Elsevier

International Immunopharmacology
国际免疫药理学

Volume 134, 15 June 2024, 111825
第134卷，2024年6月15日，111825
International Immunopharmacology

The role of Interleukin-21 (IL-21) in allergic disorders: Biological insights and regulatory mechanisms
白细胞介素-21（IL-21）在过敏性疾病中的作用：生物学见解和调控机制

SCI升级版 医学2区SCI基础版 医学2区IF 4.8
https://doi.org/10.1016/j.intimp.2024.111825 Get rights and content  获取权限和内容
Full text access  全文访问

Highlights  高光区域

  • •
    Allergic diseases are increasingly common chronic conditions worldwide.
    过敏性疾病在全球范围内越来越常见。
  • •
    Interleukin-21 (IL-21), a pleiotropic cytokine produced by different subsets of activated CD4+ T cells.
    白细胞介素-21（IL-21），一种由不同亚群活化的CD4+T细胞产生的多效性细胞因子。
  • •
    IL-21 has been shown to have both beneficial and detrimental regulatory effects on allergic responses, depending on the signaling state.
    IL-21已被证明对过敏反应具有有益和有害的调节作用，具体取决于信号状态。
  • •
    Both IL-21 and IL-21R have been identified as potential targets for novel cytokine-based immunotherapies in IgE-mediated diseases.
    IL-21和IL-21R都已被确定为IgE介导疾病中基于细胞因子的新型免疫疗法的潜在靶点。

Abstract  摘要

In recent decades, allergic diseases subsequent from an IgE-mediated response to specific allergens have become a progressively public chronic disease worldwide. They have shaped an important medical and socio-economic burden. A significant proportion of allergic disorders are branded via a form 2 immune response relating Th2 cells, type 2 natural lymphoid cells, mast cells and eosinophils. Interleukin-21 (IL-21) is a participant of the type-I cytokine family manufactured through numerous subsets of stimulated CD4+ T cells and uses controlling properties on a diversity of immune cells. Increasingly, experimental sign suggests a character for IL-21 in the pathogenesis of numerous allergic disorders. The purpose of this review is to discuss the biological properties of IL-21 and to summaries current developments in its role in the regulation of allergic disorders.
近几十年来，由IgE介导的对特定过敏原的反应引起的过敏性疾病已成为全球范围内逐渐公开的慢性疾病。它们造成了重要的医疗和社会经济负担。很大一部分过敏性疾病是通过与Th2细胞、2型天然淋巴细胞、肥大细胞和嗜酸性粒细胞相关的2型免疫反应标记的。白细胞介素-21（IL-21）是通过许多受刺激的CD4+T细胞亚群制造的I型细胞因子家族的参与者，并对多种免疫细胞具有控制特性。越来越多的实验迹象表明，IL-21在许多过敏性疾病的发病机制中具有特征。本文旨在讨论IL-21的生物学特性，并总结其在过敏性疾病调节中的作用的最新进展。

Keywords  关键词

IL-21
Cytokine
Allergic diseases
Asthma
Interleukin

IL-21细胞动力学过敏性疾病哮喘白细胞介素

1. Introduction  1.导言

Allergic disorders describe a group of conditions intermediated via innate and specific immune responses that work together to produce immunological hypersensitivity to non-self and else innocuous ecological molecules [1], [2]. The occurrence of allergic disconformity in developed countries is of concern, by a predicted 30–40 % of the world's people suffering from one or more allergic situations, which can manifest clinically as Allergic asthma, Allergic rhinitis (AR), Atopic dermatitis (AD), Food allergy, Urticaria and Anaphylaxis [3], [4], [5] (see Table 1).
过敏性疾病描述了一组通过先天和特异性免疫反应介导的疾病，这些免疫反应共同作用，对非自身和无害的生态分子产生免疫超敏反应[1]，[2]。据预测，世界上有30-40%的人患有一种或多种过敏情况，这可能在临床上表现为过敏性哮喘、过敏性鼻炎（AR）、特应性皮炎（AD）、食物过敏、荨麻疹和过敏反应[3]、[4]、[5]（见表1）。

Table 1. Animal and In vivo studies of IL-21 in Allergic diseases.
表1。IL-21在过敏性疾病中的动物和体内研究。

