Ⅱ型固有淋巴细胞与支气管哮喘的最新研究进展

Ⅱ型固有淋巴细胞(group 2 innate lymphoid cells,ILC2s)是最近才被发现的一类固有淋巴细胞群,并被认为是Th2型细胞因子的主要来源.目前,ILC2s在哮喘中的作用已引起广泛关注.当致敏原刺激气道上皮细胞后,上皮细胞来源的细胞因子IL-33、IL-25、TSLP激活ILC2s,诱导ILC2s产生大量的Th2型细胞因子以及某些生长因子如双调蛋白,这与哮喘的发生以及上皮细胞的修复密切相关.ILC2s不仅能与其他固有免疫细胞相互作用,还可以调控适应性免疫应答,在过敏性炎症反应中起着连接固有免疫与适应性免疫的桥梁作用.本文主要综述ILC2s的调控与功能以及ILC2s在哮喘发病中的最新研究进展.     

Th2／Th17细胞群与支气管哮喘机制研究

支气管哮喘（简称哮喘）是一种由多种细胞（如嗜酸粒细胞、肥大细胞、T淋巴细胞、中性粒细胞和气道上皮细胞等）和细胞组分参与的气道慢性炎症性疾病。经典的Th1／Th2细胞失衡被认为是过敏性哮喘的主要发病机制,Th17／IL-17轴被证实与重症哮喘、激素抵抗型哮喘、以中性粒细胞浸润为主的哮喘有关。近年来研究发现,机体内存在一种不同于目前已知的Thl、Th2、Thl7、Th9等的新型CD4＋T细胞,被称为Th2／Th17双表型记忆性CD4＋T细胞群（简称Th2／Th17细胞群）。在哮喘发病机制的探讨中发现,Th2／Th17细胞群既能分泌Th2表型细胞因子IL-4、IL-5、IL-13,也可以分泌Th17型细胞因子IL-17、IL-8、IL-22等;且在不同的微环境下发生不一样的生物学效应,这显示了Th2／Th17细胞群可能在哮喘发生发展（特别是重症哮喘）及各亚型相互转化过程中起着决定性作用。现就Th2／Th17细胞群的生物学功能及其与哮喘的相关性进行如下综述。     

过敏性哮喘免疫调节机制

过敏性哮喘是一种由变应原诱发的以气道高反应性、IgE升高、气道慢性炎症为特征的疾病。固有免疫和适应性免疫均在过敏性哮喘的免疫调节机制中发挥作用。支气管上皮细胞活化并释放的IL-25、IL-33和TSLP驱动Th2型免疫应答,最终导致Th2型炎症反应。近年来研究发现细胞外囊泡和微生物组学在过敏性哮喘发生发展中起到重要作用。随着新型生物治疗方法的发展,常规治疗无效的过敏性哮喘患者可以选择以IgE、IL-4/IL-13、IL-5等为靶点的生物制剂以改善哮喘症状。本文对过敏性哮喘发病过程中免疫调节机制相关研究进展进行综述。     

哮喘患者树突状细胞分泌细胞因子的变化及其对Th1/Th2细胞因子的影响

目的观察过敏性哮喘(哮喘)患者外周血单个核细胞(PBMC)来源树突状细胞(DC)分泌IL-12和IL-10的情况,及其对Th1/Th2型细胞因子平衡的影响.方法分别取9例哮喘患者和14例正常人外周血PBMC来源的DC经LPS刺激使其发育为成熟DC(mDC).另取脐血初始T淋巴细胞(Th0).Th0和两组mDC共培养,通过ELISA法检测mDC分泌的IL-12和IL-10及辅助性T淋巴细胞(Th)分泌的IFN-γ和IL-4的含量.结果①哮喘组DC产生IL-12及其亚单位IL-12p40和IL-10较对照组显著降低(P＜0.01、P＜0.05).②哮喘组Th释放Th1型细胞因子IFN-γ较对照组减少(P＜0.05);Th2型细胞因子IL-4较对照组显著增多(P＜0.01).③两组IL-12和IFN-γ均呈正相关(r＝0.7581、P＜0.01,r＝0.6028、P＜0.05),IL-12和IL-4均呈负相关(r＝-0.7498、P＜0.01,r＝-0.7481、P＜0.01).④哮喘组IL-10与IFN-γ呈正相关(r＝0.6437,P＜0.05).⑤两组IL-12和IL-10均呈正相关(P均＜0.01).结论哮喘患者DC分泌IL-12和IL-10减少,导致Th0向Th2优势分化,细胞因子平衡向Th2型倾斜,合成IL-4增多和IFN-γ减少,后者是哮喘发生的重要机制之一.     

