via production of distinct cytokines such as interleukin (IL)-17. There is growing evidence that Th17 cells are pathological in many human diseases, leading to intense interest in defining their origins, functions and developing strategies to block their pathological effects. The cytokines that regulate Th17 differentiation have been the focus of much debate, due primarily to inconsistent findings from studies in humans. Evidence from human disease suggests that their in vivo development is driven by specialized antigen-presenting cells. Knowledge of how Th17 cells interact with other immune cells is limited, but recent data suggest that Th17 cells may not be subject to strict cellular regulation by T regulatory cells. Notably, Th17 cells and T regulatory cells appear to share common developmental pathways and both cell types retain significant plasticity. Herein, we will discuss the molecular and cellular regulation of Th17 cells with an emphasis on studies in humans.     

Type 2 immunity in the skin and lungs

There has been extensive progress in understanding the cellular and molecular mechanisms of inflammation and immune regulation in allergic diseases of the skin and lungs during the last few years. Asthma and atopic dermatitis (AD) are typical diseases of type 2 immune responses. interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin are essential cytokines of epithelial cells that are activated by allergens, pollutants, viruses, bacteria, and toxins that derive type 2 responses. Th2 cells and innate lymphoid cells (ILC) produce and secrete type 2 cytokines such as IL-4, IL-5, IL-9, and IL-13. IL-4 and IL-13 activate B cells to class-switch to IgE and also play a role in T-cell and eosinophil migration to allergic inflammatory tissues. IL-13 contributes to maturation, activation, nitric oxide production and differentiation of epithelia, production of mucus as well as smooth muscle contraction, and extracellular matrix generation. IL-4 and IL-13 open tight junction barrier and cause barrier leakiness in the skin and lungs. IL-5 acts on activation, recruitment, and survival of eosinophils. IL-9 contributes to general allergic phenotype by enhancing all of the aspects, such as IgE and eosinophilia. Type 2 ILC contribute to inflammation in AD and asthma by enhancing the activity of Th2 cells, eosinophils, and their cytokines. Currently, five biologics are licensed to suppress type 2 inflammation via IgE, IL-5 and its receptor, and IL-4 receptor alpha. Some patients with severe atopic disease have little evidence of type 2 hyperactivity and do not respond to biologics which target this pathway. Studies in responder and nonresponder patients demonstrate the complexity of these diseases. In addition, primary immune deficiency diseases related to T-cell maturation, regulatory T-cell development, and T-cell signaling, such as Omenn syndrome, severe combined immune deficiencies, immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, and DOCK8, STAT3, and CARD11 deficiencies, help in our understanding of the importance and redundancy of various type 2 immune components. The present review aims to highlight recent advances in type 2 immunity and discuss the cellular sources, targets, and roles of type 2 mechanisms in asthma and AD.     

树突细胞与哮喘Th1/Th2失衡

特应性哮喘患者以Th2免疫反应为主,导致气道炎症,Th1／Th2失衡是特庆性哮喘重要的免疫病理机制,树突细胞（DCs）中肺部主要抗原递呈细胞,不但可以介志对吸入抗原初始的免疫反应,活化辅助性T细胞,而且在可以决定T细胞的分化方向,维持哮喘Th2免疫反应和Th1／Th2失衡机制中发挥重要作用而日益受到重视。本文就近年来对特应性哮喘免疫病理机制中DCs对Th1／Th2失衡影响认识作一综述。     

IgE-mediated regulation of IL-10 and type I IFN enhances rhinovirus-induced Th2 differentiation by primary human monocytes

Rhinovirus (RV) infections are linked to the development and exacerbation of allergic diseases including allergic asthma. IgE, another contributor to atopic disease pathogenesis, has been shown to regulate DC antiviral functions and influence T cell priming by monocytes. We previously demonstrated that IgE-mediated stimulation of monocytes alters multiple cellular functions including cytokine secretion, phagocytosis, and influenza-induced Th1 development. In this study, we investigate the effects of IgE-mediated stimulation on monocyte-driven, RV-induced T cell development utilizing primary human monocyte-T cell co-cultures. We demonstrate that IgE crosslinking of RV-exposed monocytes enhances monocyte-driven Th2 differentiation. This increase in RV-induced Th2 development was regulated by IgE-mediated inhibition of virus-induced type I IFN and induction of IL-10. These findings suggest an additional mechanism by which two clinically significant risk factors for allergic disease exacerbations—IgE-mediated stimulation and rhinovirus infection—may synergistically promote Th2 differentiation and allergic inflammation.     