Model of study  学习模式Effect on immune responses
对免疫反应的影响		Ref  编号
Nasal administration of rmIL-21 in AHR
经鼻给予rmIL-21治疗急性肾衰竭
  • –
    Decreased the AHR  降低AHR
  • –
    Decreased inflammatory cell
    炎性细胞减少
  • –
    Decreased B cell that produces IgE
    产生IgE的B细胞减少
  • –
    Decreased IgE in serum  血清IgE水平降低
[143]
IL21r-deficient mice model of asthma and OVA-induced asthma using Il21r-deficient mice
IL21r缺陷小鼠哮喘和OVA诱导哮喘模型
  • –
    Higher serum total Ab  血清总抗体升高
  • –
    Higher HDM-specific IgE Ab
    更高的HDM特异性IgE抗体
[87], [144]
Intranasal use of mouse rIL‑21 in OVA‑induced mouse model of AR
小鼠rIL-21在OVA诱导的AR小鼠模型中的鼻内应用
  • –
    Decreased allergic signs  过敏症状减少
  • –
    Decreased specific IgE in serum
    血清特异性IgE降低
  • –
    Decreased Th2 cytokine in nasal tissues
    鼻组织中Th2细胞因子的减少
  • –
    Suppressed ESO migration into nasal tissues
    抑制ESO向鼻组织的迁移
  • –
    Reduced IL-4-induced eotaxin-1,2 in nasal fibroblasts
    IL-4诱导的鼻成纤维细胞嗜酸性粒细胞趋化因子-1，2减少
[89], [129]
IL-21 in a mouse with cutaneous immediate hypersensitivity reaction (IHR).
IL-21在患有皮肤即刻超敏反应（IHR）的小鼠中的作用。
  • –
    Decreased IHR by suppressing specific IgE production.
    通过抑制特异性IgE的产生来降低IHR。
  • –
    Meaningfully blocked mast cell activation in skin.
    有意义地阻断了皮肤中肥大细胞的激活。
[90]
IL-21 in a mouse model of asthma induced by house dust mites (HDMs)
屋尘螨哮喘小鼠模型中IL-21的表达
  • –
    Highly expression of IL-21
    IL-21的高表达
  • –
    Prominent of IL- 21+CD4+ T cells in the airways, lung tissue, and lymph nodes of lung
    IL-21+CD4+T细胞在气道、肺组织和肺淋巴结中的显著性
  • –
    Promotion Th2 cell function by IL-21R
    IL-21R促进Th2细胞功能
[48]
Roles of IL-21 and IL-21R in AD
IL-21和IL-21R在阿尔茨海默病中的作用
  • –
    Increased IL-21 and IL-21R appearance in lesions of skin
    皮肤病变中IL-21和IL-21R的出现增加
  • –
    Both IL-21r–/– mice and WT mice treated with soluble IL-21R–IgG2aFc mixture unsuccessful to skin inflammation
    用可溶性IL-21r-IgG2aFc混合物治疗的IL-21r-/-小鼠和WT小鼠均未出现皮肤炎症
  • –
    Improved CCR7 and travelled to CCR7 ligands
    改进CCR7并转移到CCR7配体
[117]
Gene expression profile in animal models of food allergy
食物过敏动物模型中的基因表达谱
  • –
    Highest expressed of activation-induced cytidine deaminase (Aicda). IL-21 and IL-17A significant role in expression of Aicda
    活化诱导的胞苷脱氨酶（Aicda）表达最高。IL-21和IL-17A在Aicda表达中的重要作用
[145]
OVA-induced allergic asthma mouse model
OVA诱导的过敏性哮喘小鼠模型
  • –
    Reduced IL-21 in the BALF
    BALF中IL-21减少
  • –
    No important changes in airway ESO, histopathology of lung, IgE levels in sera
    气道ESO、肺组织病理学、血清IgE水平无重要变化
  • –
    Reduced ESO infiltration of nasal mucosa
    鼻黏膜ESO浸润减少
[133]
IL-21R deficiency in OVA-induced model and HDM -induced allergic mouse model
OVA诱导模型和HDM诱导的过敏小鼠模型中IL-21R缺乏
  • –
    Decrease cytokines of Th2
    减少Th2细胞因子
  • –
    Avoiding nasal fibroblasts from creating eotaxins
    避免鼻成纤维细胞产生嗜酸性粒细胞趋化因子
[87], [89], [144]
In vivo using of IL-21 in the peanut allergy model
IL-21在花生过敏模型中的体内应用
  • –
    Abolished anaphylactic reaction by the of rIL-21 or an IL-21 expression plasmid.
    通过rIL-21或IL-21表达质粒消除过敏反应。
  • –
    Blocked IgE production in splenic B cells - Reduce total and specific IgE in serum
    阻断脾脏B细胞中IgE的产生-降低血清中的总IgE和特异性IgE
[85]
Airway inflammation in IL-21R KO mice model
IL-21R基因敲除小鼠模型气道炎症
  • –
    Fewer stimulated airway hyper-responsiveness
    更少的气道高反应性刺激
  • –
    Increased levels of specific IgE in serum
    血清中特异性IgE水平升高
[87]
local airway challenge with HDM in wild type BALB/c and Il21r-deficient mice
HDM对野生型BALB/c和Il21r缺陷小鼠的局部气道攻击
  • –
    Reduction in AHR in Il21r-deficient mice - Banned of Th2 cytokines in protein levels
    Il21r缺陷小鼠AHR降低——蛋白质水平上Th2细胞因子被禁止
  • –
    Raised in IgE levels  IgE水平升高
  • –
    Reduction IgG1 and IgG2a levels
    降低IgG1和IgG2a水平
  • –
    Increased IL-21-positive cells in bronchial mucosa
    支气管黏膜IL-21阳性细胞增多
[146]
T helper type 2 (Th2) cells used for host protection are involve in the development of allergic inflammatory illnesses [6], [7]. These cells play a role in controlling B cell class switching to IgE by producing interleukin-4 (IL-4), IL-5 and IL-13. They recruit eosinophils, resulting in tissue eosinophilia, and promote mucus production, goblet cell metaplasia and airway hyperresponsiveness [8]. In the molecular stage, GATA-3 as a main transcription factor regulates the appearance of IL-4, IL-5 and IL-13 [9], [10], [11]. Surveys in experimental animals have also revealed that targeted depletion or overexpression of specific CD4+ T cell genes can significantly change the sequence of immune- and allergen-related disorders [12], [13].
用于宿主保护的T辅助2型（Th2）细胞参与过敏性炎症疾病的发展[6]，[7]。这些细胞通过产生白细胞介素-4（IL-4）、IL-5和IL-13在控制B细胞类向IgE的转换中发挥作用。它们招募嗜酸性粒细胞，导致组织嗜酸性粒血球增多，并促进粘液产生、杯状细胞化生和气道高反应性[8]。在分子阶段，GATA-3作为主要的转录因子调节IL-4、IL-5和IL-13的出现[9]、[10]、[11]。对实验动物的调查还表明，特定CD4+T细胞基因的靶向耗竭或过表达可以显著改变免疫和过敏原相关疾病的序列[12]，[13]。
In addition, Tfh cells are a diverse population that can be categorized into three subsets: Tfh1, Tfh2 and Tfh17 [14], [15]. Each subset has unique transcription factors, surface chemokine receptor expression, cytokine secretion and B-cell support capabilities [14]. Tfh1 cells express T-bet and IFN-γ, Tfh2 cells express Gata3, IL-4, IL-5 and IL-13, and Tfh17 cells express Rorγt and IL-17A [16]. the Tfh2 subset supports human naive B cells in differentiating into plasma cells and promotes class switching to IgE or IgG4 [15], [17]. Innate lymphoid cells (ILCs) are primarily found in mucosal tissues, When activated, ILCs secrete numerous cytokines that recruit other immune and inflammatory cells, activate adaptive immune cells, and mediate physiological and pathological responses [18].
此外，Tfh细胞是一个多样化的群体，可以分为三个子集：Tfh1、Tfh2和Tfh17[14]、[15]。每个子集都有独特的转录因子、表面趋化因子受体表达、细胞因子分泌和B细胞支持能力[14]。Tfh1细胞表达T-bet和IFN-γ，Tfh2细胞表达Gata3、IL-4、IL-5和IL-13，Tfh17细胞表达RorγT和IL-17A[16]。Tfh2亚群支持人类幼稚B细胞分化为浆细胞并促进向IgE或IgG4[15]、[17]的类转换。固有淋巴细胞（ILCs）主要存在于粘膜组织中。当ILCs被激活时，它会分泌许多细胞因子，招募其他免疫和炎症细胞，激活适应性免疫细胞，并介导生理和病理反应[18]。
In particular, ILC2s and Th2 cells share the same cytokine and transcription factor expression profile [19]. ILC2s and Th2 cells secrete type 2 cytokines when stimulated by epithelial factors such as IL-33 [20] and thymic stromal lymphopoietin (TSLP) [20], [21]. ILC2s are activated by epithelial-derived cytokines, such as IL-33, IL-25 and TSLP, and constitutively express IL-5, whereas IL-13 production is induced during type 2 inflammation [22], [23]. Although ILC2s mainly express IL-5 and IL-13, some can express low levels of IL-4 under certain circumstances [24]. Type 2 cytokines secreted by ILC2s or Th2 cells (or both) lead to the recruitment and activation of granulocytes such as eosinophils, mast cells and basophils [24], [25]. Thus, by releasing type 2 effector cytokines, both ILC2s and Th2 cells can cause type 2 immune pathology. Previous studies using animal models suggest that ILC2s are involved in the development of allergic airway diseases, AD, and food allergy [22], [26], [27].
特别是，ILC2s和Th2细胞具有相同的细胞因子和转录因子表达谱[19]。ILC2s和Th2细胞在受到上皮因子如IL-33[20]和胸腺基质淋巴细胞生成素（TSLP）[20]刺激时分泌2型细胞因子，[21]。ILC2s被上皮衍生的细胞因子激活，如IL-33、IL-25和TSLP，并组成型表达IL-5，而IL-13的产生是在2型炎症期间诱导的[22]、[23]。尽管ILC2s主要表达IL-5和IL-13，但在某些情况下，一些ILC2s可以表达低水平的IL-4[24]。ILC2s或Th2细胞（或两者）分泌的2型细胞因子导致粒细胞如嗜酸性粒细胞、肥大细胞和嗜碱性粒细胞的募集和激活[24]，[25]。因此，通过释放2型效应细胞因子，ILC2s和Th2细胞都可以引起2型免疫病理。之前使用动物模型的研究表明，ILC2s参与了过敏性气道疾病、AD和食物过敏的发展[22]，[26]，[27]。
Once patients with allergic disease are tested with an allergen to which they are stimulated, a two-stage immune response often occurs. This leads to allergen motivation; B cells discriminate into Ig-making cells and produce specific IgE. Following contact to the allergen stimulate mast cell activation by cross-linking high affinity IgE receptors coupling to the allergen with IgE [28], [29]. Stimulated mast cells release a number of factors including pro-inflammatory vasoactive amines, arachidonic acid derivatives, cytokines and chemokines [29], [30]. A significant increase in the incidence of allergy has been attributed to numerous factors, including both genetic and environmental factors [31], [32], [33]. Corticosteroids and antihistamines are commonly used to treat allergic diseases, but these drug classes have limitations when used in combination. New strategies to treat allergic diseases are essential [34], [35]. Although therapeutics that inhibit IgE production are not yet clinically available, neutralizing pre-existing IgE has been shown to be beneficial in patients with intense allergic asthma [36]. Blocking IL-4 is a potential strategy to lessen major allergic disorders including rhinitis, asthma and eczema. research has revealed that both altrakincept and pascolizumab decrease the employment of eosinophils to the location of allergic inflammation via blocking patients' serum IL-4, but with little clinical benefit [37], [38]. Lebrikizumab is a humanized antibody that prevents the functionality of IL-13 [39], [40]. Surveys in animal models of immune-mediated disorders have clearly demonstrated that the activity of definite T-cell genes can significantly modify illness progression. In a similar way, Sign shows that the infectious nature of T cells in immune diseases is closely linked to the ability of these cells to produce enormous amounts of inflammatory cytokines [41]. Research has shown that IL-21 plays a significant character in the producing and diversifying of B cells, which in turn contribute to allergic responses [42], [43], [44]. IL-21 is considered the signature cytokine of Tfh cells due to its role in promoting B cell proliferation and differentiation into plasma cells [45], [46].
一旦过敏性疾病患者接受了刺激他们的过敏原测试，通常会发生两阶段的免疫反应。这会导致过敏原动机；B细胞分化为Ig制造细胞并产生特异性IgE。与过敏原接触后，通过用IgE交联与过敏原偶联的高亲和力IgE受体来刺激肥大细胞活化[28]，[29]。受刺激的肥大细胞释放多种因子，包括促炎血管活性胺、花生四烯酸衍生物、细胞因子和趋化因子[29]，[30]。过敏发生率的显著增加归因于许多因素，包括遗传和环境因素[31]，[32]，[33]。皮质类固醇和抗组胺药通常用于治疗过敏性疾病，但这些药物组合使用时存在局限性。治疗过敏性疾病的新策略至关重要[34]，[35]。尽管抑制IgE产生的治疗方法尚未在临床上使用，但中和预先存在的IgE已被证明对严重过敏性哮喘患者有益[36]。阻断IL-4是减轻包括鼻炎、哮喘和湿疹在内的主要过敏性疾病的潜在策略。研究表明，altrakincept和pascolizumab都通过阻断患者的血清IL-4来减少嗜酸性粒细胞在过敏性炎症部位的使用，但临床效益很小[37]，[38]。Lebrikizumab是一种人源化抗体，可阻止IL-13的功能[39]，[40]。免疫介导疾病动物模型的调查清楚地表明，特定T细胞基因的活性可以显著改变疾病进展。 Sign以类似的方式表明，T细胞在免疫疾病中的感染性与这些细胞产生大量炎性细胞因子的能力密切相关[41]。研究表明，IL-21在B细胞的产生和多样化中起着重要作用，这反过来又导致了过敏反应[42]，[43]，[44]。IL-21被认为是Tfh细胞的标志性细胞因子，因为它在促进B细胞增殖和分化为浆细胞方面起着重要作用[45]，[46]。
This review covers current research on IL-21 in both animal models and humans with allergic diseases. It also discusses therapeutic approaches involving modulation of IL-21 in allergic inflammation (see Table 2).
本文综述了IL-21在动物模型和过敏性疾病患者中的最新研究。它还讨论了涉及调节IL-21在过敏性炎症中的治疗方法（见表2）。