过敏性支气管哮喘免疫发病机制的最新研究进展

过敏性支气管哮喘(简称哮喘)是一种由不同的辅助性T细胞亚型决定的慢性气道炎症性疾病.既往认为“Th2哮喘假说”是过敏性哮喘的主要发病机制,而越来越多的研究表明,除了Th2之外其他辅助性T细胞也参与了哮喘的发病机制,尤其是Th1和Th17细胞对于气道中性粒细胞型炎症的发展至关重要.抑制这些免疫细胞也许为过敏性哮喘的有效治疗提供了方向.     

Ⅱ型固有淋巴细胞及其在支气管哮喘中的作用

Ⅱ型固有淋巴细胞(ILC2s)是新近发现的一类固有免疫细胞群,在上皮细胞源性细胞因子白细胞介素(IL)-25、IL-33、胸腺基质淋巴细胞生成素(TSLP)及脂质递质等的刺激下可产生IL-5、IL-13等Th2型细胞因子,促进气道嗜酸粒细胞性炎症的发生。近年来,对于ILC2s介导的2型免疫应答在哮喘发病过程中作用方面所取得的研究取得了重大突破。本文就ILC2s及其在哮喘中的作用进行综述。     

辅助性T细胞17在不同类型哮喘中的状态及临床意义

目的探讨辅助性T细胞(Th)17在不同类型哮喘中的状态及临床意义。方法选取2012年1月—2015年1月延安大学附属医院收治的哮喘患者106例作为病例组,分为过敏性哮喘组50例和非过敏性哮喘组56例;另选取同期进行体检的健康成年人50例作为对照组。比较3组受试者单个核细胞中Th17、Th2及调节性T细胞(Treg)比例,血浆及诱导痰中白介素(IL)-17A、IL-10、IL-4、IL-5及IL-18水平,以及诱导痰中嗜酸粒细胞和中性粒细胞比例。结果 (1)过敏性哮喘组患者Th2比例高于非过敏性哮喘组和对照组(P0.05);非过敏性哮喘组患者Th17比例高于过敏性哮喘组,过敏性哮喘组高于对照组(P0.05)。(2)非过敏性哮喘组患者血浆IL-17A水平高于过敏性哮喘组,过敏性哮喘组高于对照组(P0.05);过敏性哮喘组患者血浆IL-4水平高于非过敏性哮喘组,非过敏性哮喘组高于对照组(P0.05)。(3)非过敏性哮喘组患者诱导痰中IL-17A、IL-18水平高于过敏性哮喘组,过敏性哮喘组高于对照组(P0.05);过敏性哮喘组患者诱导痰中IL-4水平高于非过敏性哮喘组,非过敏性哮喘组高于对照组(P0.05)。(4)过敏性哮喘组患者诱导痰中嗜酸粒细胞比例高于非过敏性哮喘组,非过敏性哮喘组高于对照组(P0.05);非过敏性哮喘组患者诱导痰中中性粒细胞比例高于过敏性哮喘组,过敏性哮喘组高于对照组(P0.05)。结论不同类型哮喘患者的Th17及其相关细胞因子水平存在差异,且非过敏性哮喘患者以上指标水平较高,Th17水平可能决定了哮喘类型。     