Exploiting worm and allergy models to understand Th2 cytokine biology

PURPOSE OF REVIEW: Helminthic parasites and many allergens trigger highly polarized Th2-type immune responses. In most helminth infections, the Th2 response often leads to parasite expulsion or sequestration. During murine Schistosoma mansoni infection, however, the parasites persist and the chronic Th2 response induces severe pathological changes in the gut and liver. Thus, the study of schistosome infections in mice has become a popular model to study the pathogenesis of Th2 cytokine-mediated disease. This review will discuss recent findings from the schistosomiasis model that may be relevant to the understanding of allergic inflammation, asthma and Th2 cytokine biology in general. RECENT FINDINGS: Evidence is accumulating that the Th2 pathway is not a 'default pathway' but one that is actively instructed by mechanisms that are only beginning to be understood. Other areas of intensive investigation include studies on alternatively activated macrophages, the role of dendritic cells in Th2 response development, the inhibitory function of IL-10, regulatory T-cells and decoy receptors on chronic Th2-mediated inflammation, and the role of chitinases in mediating Th2 disease. Finally, the development of novel eosinophil-deficient mice has also accelerated our understanding of the contribution of this important cell type to Th2 immunity. SUMMARY: Many findings from the schistosomiasis model have been subsequently demonstrated in models of allergic disease, illustrating the utility of this model to dissect basic mechanisms of Th2-mediated inflammation. Further study of helminth-induced Th2 responses may expedite the discovery of new therapeutics for a wide range of Th2-associated diseases.     

T-cell fate and function: PKC-theta and beyond

The serine/threonine-specific protein kinase C-theta (PKC-theta) is a core component of the immunological synapse that was shown in vitro to play a central role in the activation of T cells after T cell receptor (TCR) and co-stimulatory molecule engagement. In recent years, a series of in vivo studies have shown that the situation is far more complex; specifically, PKC-theta signaling is differentially required for Th1, Th2, Th17 and CD8+ cytotoxic T-cell responses. These studies highlight the combination of signals that directly regulate T-cell differentiation and effector responses. In this review, we highlight recent in vivo studies investigating PKC-theta function and discuss this in the context of how the integration of extrinsic signals determines T cell fate and function.     

IL-17 and IL-22 in atopic allergic disease

A long standing paradigm is that antigen-specific Th2 cells and their cytokines such as IL-4, IL-5, and IL-13 orchestrate the characteristic features of atopic allergy. The discovery of a role for IL-17-producing (Th17) and IL-22-producing (Th22) T helper cells in inflammatory diseases has added an additional layer of complexity to the understanding of the pathogenesis of allergic diseases. Here we re-evaluate the role of T helper cells, with special focus on the Th17 and Th22 subsets in allergic asthma and atopic dermatitis. Whereas sparse data point to a protective role of the increasing amounts of Th22 cells that are found in chronic stages of both allergies, the data on Th17 cells paint different pictures for the contribution of Th17 cells during subsequent stages of these two forms of allergy.     

T regulatory cells and their counterparts: masters of immune regulation

The interaction of environmental and genetic factors with the immune system can lead to the development of allergic diseases. The essential step in this progress is the generation of allergen-specific CD4⁺ T-helper (Th) type 2 cells that mediate several effector functions. The influence of Th2 cytokines leads to the production of allergen-specific IgE antibodies by B cells, development and recruitment of eosinophils, mucus production and bronchial hyperreactivity, as well as tissue homing of other Th2 cells and eosinophils. Meanwhile, Th1 cells may contribute to chronicity and the effector phases. T cells termed T regulatory (Treg) cells, which have immunosuppressive functions and cytokine profiles distinct from that of either Th1 or Th2 cells, have been intensely investigated during the last 13 years. Treg cell response is characterized by an abolished allergen-specific T cell proliferation and the suppressed secretion of Th1 and Th2-type cytokines. Treg cells are able to inhibit the development of allergen-specific Th2 and Th1 cell responses and therefore play an important role in a healthy immune response to allergens. In addition, Treg cells potently suppress IgE production and directly or indirectly suppress the activity of effector cells of allergic inflammation, such as eosinophils, basophils and mast cells. Currently, Treg cells represent an exciting area of research, where understanding the mechanisms of peripheral tolerance to allergens may soon lead to more rational and safer approaches for the prevention and cure of allergic diseases.     

Metabolic control of the Treg/Th17 axis

The interplay of the immune system with other aspects of physiology is continually being revealed and in some cases studied in considerable mechanistic detail. A prime example is the influence of metabolic cues on immune responses. It is well appreciated that upon activation, T cells take on a metabolic profile profoundly distinct from that of their quiescent and anergic counterparts; however, a number of recent breakthroughs have greatly expanded our knowledge of how aspects of cellular metabolism can shape a T-cell response. Particularly important are findings that certain environmental cues can tilt the delicate balance between inflammation and immune tolerance by skewing T-cell fate decisions toward either the T-helper 17 (Th17) or T-regulatory (Treg) cell lineage. Recognizing the unappreciated immune-modifying potential of metabolic factors and particularly those involved in the generation of these functionally opposing T-cell subsets will likely add new and potent therapies to our repertoire for treating immune mediated pathologies. In this review, we summarize and discuss recent findings linking certain metabolic pathways, enzymes, and by-products to shifts in the balance between Th17 and Treg cell populations. These advances highlight numerous opportunities for immune modulation.     