Table 2. Human studies of IL-21 in Allergic diseases.
表2。IL-21在过敏性疾病中的人体研究。

Model of study  学习模式Effect on immune responses
对免疫反应的影响		Ref  编号
Nucleotide polymorphisms (SNP; C1455T, G1472T, C5250T and C8381T), In asthmatics patients
哮喘患者的核苷酸多态性（SNP；C1455T、G1472T、C5250T和C8381T）
  • –
    Association between atopic asthma and Exon-3 polymorphism C5250T
    特应性哮喘与外显子-3基因C5250T多态性的相关性
  • –
    Association between level of serum IL-21 and C5250T polymorphism
    血清IL-21水平与C5250T多态性的相关性
[129]
Expression levels of IL-6, IL-18, IL-21, IL-23, and TGF-β in nasal biopsies in AR patients
AR患者鼻活检中IL-6、IL-18、IL-21、IL-23和TGF-β的表达水平
  • –
    Not important alteration in the appearance of the IL-21 gene between AR+ and AR- groups.
    AR+组和AR-组之间IL-21基因的外观没有重要变化。
  • –
    Amplified appearance of IL-6, IL-18, and IL-23 in AR
    AR中IL-6、IL-18和IL-23的出现增强
  • –
    Reduced gene appearance of the TGF-β in the control group
    对照组TGF-β基因出现减少
[147]
Signaling lymphocytic activation molecules (SLAMs) in the regulation of Tfh cells in Allergic rhinitis
信号淋巴细胞活化分子（SLAM）在变应性鼻炎Tfh细胞调节中的作用
  • –
    Unchanged incidences of CD4+CXCR5+ Tfh-like cells in AR
    AR中CD4+CXCR5+Tfh样细胞的发生率不变
  • –
    Reduced expression of SLAMs and SLAM-related protein (SAP) on circulating Tfh-like cells
    循环Tfh样细胞上SLAM和SLAM相关蛋白（SAP）的表达降低
  • –
    Improved serum IL-21 level in AR
    AR患者血清IL-21水平的改善
  • –
    Negative association among the IL-21 and SLAM or SAP appearance on CD4+CXCR5+ T cells.
    IL-21与CD4+CXCR5+T细胞上SLAM或SAP的出现呈负相关。
[148]
Role of IL-21/IL-21 receptor (IL-21R) in patients with allergic rhinitis.
IL-21/IL-21受体（IL-21R）在变应性鼻炎患者中的作用。
  • –
    Not association in levels of IL-21 among AR and control.
    AR和对照组的IL-21水平没有关联。
  • –
    Increased of IL-21R on naive and memory B cells in AR
    AR患者幼稚和记忆B细胞IL-21R水平升高
  • –
    IL-21R upregulated through stimulation by the combination of CD40 ligand (CD40L) and IL-4.
    IL-21R通过CD40配体（CD40L）和IL-4的联合刺激上调。
  • –
    IL-21 banned IgE production of B cells that stimulated via the grouping of CD40L and IL-4 in AR.
    IL-21抑制了通过AR中CD40L和IL-4的分组刺激的B细胞的IgE产生。
[149]
Single nucleotide polymorphism (T-83C) in the IL-21R
IL-21R的单核苷酸多态性（T-83C）
  • –
    Raised serum levels of IgE
    血清IgE水平升高
  • –
    Negative controlling in IgE making
    IgE生成中的阴性对照
  • –
    Associated IFN- γ -Mediated inhibition of IgE with polymorphism (T–83C) of IL-21R
    IFN-γ介导的IgE抑制与IL-21R多态性（T-83C）的相关性
[150], [151]