白介素-13和哮喘发病的研究进展

支气管哮喘（简称哮喘）是一种严重威胁人类健康的慢性呼吸道疾病。在世界范围内,过敏性哮喘的发病率和病死率逐年上升。研究表明,哮喘的发病是由于Th2型细胞过度释放细胞因子后诱导IgE产生,导致肥大细胞和嗜酸粒细胞脱颗粒,引起气道速发性过敏反应和以嗜酸粒细胞、肥大细胞、T细胞等多种炎症细胞参与的慢性气道炎症。白介素-13（IL-13）是一种由CD4^＋、Th2型细胞分泌的多效性细胞因子,介导变态反应的发生,与哮喘的发生有密切的关联。     

细胞因子与过敏性哮喘

支气管哮喘是一种慢性气道炎症性疾病。在气道炎症反应中，无论是Th2型细胞因子（IL-4、IL-5、IL-13等），还是Th1型细胞因子IFN-γ均起着重要作用。新近研究进一步表明调节性T细胞（Treg）产生的细胞因子也与过敏性哮喘的发病密切相关。     

IL-18作为疫苗佐剂的研究进展

白细胞介素-18(IL-18)是一种免疫调节因子,具有多种生物学功能,能够刺激T细胞及NK细胞产生IFN-γ、IL-12等多种细胞因子,为增强Th1型细胞介导细胞免疫的细胞因子.该文对近年来IL-18作为免疫佐剂增强疫苗免疫效果的研究进行简要综述.     

Airway innate lymphoid cells in the induction and regulation of allergy

The recent discovery of innate lymphoid cells has revolutionized our understanding of the pathogenesis of immune diseases including allergy and asthma. Innate lymphoid cells (ILCs) are a heterogeneous collection of lymphocytes that lack antigen-specificity (non-T, non-B cells) and potently produce characteristic cytokines of T cell subsets (Th1, Th2, Th17). ILCs are divided into group 1 (ILC1s), group 2 (ILC2s), or group 3 (ILC3s). Similar to Th2 cells, ILC2s produce IL-4, IL-5, and IL-13, among others, and are present in increased numbers in samples from patients with many allergic disorders including asthma and chronic rhinosinusitis (CRS). Animal models have identified that ILC2s contribute to eosinophilic tissue infiltration, airway hyperresponsiveness, mucus production, as well as coordinate adaptive immune responses. Finally, recent studies support regulation of ILC2s by neuro-immune mechanisms as well as demonstrate a significant degree of plasticity between ILC subsets that may impact the immune responses in asthma and allergic airway diseases. Here, we review the current literature on ILC2s in human asthma and allergic airway diseases, as well as highlight some recent mechanistic insights into ILC2 function from in vitro studies and in vivo animal models.     

Trained innate lymphoid cells in allergic diseases

Group 2 innate lymphoid cells (ILC2s) reside in peripheral tissues such as the lungs, skin, nasal cavity, and gut and provoke innate type 2 immunity against allergen exposure, parasitic worm infection, and respiratory virus infection by producing T_H2 cytokines. Recent advances in understanding ILC2 biology revealed that ILC2s can be trained by IL-33 or allergic inflammation, are long-lived, and mount memory-like type 2 immune responses to any other allergens afterwards. In contrast, IL-33, together with retinoic acid, induces IL-10-producing immunosuppressive ILC2s. In this review, we discuss how the allergic cytokine milieu and other immune cells direct the generation of trained ILC2s with immunostimulatory or immunosuppressive recall capability in allergic diseases and infections associated with type 2 immunity. The molecular mechanisms of trained immunity by ILCs and the physiological relevance of trained ILC2s are also discussed.     