Effector and Regulatory T‐cell Subsets in Autoimmunity and Tissue Inflammation

Many autoimmune diseases are driven by self‐reactive T helper cells. Until recently, organ‐specific autoimmune diseases were primarily associated with Th1 cells but not Th2 cells. However, the discovery of a number of new effector T‐cell subsets, like Th17 and Th9 cells, and regulatory T cells, like Tregs and Tr1 cells, has changed the way we view and understand autoimmunity at cellular and molecular levels. In recent years, IL‐17‐producing Th17 cells have emerged as major players in autoimmunity. The complicated relationship between Th1 and Th17 cells, as well as the intricate balance between Tregs and Th17 cells, provides a basis for understanding the immunological mechanisms that induce and regulate autoimmunity. Here, we give an overview of the interplay between different effector T‐cell subsets and regulatory T‐cell subsets, and how they contribute to the development of autoimmunity and tissue inflammation.     

Search of a novel diagnostic marker for allergic diseases by the microarray approach

It is well known that Th2-type immune response is important for the pathogenesis of allergic diseases, such as bronchial asthma, allergic rhinitis, and atopic dermatitis. However, the pathogenesis of allergic diseases is heterogeneous, in that various cells and mediators are involved. If a relevant marker to discriminate the pathogenesis of allergic diseases in each individual could be found, such a marker would be beneficial to carry out personalized therapy for allergic diseases. We have recently found that squamous cell carcinoma antigens 1 and 2, which are now widely used as biomarkers to diagnose squamous cell carcinomas, are downstream molecules of interleukin-4 and interleukin-13, Th2-type cytokines, by the microarray approach. We furthermore found that these molecules are relevant biomarkers for bronchial asthma and atopic dermatitis. It is hoped that the measurement of squamous cell carcinoma antigens will be useful to diagnose allergic patients to apply agents targeting interleukin-4 or interleukin-13 in the future.     

Airway responses towards allergens – from the airway epithelium to T cells

The prevalence of allergic diseases such as allergic rhinitis is increasing, affecting up to 30% of the human population worldwide. Allergic sensitization arises from complex interactions between environmental exposures and genetic susceptibility, resulting in inflammatory T helper 2 (Th2) cell‐derived immune responses towards environmental allergens. Emerging evidence now suggests that an epithelial dysfunction, coupled with inherent properties of environmental allergens, can be responsible for the inflammatory responses towards allergens. Several epithelial‐derived cytokines, such as thymic stromal lymphopoietin (TSLP), IL‐25 and IL‐33, influence tissue‐resident dendritic cells (DCs) as well as Th2 effector cells. Exposure to environmental allergens does not elicit Th2 inflammatory responses or any clinical symptoms in nonatopic individuals, and recent findings suggest that a nondamaged, healthy epithelium lowers the DCs' ability to induce inflammatory T‐cell responses towards allergens. The purpose of this review was to summarize the current knowledge on which signals from the airway epithelium, from first contact with inhaled allergens all the way to the ensuing Th2‐cell responses, influence the pathology of allergic diseases.     

Cytokine pathways in allergic disease

Cytokines are critical in allergic intercellular communication networks, and they contribute to disease pathology through the recruitment and activation of pro-inflammatory leukocytes and in chronic disease to pro-fibrotic/remodeling events. Th2 cytokines predominate primarily in mild to moderate allergic asthma, although clinical trials with inhibitors of IL-4 and IL-5 have not provided the robust efficacy observed in animal models of allergy. These results not only highlight the complexity of allergic disease, but they also point to the importance of other cytokine networks in driving pathology. The heterogeneous nature of the disease is emphasized by the fact that the Th2/Th1/Th17 cytokine balance can be influenced by the initiating allergic trigger. For example, the house dust mite allergen Der p 2 mimics the activity of MD-2 by presenting lipopolysaccharide to Toll-like receptor-4 for the activation of inflammatory genes including innate-type cytokines. Here we discuss the functions of the novel cytokine players, thymic stromal lymphopoetin (TSLP), IL-33, IL-25, and IL-9 and delineate nonredundant roles for IL-4 and IL-13 in allergic disease. Persistent efforts in the characterization of these and other cytokine networks will be essential for understanding the complex pathogenic mechanisms that underpin allergic disease and for guiding targeted therapeutic interventions.     

Interleukin-12 family members and type I interferons in Th17-mediated inflammatory disorders

Cytokines produced by antigen-presenting cells govern the fate of helper T-cell responses. Herein, we review the impact of interleukin (IL)-23 and IL-27 on the outcome of T-helper (Th) 17 cell responses and discuss their impact in the pathogenesis of T-cell-mediated inflammatory disorders of autoimmune or allergic origin. We then discuss how type I interferons might influence the course of autoimmune diseases by tipping the balance between IL-12 family members.