2. Structure and functions of Interleukin-21
2.白细胞介素-21的结构和功能

IL-21 is a class I cytokine generated by various lymphoid populations such as activated CD4+ T cells, Th17 cells, Th2 cells, follicular helper T (Tfh) cells and activated NKT cells [41], [47], [48]. This cytokine forms a four-helix bundle structure similar to IL-15, IL-2 and IL-4 [49].
IL-21是一种I类细胞因子，由各种淋巴群体产生，如活化的CD4+T细胞、Th17细胞、Th2细胞、卵泡辅助T（Tfh）细胞和活化的NKT细胞[41]、[47]、[48]。这种细胞因子形成类似于IL-15、IL-2和IL-4[49]的四螺旋束结构。
The IL-21 gene is located in the human chromosomal region 4q26-q27 and is separated from the IL-2 gene by 180 kb. The gene spans 8432 base pairs and encodes a precursor polypeptide of 162 amino acids, which is further processed to produce a 15 kDa protein of 133 amino acids [50]. The biological functions of IL-21 are facilitated via a heterodimeric receptor shaped through the shared γ-chain subunit shared with other cytokine receptors(IL-2, IL-4, IL-7, IL-9 and IL-15) and a unique receptor (termed IL-21R), a member of the type I cytokine receptor family [51], [52], [53].
IL-21基因位于人类染色体4q26-q27区域，与IL-2基因相距180 kb。该基因跨越8432个碱基对，编码162个氨基酸的前体多肽，进一步加工产生133个氨基酸的15kDa蛋白质[50]。IL-21的生物学功能是通过一种异二聚体受体和一种独特的受体（称为IL-21R）促进的，该受体是通过与其他细胞因子受体（IL-2、IL-4、IL-7、IL-9和IL-15）共享的共享γ链亚基形成的，该独特的受体是I型细胞因子受体家族的成员[51]、[52]、[53]。
IL-21R is highly expressed in lymphoid tissues such as the thymus, spleen and lymph nodes, and on various immune and non-immune cell types such as keratinocytes, fibroblasts and endothelial cells [12], [54], [55]. With a wide range of functions, B cells exhibit a prominent role in the expression of IL-21R [56]. The circulation of IL-21R across multiple immune cells designates the involvement of IL-21 signaling in both the innate and adaptive immune systems [41], [57], [58], [59]. Similar to other cytokines that signal via the common γ-chain subunit, IL-21R/γc-driven signaling result to the autophosphorylation of JAK1 and JAK3.
IL-21R在胸腺、脾脏和淋巴结等淋巴组织中高度表达，在角质形成细胞、成纤维细胞和内皮细胞等各种免疫和非免疫细胞类型上高度表达[12]、[54]、[55]。B细胞具有广泛的功能，在IL-21R的表达中起着重要作用[56]。IL-21R在多个免疫细胞中的循环表明IL-21信号传导参与了先天免疫系统和适应性免疫系统[41]，[57]，[58]，[59]。与通过常见γ链亚基发出信号的其他细胞因子类似，IL-21R/γc驱动的信号传导导致JAK1和JAK3的自磷酸化。
During this process, JAK1 binds to IL-21R while JAK3 binds to the common γ-chain, leading to the phosphorylation of signal transducer and activator of transcription (STAT) 3, STAT1, STAT5a and STAT5b [60], [61], [62]. Of the STAT proteins, STAT3 seems to be the most significant for IL-21 signaling, and deficiency of STAT3 appearance results in incomplete IL-21 signaling in T cells [61]. Indeed, the PI3K/Akt and MAPK pathways, together with the JAK/STAT pathway, contribute significantly to the overall IL-21-mediated proliferative response [51], [61], [63]. IL-21 enhances the stimulation, proliferation and diversity of CD4+ and CD8+ T cells while controlling their cytokine production, increases the cytotoxic activity of CD8+ T cells and NK cells, reduces the variability of stimulable regulatory T cells and plays a role in the diversification of Tfh and TH17 cells [54], [64], [65], [66]. In addition, IL-21 negatively affects the maturation and function of DCs [67]. This cytokine stimulates the differentiation of B cells into memory cells and ultimately into discriminated plasma cells, while also regulating the rearrangement of antibody class switching, either alone or in mix with other T cell-derived cytokines [68]. In vitro research has shown that IL-21 can have both constructive and negative outcomes on B lineage cells, depending on whether other signals are present or not [69], [70](Fig. 1).
在此过程中，JAK1与IL-21R结合，而JAK3与共同的γ链结合，导致信号转导子和转录激活子（STAT）3、STAT1、STAT5a和STAT5b的磷酸化[60]、[61]、[62]。在STAT蛋白中，STAT3似乎对IL-21信号传导最为重要，STAT3出现不足会导致T细胞中IL-21信号转导不完整[61]。事实上，PI3K/Akt和MAPK通路，以及JAK/STAT通路，对IL-21介导的整体增殖反应有显著贡献[51]，[61]，[63]。IL-21增强CD4+和CD8+T细胞的刺激、增殖和多样性，同时控制其细胞因子的产生，增加CD8+T细胞和NK细胞的细胞毒性活性，降低可刺激调节T细胞的变异性，并在Tfh和TH17细胞的多样化中发挥作用[54]，[64]，[65]，[66]。此外，IL-21对DCs的成熟和功能有负面影响[67]。这种细胞因子刺激B细胞分化为记忆细胞，并最终分化为分化的浆细胞，同时单独或与其他T细胞衍生的细胞因子混合调节抗体类转换的重排[68]。体外研究表明，IL-21对B系细胞既有建设性结果，也有负面结果，这取决于是否存在其他信号[69]，[70]（图1）。
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Fig. 1. Sources and its cellular targets of IL-21. Interleukin‑21 (IL‑21) is produced by CD4+ T cell populations, with the highest production by T follicular helper (Tfh) cells and Th17 cells, Natural killer T (NKT) cells and also CD8+ T cells. IL‑21 exerts actions on multiple lymphoid and myeloid populations as well as on epithelial cells. Treg, regulatory; DC, dendritic cell; MQ, macrophage; Th17, T helper 17 [41], [47], [48], [52], [59].
图1。IL-21的来源及其细胞靶点。白细胞介素-21（IL-21）由CD4+T细胞群产生，其中T滤泡辅助细胞（Tfh）和Th17细胞、自然杀伤T细胞（NKT）以及CD8+T细胞的产量最高。IL-21对多种淋巴样和髓样细胞群以及上皮细胞具有作用。Treg，监管；DC，树突状细胞；MQ，巨噬细胞；Th17，T辅助细胞17[41]，[47]，[48]，[52]，[59]。

IL-21 is important in modulating the production of several antibodies via B cells [71]. Numerous studies have shown that IL-21 strongly inhibits the transition to IgE, whereas IL-4 strongly promotes IgE production [72], [73]. In addition, research has shown that IL-21 inhibits IgE manufacture from IL-4 encouraged B cells by suppressing germline C transcription [71] and indirectly inhibits IL-4 stimulated IgE production via inducing IFN-γ secretion from T and NK cells [74]. IL-21 indorse B cell differentiation by acting in synergy with BAFF and improving CD40-induced activation of deaminase and Blimp1 [75], [76]. Conversely, Avery et al. surprisingly reported that IL-21 induces IgE production in naive human B cells induced with CD40L [77]. The amplified levels of serum IgE in mice deficient in IL-21 or IL-21R may be due to the capacity of IL-21 to prevent class switching to IgE in their B cells [71], [78]. In addition, IL-21 has been found to stimulate the production of IgG1 and IgG3 in naive IgG surface B lymphocytes through Ab class switching [79].
IL-21在通过B细胞调节几种抗体的产生方面很重要[71]。许多研究表明，IL-21强烈抑制向IgE的转变，而IL-4强烈促进IgE的产生[72]，[73]。此外，研究表明，IL-21通过抑制种系C转录抑制IL-4刺激的B细胞产生IgE[71]，并通过诱导T细胞和NK细胞分泌IFN-γ间接抑制IL-4诱导的IgE产生[74]。IL-21通过与BAFF协同作用并改善CD40诱导的脱氨酶和Blimp1的激活来支持B细胞分化[75]，[76]。相反，Avery等人令人惊讶地报道，IL-21诱导CD40L诱导的幼稚人类B细胞产生IgE[77]。IL-21或IL-21R缺乏的小鼠血清IgE水平升高可能是由于IL-21能够防止其B细胞向IgE的类转换[71]，[78]。此外，已发现IL-21通过抗体类转换刺激幼稚IgG表面B淋巴细胞中IgG1和IgG3的产生[79]。