Insights into Group 2 Innate Lymphoid Cells in Human Airway Disease

Recent discoveries have led to the identification of a novel group of immune cells, the innate lymphoid cells (ILCs). The members of this group are divided into three subpopulations: ILC1s, ILC2s, and ILC3s. ILC2s produce Th2 cytokines, IL-4, IL-5, and IL-13, upon activation by epithelial cell-derived cytokines, lipid mediators (cysteinyl leukotrienes and prostaglandin D₂), and TNF family member TL1A and promote structural and immune cell responses in the airways after antigen exposure. In addition, ILC2 function is also influenced by inducible T cell costimulator (ICOS)/ICOS-ligand (ICOS-L) interactions via direct contact between immune cells. The most common airway antigens are allergens and viruses which are highly linked to the induction of airway diseases with underlying type 2 inflammation including asthma and allergic rhinitis. Based on recent findings linking ILC2s and airway Th2 responses, there is intensive investigation into the role of ILC2s in human disease with the hope of a better understanding of the pathophysiology and the discovery of novel potential therapeutic targets. This review summarizes the recent advances made in elucidating ILC2 involvement in human Th2 airway disease.     

Group 2 innate lymphoid cells in human asthma

Asthma is characterized by increased airway hyperresponsiveness, reversible airflow limitation, and remodeling due to allergic airway inflammation. Asthma has been proposed to be classified into various phenotypes by cluster analyses integrating clinical information and laboratory data. Recently, asthma has been classified into two major endotypes, Type 2-high and Type 2-low asthma, and various subtypes based on the underlying molecular mechanisms. In Type 2-high asthma, Th2 cells, together with group 2 innate lymphoid cells (ILC2s), produce type 2 cytokines such as IL-4, IL-5, IL-9, and IL-13, which play crucial roles in causing airway inflammation. The roles of ILC2s in asthma pathogenesis have been analyzed primarily in murine models, demonstrating their importance not only in IL-33- or papain-induced innate asthma models but also in house dust mite (HDM)- or ovalbumin (OVA)-induced acquired asthma models evoked in an antigen-specific manner. Recently, evidence regarding the roles of ILC2s in human asthma is also accumulating. This minireview summarizes the roles of ILC2s in asthma, emphasizing human studies.     

The Regulation of the IL-18 on Group 2 Innate Lymphoid Cells in Allergic Rhinitis

Background: Group 2 innate lymphoid cells (ILC2s) promote allergic inflammation by producing interleukin-4 (IL-4), IL-5, IL-9, and IL-13. IL-18 can promote T helper 2 cell (Th2) response by inducing IL-4, and IL-13 production from mast cells and basophils. However, the regulation of IL-18 on ILC2s remained unknown. Objective: To investigate the regulatory role of IL-18 in inducing the type 2 innate lymphoid cells. Methods: Twenty patients with allergic rhinitis (AR) and 20 controls were enrolled. The mRNA and protein levels of IL-18 in serum, as well as the frequencies of ILC2 in peripheral blood mononuclear cells (PBMCs) were measured by real-time polymerase chain reaction (PCR), enzyme-linked immunosorbent assay (ELISA), and flow cytometry. The ILC2s were sorted and the mRNA expression of IL-18 receptor in ILC2 was analyzed by real-time PCR. The effects of IL-18 on the proliferation and type 2 cytokine production were detected by tritiated thymidine incorporation test, real-time PCR, and ELISA, respectively. Results: The levels of IL-18 mRNA and protein were significantly higher in AR patients than in the controls (P<0.05). The frequency of ILC2 in peripheral blood was elevated in the AR patients than in the controls. After stimulation by IL-18 and house dust mite (HDM), the expression of IL-18 receptor (IL-18R) by ILC2 was significantly up-regulated. The tritiated thymidine incorporation results showed that IL-18 promoted the proliferation of ILC2 in a dose-dependent manner. IL-18 also induced the expression of IL-5 and IL-13 proteins by ILC2. Conclusion: Our results confirmed -for the first time- the effect of IL-18 in innate immunity, which was demonstrated by direct effect on the differentiation and function of ILC2.     