3. IL-21 in different allergic diseases
3.不同过敏性疾病中的IL-21

B cells play a role in the immunoreactivity of allergic diseases by making significant amounts of IgE antibodies [80]. IL-21 is recognized as a multi-functional cytokine with variable effects on immune responses depending on the experimental setting. In the lack of a specific antigen or in the existence of a non-specific polyclonal indicator, IL-21 encourage apoptosis of naive B cells. However, under the influence of a B cell receptor signal and/or co-stimulatory interactions with T cells, IL-21 induces proliferation, isotype switching and differentiation into memory B cells or fully differentiated plasma cells [81], [82]. However, it has been described that IL-21 is not critical for B cell improvement, as evidenced by the lack of defects in B cell subgroups inside the bone marrow or periphery in IL-21R KO mice [78]. Several research groups have presented accumulating evidence that IL-21 has a negative impact on IgE manufacture [42], [68], [83]. IL-21 may lead to downregulation of IgE by causing IgE-expressing B cells to activate a pro-apoptotic factor that modifies Bcl-2, inducing repressor of differentiation-2 in B cells, or decreasing germline Cε copies, resulting in decreased IgE-specific switching [84], [85]. In addition, studies in mice show that IL-21 inhibits IL-4-driven IgE manufacture via B cells in vivo and in vitro [86]. IL-21 has been shown to have both beneficial and detrimental regulatory impacts on allergic responses. In a mouse model of allergic airway inflammation, administration of IL-21 during sensitization decreased eosinophil recruitment to inflamed sites by preventing allergen-specific IgE making [71], whereas the penetration of allergen-stimulated ESO into the inflamed airways was found to be lower in mice lacking IL-21 receptors [87](Fig. 2).
B细胞通过产生大量IgE抗体在过敏性疾病的免疫反应中发挥作用[80]。IL-21被认为是一种多功能细胞因子，其对免疫反应的影响因实验环境而异。在缺乏特定抗原或存在非特异性多克隆指示剂的情况下，IL-21会促进幼稚B细胞的凋亡。然而，在B细胞受体信号和/或与T细胞的共刺激相互作用的影响下，IL-21诱导增殖、同种型转换和分化为记忆B细胞或完全分化的浆细胞[81]，[82]。然而，已有研究表明，IL-21对B细胞改善并不重要，IL-21R KO小鼠骨髓或外周的B细胞亚群中没有缺陷就证明了这一点[78]。几个研究小组已经提出了越来越多的证据，表明IL-21对IgE的产生有负面影响[42]，[68]，[83]。IL-21可能通过使表达IgE的B细胞激活一种修饰Bcl-2的促凋亡因子，诱导B细胞分化抑制剂-2，或减少种系Cε拷贝，导致IgE特异性转换减少，从而导致IgE下调[84]，[85]。此外，对小鼠的研究表明，IL-21在体内和体外抑制了IL-4通过B细胞驱动的IgE的产生[86]。IL-21已被证明对过敏反应既有有益的调节作用，也有有害的调节作用。在过敏性气道炎症的小鼠模型中，致敏期间给予IL-21通过阻止过敏原特异性IgE的产生来减少嗜酸性粒细胞向炎症部位的募集[71]，而在缺乏IL-21受体的小鼠中，发现过敏原刺激的ESO对炎症气道的渗透较低[87]（图2）。
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Fig. 2. Mechanisms of allergic diseases. Fig. 2: Mechanisms of allergic sensitization. When allergen uptake by DCs. Then, DCs migrate to draining lymph nodes where they present allergen- derived peptides on MHC class II molecules to naive T cells. With the presence of several co– stimulatory and cytokine signals, those T cells are differentiated to Th2 cells. Type 2 cytokines involving allergic inflammation including IL- 4, IL- 5, IL- 13, are predominantly secreted by Th2 cells. Whereas, IL- 21, IL- 4, and IL- 13 are secreted by TFH cells and initiate the B- cell class– switching to IgE, plasma cell differentiation and allergen- specific IgE production. The secreted allergen- specific IgE antibodies from plasma cells bind to FcεRI molecules on mast cells and basophils. Subsequent exposure to allergen induces mast cell and basophil degranulation. IL-21 induces selective apoptosis of IgE-committed B cells, leading to reduced production of IgE in the presence of IL-21. DC, dendritic cell; FcεRI, Fc epsilon receptor I; Ig, immunoglobulin; IL, interleukin; MHC, major histocompatibility complex; Th, T helper cell; Tfh, T follicular helper cell [42], [84], [85], [86], [91].
图2。过敏性疾病的机制。图2：过敏致敏机制。当DC摄取过敏原时。然后，DC迁移到引流淋巴结，在那里它们将MHC II类分子上的过敏原衍生肽呈递给幼稚T细胞。在几种共刺激和细胞因子信号的存在下，这些T细胞分化为Th2细胞。涉及过敏性炎症的2型细胞因子，包括IL-4、IL-5、IL-13，主要由Th2细胞分泌。然而，IL-21、IL-4和IL-13由TFH细胞分泌，并启动B细胞类转化为IgE、浆细胞分化和过敏原特异性IgE的产生。浆细胞分泌的过敏原特异性IgE抗体与肥大细胞和嗜碱性粒细胞上的FcεRI分子结合。随后接触过敏原会诱导肥大细胞和嗜碱性粒细胞脱颗粒。IL-21诱导IgE导向的B细胞选择性凋亡，导致在IL-21存在的情况下IgE的产生减少。DC，树突状细胞；FcεRI、Fcε受体I；Ig，免疫球蛋白；IL、白细胞介素；MHC，主要组织相容性复合体；Th、T辅助细胞；Tfh，T卵泡辅助细胞[42]，[84]，[85]，[86]，[91]。

Serum IL-21 levels rise throughout acute asthma exacerbations and decrease with subsequent recovery [88]. Further research suggests that the use of IL-21 decreases allergic responses by overwhelming the making of allergen-specific IgE or chemokines in mouse models of anaphylaxis, allergic rhinitis and immediate hypersensitivity [85], [89], [90]. In a mouse model of allergic disease, suppression of IL-21 production inhibited the manufacture of antigen-specific IgE and prevented the recruitment of eosinophils into the airways of sensitized mice, as demonstrated in previous studies [12]. Recent research has shown that patients with vigorous atopic dermatitis have lower serum levels of IL-21 than healthy controls, suggesting a possible role for IL-21 in allergic reactions [91]. In addition, a separate study shows that IL-21 enhances the production of the immune-protective IgG4 antibody against allergy, while suppressing that of IgE [86]. Both IL-21 and IL-21R have been identified as potential targets for innovative cytokine-based immunotherapies in IgE-mediated diseases [92], [93]. Such therapies are expected to become a viable treatment option for patients affected by these diseases.
血清IL-21水平在急性哮喘发作期间升高，随后随着恢复而降低[88]。进一步的研究表明，在过敏反应、过敏性鼻炎和速发型超敏反应的小鼠模型中，使用IL-21可以通过抑制过敏原特异性IgE或趋化因子的产生来减少过敏反应[85]、[89]、[90]。在过敏性疾病的小鼠模型中，抑制IL-21的产生抑制了抗原特异性IgE的产生，并阻止了嗜酸性粒细胞募集到致敏小鼠的气道中，如先前的研究所示[12]。最近的研究表明，剧烈特应性皮炎患者的血清IL-21水平低于健康对照组，这表明IL-21可能在过敏反应中发挥作用[91]。此外，另一项研究表明，IL-21可增强抗过敏免疫保护性IgG4抗体的产生，同时抑制IgE的产生[86]。IL-21和IL-21R均已被确定为IgE介导疾病中基于细胞因子的创新免疫疗法的潜在靶点[92]，[93]。这种疗法有望成为受这些疾病影响的患者的可行治疗选择。

3.1. Allergic rhinitis (AR)
3.1. 变应性鼻炎（AR）

Allergic rhinitis is a common upper respiratory disorder. AR is considered by nasal itching, sneezing, nasal discharge and nasal congestion [94]. It is widely believed that AR is caused by IgE-mediated inflammation of the nasal mucosa, leading to infiltration by eosinophils and Th2 cells [95]. A major contributor to the development of AR is the disparity among Th1 and Th2 immune replies. Numerous cytokines produced by Th2 cells - including IL-3, IL-4, IL-5 and IL-13 - play a critical role in the induction and maintenance of IgE synthesis by plasma cells. The relationship between AR and ILC2s has been observed both in allergen challenge models and in natural exposure to airborne allergens [96]. Furthermore, individuals with AR who are sensitive to a perennial allergen, HDM, have higher blood ILC2 frequencies than non-allergic controls [97], [98]. The number of circulating ILC2s in patients with AR also correlated with markers of disease severity, such as symptom scores [98]. current research and advances in the understanding of the mechanism of AR have propose that Th17 cells and Tfh cells, along with related cytokines, contribute to the pathological process of AR [99]. Tfh cells are involved in the genesis and maintenance of the germinal center (GC), where B cell affinity maturation, isotype switching, plasma cell differentiation and memory B cell differentiation mainly occur [100]. IL-21 is the most potent cytokine secreted by Tfh cells [101]. The ability of IL-21 to decrease IgE production indicates that IL-21 could potentially alleviate the severity of allergies. In an experiment using ovalbumin-induced allergic rhinitis in mice, nasal administration of IL-21 during the initial antigen challenge was shown to significantly reduce allergy symptoms, which was associated with a reduction in antigen-specific serum IgE and Th2 cytokines in nasal tissue, as well as a reduction in IL-4-induced levels of eotaxin-1 and eotaxin-2 in nasal fibroblasts. This was also found to block eosinophil infiltration into nasal tissue [89]. The ability of IL-21 to regulate IgE production makes it a critical participant in the guideline of responses associated with IgE-related allergic rhinitis. When administered, IL-21 lessen murine allergic rhinitis via preventing the local appearance of IL-4, IL-5 and IL-13, inhibiting IgE making by B cells and eotaxin creation by fibroblasts [85], [89]. Huang et al. and colleagues found no significant changes in serum IL-21 levels between people with allergic rhinitis and healthy subjects. Moreover, there was no association found between IL-21 and serum-specific IgE levels [102]. Furthermore, another study found that Tfh2 cells from AR produced higher levels of IL-4 and had an increased ability to stimulate IgE production compared to those from the control group [103]. No differences in Tfh1, Tfh17 or CXCR5 conventional Th2 cells were observed between patients with AR and healthy subjects [103]. The frequency of Der p 1-specific IL-4+ Tfh2 cells, positively correlated with the level of Der p-specific IgE. However, both cell types were increased in patients with AR who were allergic to HDM, suggesting that Tfh2 cells orchestrate IgE production in an antigen-specific manner in AR [103].
变应性鼻炎是一种常见的上呼吸道疾病。AR被认为是由鼻腔瘙痒、打喷嚏、流鼻涕和鼻塞引起的[94]。人们普遍认为，AR是由IgE介导的鼻黏膜炎症引起的，导致嗜酸性粒细胞和Th2细胞浸润[95]。AR发展的一个主要原因是Th1和Th2免疫反应之间的差异。Th2细胞产生的多种细胞因子，包括IL-3、IL-4、IL-5和IL-13，在浆细胞诱导和维持IgE合成中起着关键作用。AR和ILC2s之间的关系在过敏原挑战模型和自然暴露于空气中的过敏原中都得到了观察[96]。此外，对常年性过敏原HDM敏感的AR患者的血液ILC2频率高于非过敏对照[97]，[98]。AR患者中循环ILC2的数量也与疾病严重程度的标志物相关，如症状评分[98]。目前对AR机制的研究和理解进展表明，Th17细胞和Tfh细胞以及相关细胞因子参与了AR的病理过程[99]。Tfh细胞参与生发中心（GC）的发生和维持，其中B细胞亲和力成熟、同种型转换、浆细胞分化和记忆B细胞分化主要发生[100]。IL-21是Tfh细胞分泌的最强细胞因子[101]。IL-21减少IgE产生的能力表明，IL-21可能会减轻过敏的严重程度。 在一项使用卵清蛋白诱导的小鼠变应性鼻炎的实验中，在初始抗原攻击期间经鼻给予IL-21可显著减轻过敏症状，这与鼻组织中抗原特异性血清IgE和Th2细胞因子的减少以及IL-4诱导的鼻成纤维细胞中eotaxin-1和eotaxin-2水平的降低有关。这也被发现可以阻断嗜酸性粒细胞浸润到鼻组织中[89]。IL-21调节IgE产生的能力使其成为IgE相关变应性鼻炎反应指南的关键参与者。当施用时，IL-21通过防止IL-4、IL-5和IL-13的局部出现，抑制B细胞产生IgE和成纤维细胞产生嗜酸性粒细胞趋化因子来减轻小鼠变应性鼻炎[85]，[89]。Huang等人及其同事发现，变应性鼻炎患者和健康受试者之间的血清IL-21水平没有显著变化。此外，在IL-21和血清特异性IgE水平之间没有发现关联[102]。此外，另一项研究发现，与对照组相比，AR的Tfh2细胞产生了更高水平的IL-4，并具有更强的刺激IgE产生的能力[103]。在AR患者和健康受试者之间没有观察到Tfh1、Tfh17或CXCR5常规Th2细胞的差异[103]。Der p 1特异性IL-4+Tfh2细胞的频率与Der p特异性IgE的水平呈正相关。然而，在对HDM过敏的AR患者中，这两种细胞类型都有所增加，这表明Tfh2细胞在AR中以抗原特异性的方式协调IgE的产生[103]。

3.2. Atopic dermatitis (AD)
3.2. 特应性皮炎

Atopic dermatitis is a form of eczema that affects the whole body. It is an itchy, allergic and inflammatory skin condition caused by a variety of factors [104], [105]. The global prevalence of AD is thought to be between 15 and 30 % in children and 2–10 % in adults [106]. Epidermal and dermal thickening, dermal CD4+ T cell and eosinophil infiltration and Th2 cytokine expression are seen in acute AD skin scratches [107].
特应性皮炎是一种影响全身的湿疹。这是一种由多种因素引起的瘙痒、过敏和炎症性皮肤病[104]，[105]。AD的全球患病率被认为在儿童中为15%-30%，在成人中为2-10%[106]。急性AD皮肤划痕可见表皮和真皮增厚、真皮CD4+T细胞和嗜酸性粒细胞浸润以及Th2细胞因子表达[107]。
Genetic sequencing has identified several mutations in genes responsible for epidermal mechanical proteins, such as filaggrin, and cytokines involved in IgE production, including IL-4, IL-5, IL-12 and IL-13 [105], [108], [109]. Epicutaneous sensitization to allergens acting a significant character in the pathogenesis of AD. This is evidenced via raised serum total IgE levels and specific IgE antibodies to environmental and/or food allergens, with approximately 80 % of patients with AD showing sensitization to allergens [110]. Dry, itchy skin is a symbol of atopic dermatitis (AD), possibly due to skin gene defects that performance a vital role in maintaining skin barrier function and turgidity [111]. The intense pruritus caused by scratching mechanically injures the skin, which in turn increases the skin's susceptibility to allergens, leading to the discharge of cytokines and chemokines, culminating in a Th2-mediated allergic response [112]. Several mouse models suggest that skin ILC2s play a pathological role in promoting the development of AD-like lesions, even in the absence of adaptive immunity, suggesting a potential role for ILC2s in the development of AD. In humans, lesional skin biopsies from patients with AD disease have shown an increase in ILC2s [113], [114]. In atopic dermatitis, thymic stromal lymphopoietin (TSLP) production is elevated in injured skin. This leads to Th2-type allergic inflammation [115], [116]. TSLP has also been found to boost IL-21 creation in mast cells [117]. Another study recognized IL-21 as a key regulator responsible for the induction of sensitization and allergic skin inflammation [117]. The research employed a mouse model of allergic skin inflammation and demonstrated an important increase in gene expression levels of IL-21 and IL-21R in mouse skin following tape stripping, which serves as a surrogate for scratching [117]. However, the research by Lin et al. showed that serum levels of IL-21 were significantly lower in AD patients than in healthy controls. In addition, their research showed an inverse association between serum IL-21 levels and AD severity, with the severity of skin signs also inversely correlated with serum IL-21 titer [91]. Alterations in IL-21 expression among skin lesions and serum may be due to irregular circulation, disorder period or treatment schedule [91].
基因测序已经确定了负责表皮机械蛋白（如聚丝蛋白）和参与IgE产生的细胞因子（包括IL-4、IL-5、IL-12和IL-13[105]、[108]、[109]）的基因中的几个突变。对过敏原的皮肤致敏在阿尔茨海默病的发病机制中起着重要作用。这可以通过血清总IgE水平和对环境和/或食物过敏原的特异性IgE抗体的升高来证明，大约80%的阿尔茨海默病患者对过敏原表现出致敏性[110]。干燥、发痒的皮肤是特应性皮炎（AD）的标志，可能是由于皮肤基因缺陷在维持皮肤屏障功能和肿胀方面起着至关重要的作用[111]。抓挠引起的强烈瘙痒会机械性损伤皮肤，进而增加皮肤对过敏原的敏感性，导致细胞因子和趋化因子的释放，最终导致Th2介导的过敏反应[112]。几种小鼠模型表明，即使在缺乏适应性免疫的情况下，皮肤ILC2在促进AD样病变的发展中也起着病理作用，这表明ILC2在AD的发展中可能起作用。在人类中，AD患者的病变皮肤活检显示ILC2增加[113]，[114]。在特应性皮炎中，受损皮肤中胸腺基质淋巴细胞生成素（TSLP）的产生升高。这会导致Th2型过敏性炎症[115]，[116]。TSLP也被发现可以促进肥大细胞中IL-21的产生[117]。另一项研究发现，IL-21是导致致敏和过敏性皮肤炎症的关键调节因子[117]。 该研究采用了一种过敏性皮肤炎症的小鼠模型，并证明了胶带剥离后小鼠皮肤中IL-21和IL-21R的基因表达水平显著增加，这可以作为抓挠的替代品[117]。然而，Lin等人的研究表明，AD患者的血清IL-21水平明显低于健康对照组。此外，他们的研究表明，血清IL-21水平与AD严重程度呈负相关，皮肤症状的严重程度也与血清IL-21滴度呈负相关[91]。皮肤病变和血清中IL-21表达的改变可能是由于循环不规则、疾病期或治疗计划[91]。
Currently, numerous indications have proposed that tissue levels of IL-21 and the IL-21 receptor are raised in AD patients [117], [118]. In addition, inhibition of IL-21 levels could effectively prevent tissue injury in mouse models of allergic rhinitis and AD, implicating IL-21 in the pathogenesis of these illnesses [89]. An study of the function of IL-21 in a mouse model of allergic skin responses displayed that systemic administration of IL-21 throughout the sensitization stage inhibited the allergic response by reducing the making of allergen-specific IgE [90]. In children with AD, expansion of CXCR5+ICOS+PD-1+ Tfh cells with enhanced IL-21 production was found, and the frequency of CXCR5+ICOS+PD-1+ Tfh cells was found to correlate with disease severity [119].
目前，许多迹象表明，AD患者的IL-21和IL-21受体的组织水平升高[117]，[118]。此外，抑制IL-21水平可以有效预防变应性鼻炎和AD小鼠模型的组织损伤，表明IL-21参与了这些疾病的发病机制[89]。一项关于IL-21在过敏性皮肤反应小鼠模型中的功能的研究表明，在整个致敏阶段全身施用IL-21通过减少过敏原特异性IgE的产生来抑制过敏反应[90]。在患有AD的儿童中，发现CXCR5+ICOS+PD-1+Tfh细胞扩增，IL-21产生增强，并且发现CXCR6+ICOS+PD-1+Tfh细胞的频率与疾病严重程度相关[119]。
Additionally, the usage of IL-21 following the sensitization phase does not decrease the manufacture of IgE, but instead prevents mast cell degranulation. These results provide insight into a possible mechanism linking IL-21 signaling to the development of allergic dermatitis, which contributes to the inflammation of the skin caused by allergy. This cytokine may be a suitable therapeutic target for adults with severe symptoms of AD.
此外，在致敏阶段后使用IL-21不会减少IgE的产生，而是可以防止肥大细胞脱颗粒。这些结果为将IL-21信号传导与过敏性皮炎的发展联系起来的可能机制提供了见解，过敏性皮炎导致过敏引起的皮肤炎症。这种细胞因子可能是患有严重AD症状的成年人的合适治疗靶点。