Control of immunity and allergy by steroid hormones

Steroid hormones, especially glucocorticoids, androgens, and estrogens, have profound influence on immunity. Recent studies using cell-type specific steroid hormone receptor-deficient mice have revealed the precise roles of some of these hormones in the immune system. Glucocorticoids are known to have strong anti-inflammatory and immunosuppressive effects and pleiotropic effects on innate and adaptive immune responses. They suppress the production of inflammatory cytokines by macrophages and DCs and the production of IFN-γ by NK cells, thus inhibiting innate immunity. By contrast, glucocorticoids enhance the immune response by inducing the expression of IL-7R and CXCR4 in T cells and the accumulation of T cells in lymphoid organs in accordance with the diurnal change of the glucocorticoid concentration. Thus, glucocorticoids suppress innate immunity but enhance adaptive immunity. Androgens suppress the homeostasis and activation of ILC2s and the differentiation of Th2 and Th17 cells and enhance the suppressive function of Tregs, thereby alleviating allergic airway inflammation. Thus, these steroid hormones have pleiotropic functions in the immune system. Further investigations are awaited on the regulation of immunity and allergy by estrogens using cell-specific steroid hormone receptor-deficient mice.     

Type 2 Innate Lymphocytes in Allergic Airway Inflammation

CD4⁺ T helper-2 (Th2) cells, which produce a unique profile of IL-4, IL-5 and IL-13 pro-inflammatory cytokines, are thought to be central in the orchestration and amplification of allergic asthma. However, a novel non-T/non-B lymphoid cell population, named type 2 innate lymphocytes (ILC2s), that produces high amounts of IL-5 and IL-13 was recently discovered. Unlike Th2 cells, these ILC2s are not antigen-restricted and are activated by epithelial cell-derived cytokines IL-25 and IL-33. In this review, we will focus on recent studies, mainly involving allergen-based mouse models, that have provided evidence for a significant contribution of ILC2 to allergic airway information.     

Severe asthma ILC2s demonstrate enhanced proliferation that is modified by biologics

Background and Objective

Type 2 (T2) innate lymphoid cells (ILC2s) contribute to airway inflammation and disease in asthma. We hypothesize that ILC2s isolated from people with severe allergic and eosinophilic asthma would exhibit an enhanced T2 inflammatory activity that would be altered following treatment with mepolizumab and omalizumab. We compare peripheral blood (PB) isolated ILC2's proliferative capacity, IL-5 and IL-13 secretion and phenotype between healthy without asthma (HC), non-asthma allergic (NAA), mild asthma (MA) and severe allergic and eosinophilic asthma (SA) subjects. We then determined the impact of 6 months treatment with either mepolizumab or omalizumab on ILC2s physiology of SA subjects.

Methods

ILC2s were sorted and cultured in the presence of IL-2, IL-25, IL-33 and thymic stromal lymphopoietin (TSLP) for 14 days. ILC2s proliferation, phenotypes and functions were assessed using flowcytometry. The ILC2s response was then reassessed following clinically successful treatment of SA subjects with mepolizumab and omalizumab.

Results

SA ILC2s demonstrated increased proliferative capacity, TSLP receptor (TSLPR), GATA3 and NFATc1 protein expressions and increased IL-5 and IL-13 release. ILC2s were also capable of releasing IL-6 in response to stimulation. Mepolizumab treatment reduced ILC2s proliferative capacity and expression of TSLPR, GATA3 and NFATc1. Both mepolizumab and omalizumab were associated with reduced ILC2s release of IL-5 and IL-13, only mepolizumab reduced IL-6.

Conclusion

ILC2s from severe allergic and eosinophilic asthma demonstrated an active phenotype typified by increased proliferation, TSLPR, GATA3 and NFATc1 expression and increased IL-5, IL-13 and IL-6 release. Mepolizumab reduced markers of ILC2s activation.