3.3. Allergic asthma  3.3. 过敏性哮喘

Asthma is a common respiratory disorder branded via airway inflammation, bronchoconstriction and airway hyperresponsiveness [120]. It is an increasingly pressing global health issue linked to the strengthening of vigorous Th2 cell- related immunity [121]. It is predicted that around 334 million people around the world suffer from asthma [122]. In atopic asthma, airway inflammation is typically induced by specific allergens, including house dust mite allergens, or non-specific inducers, for example air pollution [123]. Although the exact etiology of asthma is unclear, it is extensively believed that Th2 cells performance a key role in both the development and maintenance of the disease. The Th2 cytokines are particularly important in the development of airway inflammation and increased IgE-related sensitization, airway hyperreactivity (AHR) and eosinophil penetration [122], [124]. There is compelling indication that Th2 cells are the main cell type responsible for initiating the development of asthma in both mice and humans. But, developing indication proposes that Tfh cells, more than Th2 cells, mainly generate IL-4 and IL-21 in B cell follicles and tightly control IgE isotype switching throughout the development of vigorous asthma in both mice and humans [125], [126]. The mechanisms of ILC2 activation in human asthma are not fully understood, but animal models of allergen-induced airway inflammation suggest that ILC2-derived IL-5 and IL-13, induced by epithelial cytokines, play an important role in airway eosinophilia, mucus production and airway remodeling [127], [128]. The research shows a relevant association between the exon 3 polymorphism C5250T of the IL-21 gene and atopic asthma, as well as serum total IgE levels. In addition, the C5250T polymorphism affects serum IL-21 levels in atopic asthmatics [129]. Notably, IL-21R-deficient mice showed an unpredictably decreased airway hyperresponsiveness despite elevated serum IgE levels [87], However, recent evidence from animal models suggests that IL-21 may have the ability to reduce the harshness of allergies [89], [129]. A possible explanation for this inconsistency is that IL-21 may have different functions relating on the immunological context and its interaction with different cytokines. Additional investigation is required to completely recognize the role of IL-21 in the pathogenesis of atopic asthma. In the OVA-induced asthma model, administering exogenic IL-21 result to a decline in IgE making as well as a reduction in eosinophil recruitment to the airway [71]. A study by Lin et al has provided in vivo evidence that intranasal use of IL-21-expressing adenovirus can suppress allergic reactions [130]. However, mice lacking IL-21R showed reduced eosinophilic airway inflammation after exposure to antigen in contrast to their wild-type counterparts.[87]. In this model, the use of IL-21 not only decreases the presence of Th2 cells, but also overwhelms the discharge of Th2-associated cytokines [130]. In addition, elevated protein levels of IL-21 and IL-21R are observed in the lung tissue of rats with asthma [131]. IL-21 is also raised in the serum and bronchoalveolar lavage fluid (BALF) of asthmatic mice [132], [133]. Furthermore, research suggest that individuals with asthma have elevated plasma levels of IL-21 in contrast to healthy individuals [134], and there is an raised prevalence of IL-21-expressing CD4+ T cells in asthmatic patients, which is strongly associated with raised levels of total IgE in the bloodstream [134]. In a mouse model of allergic asthma induced by HDM, IL-21-producing Tfh-like cells were found to enhance the function of Th2 cells [48]. Another research show that sensitization to HDM resulted in the development of IL-4-committed Tfh cells in draining lymph nodes. After HDM challenge, these cells further differentiated into HDM-specific Th2 cells and migrated to the lungs of mice [135]. Supplementation with IL-21 may be useful in rebalancing elevated IgE levels in asthma due to its profound effects in controlling IgE production [78]. The findings suggest that IL-21 may have different functions in asthma. It may promote the germinal center response while inhibiting Ab isotype switching towards IgE. This difference in IL-21 properties in asthma may be related to the timing and site of IL-21 uptake [85], [89].
哮喘是一种常见的呼吸道疾病，表现为气道炎症、支气管收缩和气道高反应性[120]。这是一个日益紧迫的全球健康问题，与加强Th2细胞相关的免疫有关[121]。据预测，全球约有3.34亿人患有哮喘[122]。在特应性哮喘中，气道炎症通常是由特定的过敏原引起的，包括屋尘螨过敏原，或非特异性诱因，如空气污染[123]。尽管哮喘的确切病因尚不清楚，但人们普遍认为Th2细胞在疾病的发展和维持中起着关键作用。Th2细胞因子在气道炎症的发展和IgE相关致敏、气道高反应性（AHR）和嗜酸性粒细胞渗透的增加中尤为重要[122]，[124]。有令人信服的迹象表明，Th2细胞是引发小鼠和人类哮喘发展的主要细胞类型。但是，发展中的迹象表明，Tfh细胞比Th2细胞更多，主要在B细胞卵泡中产生IL-4和IL-21，并在小鼠和人类剧烈哮喘的整个发展过程中严格控制IgE同种型转换[125]，[126]。人类哮喘中ILC2激活的机制尚不完全清楚，但过敏原诱导的气道炎症动物模型表明，由上皮细胞因子诱导的ILC2衍生的IL-5和IL-13在气道嗜酸性粒细胞增多、粘液产生和气道重塑中起着重要作用[127]，[128]。该研究表明，IL-21基因的外显子3多态性C5250T与特应性哮喘以及血清总IgE水平之间存在相关关联。 此外，C5250T多态性影响特应性哮喘患者的血清IL-21水平[129]。值得注意的是，尽管血清IgE水平升高，但IL-21R缺陷小鼠表现出不可预测的气道高反应性降低[87]。然而，最近动物模型的证据表明，IL-21可能有能力减轻过敏的严重程度[89]，[129]。这种不一致的一种可能解释是，IL-21可能在免疫背景及其与不同细胞因子的相互作用方面具有不同的功能。需要进一步的研究来完全认识IL-21在特应性哮喘发病机制中的作用。在OVA诱导的哮喘模型中，施用外源性IL-21会导致IgE生成减少以及嗜酸性粒细胞向气道募集减少[71]。Lin等人的一项研究提供了体内证据，表明鼻内使用表达IL-21的腺病毒可以抑制过敏反应[130]。然而，与野生型小鼠相比，缺乏IL-21R的小鼠在接触抗原后嗜酸性气道炎症减少。[87]. 在该模型中，使用IL-21不仅可以减少Th2细胞的存在，还可以抑制Th2相关细胞因子的释放[130]。此外，在哮喘大鼠的肺组织中观察到IL-21和IL-21R的蛋白水平升高[131]。IL-21在哮喘小鼠的血清和支气管肺泡灌洗液（BALF）中也升高[132]，[133]。此外，研究表明，与健康个体相比，哮喘患者的血浆IL-21水平升高[134]，哮喘患者中表达IL-21的CD4+T细胞的患病率升高，这与血液中总IgE水平升高密切相关[134]。 在HDM诱导的过敏性哮喘小鼠模型中，发现产生IL-21的Tfh样细胞可增强Th2细胞的功能[48]。另一项研究表明，对HDM的致敏导致引流淋巴结中IL-4分泌的Tfh细胞的发育。HDM攻击后，这些细胞进一步分化为HDM特异性Th2细胞，并迁移到小鼠肺部[135]。补充IL-21可能有助于重新平衡哮喘中升高的IgE水平，因为它在控制IgE产生方面具有深远的影响[78]。研究结果表明，IL-21在哮喘中可能具有不同的功能。它可能促进生发中心反应，同时抑制抗体同种型向IgE的转换。哮喘中IL-21特性的这种差异可能与IL-21摄取的时间和部位有关[85]，[89]。

3.4. Food allergy  3.4. 食物过敏

Food allergy is a toxicological effect on the specific food as a result of an immune response. The prevalence of food allergy in Western countries is predicted to be between 1 and 3 % in adults and 3–8 % in infants, with possible growth [136], [137]. Affected to food allergy frequently exists with cutaneous and gastrointestinal symptoms, as the allergic response induced by food-specific IgE can occur quickly after exposure to allergens, and in a very small number of patients, fatal anaphylactic shock can occur [138], [139]. At present, the assessment of food allergens remains challenging and the process of food allergy is not fully understood, so patients with food allergy can only keep themselves by severely avoiding all potentially allergenic foods [140]. In a mouse model sensitized by intraperitoneal injection of OVA, ILC2s isolated from the lamina propria produced type 2 cytokines. It was observed that IL-13-deficient ILC2s lost their ability to promote IgE antibody production [141]. The role of IL-21 in allergy in humans and mice remains controversial. To improve the treatment of food allergy, the generation of antigen-specific IgE antibodies is critical. In a mouse model of food allergy, systemic using of IL-21 banned antigen-induced anaphylaxis [71].
食物过敏是免疫反应对特定食物的毒理学影响。据预测，西方国家的食物过敏患病率在成人中为1%至3%，在婴儿中为3%至8%，并可能增长[136]，[137]。受食物过敏影响的患者通常会出现皮肤和胃肠道症状，因为食物特异性IgE在接触过敏原后会迅速引起过敏反应，在极少数患者中，可能会发生致命的过敏性休克[138]，[139]。目前，对食物过敏原的评估仍然具有挑战性，食物过敏的过程尚未完全了解，因此食物过敏患者只能通过严格避免所有可能引起过敏的食物来保持自己[140]。在通过腹腔注射OVA致敏的小鼠模型中，从固有层分离的ILC2s产生2型细胞因子。观察到IL-13缺陷型ILC2s失去了促进IgE抗体产生的能力[141]。IL-21在人类和小鼠过敏中的作用仍然存在争议。为了改善食物过敏的治疗，产生抗原特异性IgE抗体至关重要。在食物过敏的小鼠模型中，全身使用IL-21可以抑制抗原诱导的过敏反应[71]。
This embarrassment was caused by the initiation of Id2, resulting in a decrease in IgE class switch recombination and antigen-specific IgE production. The link between IL-21 and the inhibition of CSR and anaphylaxis was established by the finding that IL-21 failed to prevent anaphylaxis in Id2-deficient mice [71]. When Ad-IL-21 was administered in Th2-driven OVA-induced airway inflammation, IL-21 reduced Th2 cytokines in BALF[130]. IL-21 affects both IgE creation in B cells and the discharge of Th2-related cytokines by T cells. This leads to the suppression of allergic responses. In a mouse model of peanut allergy, inhalation of peanut flour led to expansion of Tfh cells in the draining lymph nodes, which promoted peanut-specific IgE production more efficiently than Th2 cells [142]. Genetic depletion of Tfh cells protected mice from anaphylaxis and impaired IgE production without affecting Th2 cells [142].
这种尴尬是由Id2的启动引起的，导致IgE类转换重组和抗原特异性IgE的产生减少。IL-21与抑制CSR和过敏反应之间的联系是通过发现IL-21未能预防Id2缺陷小鼠的过敏反应而建立的[71]。当在Th2驱动的OVA诱导的气道炎症中施用Ad-IL-21时，IL-21减少了BALF中的Th2细胞因子[130]。IL-21影响B细胞中IgE的产生和T细胞释放Th2相关细胞因子。这导致了过敏反应的抑制。在花生过敏的小鼠模型中，吸入花生粉导致引流淋巴结中Tfh细胞的扩增，这比Th2细胞更有效地促进了花生特异性IgE的产生[142]。Tfh细胞的基因耗竭保护小鼠免受过敏反应和IgE产生受损，而不影响Th2细胞[142]。

4. Conclusion  4.结论

Allergic diseases are a major health and economic challenge in today's societies. These diseases are result of interaction of genetic and environmental factors. Th2 cells and the cytokines they produce, in particular IL-4, 5 and 13, play a main role in the pathogenesis of these diseases. Following the identification of interleukin-21 and its receptor, a slew of research has examined the impact and target cells of this distinct cytokine. Interleukin-21 is widely recognized as a key cytokine in many diseases. Its diverse functions and pathological effects in various tissues suggest that interfering with it signaling pathway may be a viable treatment for allergic diseases. Several studies have highlighted the need to explore the therapeutic potential of interleukin-21 inhibition in allergic diseases.
过敏性疾病是当今社会的一大健康和经济挑战。这些疾病是遗传和环境因素相互作用的结果。Th2细胞及其产生的细胞因子，特别是IL-4、5和13，在这些疾病的发病机制中起着主要作用。在鉴定出白细胞介素-21及其受体后，一系列研究检查了这种独特细胞因子的影响和靶细胞。白细胞介素-21被广泛认为是许多疾病中的关键细胞因子。其在各种组织中的不同功能和病理作用表明，干扰其信号通路可能是治疗过敏性疾病的可行方法。几项研究强调了探索白细胞介素-21抑制在过敏性疾病中的治疗潜力的必要性。

Funding  基金

The authors extend their appreciation to the Deputyship for Research& Innovation, Ministry of Education in Saudi Arabia for funding this research work through the project number ISP-2024.
作者对沙特阿拉伯教育部研究与创新部通过ISP-2024项目资助这项研究工作表示感谢。

CRediT authorship contribution statement
CRediT作者贡献声明

Mohamed J. Saadh: Writing – original draft, Methodology, Investigation. Mohammed A. Alfattah: Writing – original draft, Methodology, Investigation. Ahmed H. Ismail: Writing – original draft, Methodology, Investigation. Bashar Abdullah Saeed: Writing – original draft, Methodology, Investigation. Huda hayder abbas: Writing – original draft, Methodology, Investigation. Nabila F. Elashmawy: Writing – review & editing, Visualization. Ghassan A. hashim: Writing – review & editing, Visualization. Khatib Sayeed Ismail: Writing – original draft. Mabrouk A. Abo-Zaid: Writing – original draft, Supervision, Project administration. Hisham Ali Waggiallah: Writing – review & editing.
穆罕默德·J·萨德：写作——初稿，方法论，调查。穆罕默德A.阿尔法塔：写作——初稿，方法论，调查。Ahmed H.Ismail：写作——初稿，方法论，调查。巴沙尔·阿卜杜拉·赛义德：写作——初稿，方法论，调查。Huda hayder abbas：写作-初稿，方法论，调查。Nabila F.Elashmawy：写作-评论和编辑，可视化。Ghassan A.hashim：写作-评论和编辑，可视化。哈提卜·赛义德·伊斯梅尔：写作——初稿。Mabrouk A.Abo-Zaid：写作——初稿、监督、项目管理。Hisham Ali Waggiallah：写作-评论和编辑。

Declaration of competing interest
竞争利益声明

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
作者声明，他们没有已知的竞争性财务利益或个人关系，这些利益或关系可能会影响本文中报告的工作。

Acknowledgment  致谢

The authors extend their appreciation to the Deputyship for Research& Innovation, Ministry of Education in Saudi Arabia for funding this research work through the project number ISP-2024.
作者对沙特阿拉伯教育部研究与创新部通过ISP-2024项目资助这项研究工作表示感谢。

Data availability  数据可用性

No data was used for the research described in the article.
文章中描述的研究没有使用任何数据。

References  参考文献

Cited by (1)  引用人（1）

  • Follicular T cells and the control of IgE responses
    卵泡T细胞与IgE反应的控制

    2025, Allergology International
    2025年，国际变态反应学
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