Review of CD4+ T cell subsets in asthma phenotypes: molecular mechanisms and biologic treatment options
ZHAO Yanhong,, WANG Chuanping,
Department of Pulmonary and Cntical Care Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201999, China
哮喘是一种慢性炎症性气道疾病，主要由不同的CD4+ T细胞亚群［辅助性T细胞（helper T cell，Th细胞）］驱动。CD4+ T细胞亚群是一类重要的免疫细胞，能够分泌多种细胞因子，调节机体对各种抗原的免疫反应。根据分泌的细胞因子的不同，CD4+ T细胞可以分为Th1、Th2、Th17、滤泡性辅助性T细胞（follicular helper T cell，Tfh细胞）和调节性T细胞（regulatory T cell，Treg细胞）等亚群，它们在哮喘的发生发展中起着不同的作用。生物治疗是一种针对特定分子和途径的新治疗手段，为哮喘患者提供了更多的选择。生物制剂是一类利用生物技术制备的药物，能够特异性地识别和中和目标分子，从而干预相关的信号通路。该文回顾了各种CD4+ T细胞亚群在哮喘表型中的角色及分子机制，总结了嗜酸性粒细胞哮喘、中性粒细胞哮喘、混合性哮喘的免疫病理学特征和针对Th2、Th1、Th17、Tfh、Treg细胞相关因子的生物制剂的临床效果和安全性，以及相应生物制剂的选择和发展方向；并讨论了Treg细胞受损和树突状细胞（dendritic cell，DC）异常在哮喘发病机制中的作用，以及利用这些细胞的免疫治疗潜力。该文旨在为哮喘生物治疗的个性化选择和新药开发提供参考。
关键词：哮喘
;
CD4+辅助性T细胞
;
嗜酸粒细胞哮喘
;
中性粒细胞哮喘
;
生物治疗
Abstract
Asthma is a chronic inflammatory airway disease, mainly driven by different CD4+ T cell subsets [helper T cell (Th cell)]. CD4+ T cell subsets are a type of important immune cells, capable of secreting various cytokines, and regulating the immune response of the body to various antigens. According to the difference of secreted cytokines, CD4+ T cell subsets can be divided into subgroups such as Th1, Th2, Th17, follicular helper T cell (Tfh) and regulatory T cell (Treg), which play different roles in the occurrence and development of asthma. Biologic therapy is a new treatment method that targets specific molecules and pathways, and has provided more options for asthma patients. Biologics is a type of drugs prepared by biotechnology, which can specifically recognize and neutralize target molecules, thereby interfering with related signaling pathways. This article reviews the roles and molecular mechanisms of various CD4+ T cell subsets in asthma phenotypes, summarizes the immunopathological characteristics of eosinophilic asthma, neutrophilic asthma and mixed asthma, the clinical efficacy and safety of biologics targeting Th2, Th1, Th17, Tfh and Treg cell-related factors, and the selection and development direction of corresponding biologics. This article also discusses the role of impaired Treg cells and abnormal dendritic cells (DC cells) in the pathogenesis of asthma, as well as the potential of immunotherapy using these cells. This article aims to provide reference for the personalized selection and new drug development of biologic therapy for asthma.
ZHAO Yanhong, WANG Chuanping. Review of CD4+ T cell subsets in asthma phenotypes: molecular mechanisms and biologic treatment options. Journal of Shanghai Jiao Tong University (Medical Science)[J], 2023, 43(8): 1064-1070 doi:10.3969/j.issn.1674-8115.2023.08.016
DC上的MHC Ⅱ类分子呈递低剂量抗原有利于Th0细胞分化为Th2细胞，但还需要DC上共刺激分子如OX-40L才能实现最佳启动。Th2细胞的主要转录因子GATA-3（GATA binding protein 3）被激活将诱导白细胞介素-2（interleukin 2，IL-2）产生，IL-2表达反过来激活分化的Th2细胞中信号转导和转录激活因子5（signal transducer and activator of transcription 5，STAT5），STAT5与GATA-3结合诱导TCR依赖性IL-4转录，这种内源性产生的IL-4将继续激活STAT5并决定Th2细胞的命运［5］。
高剂量抗原激活DC产生增量IL-12和驱动Th1细胞分化。高剂量抗原诱导性强的TCR直接激活Th1细胞上的转录因子STAT1，而被激活的STAT1进一步诱导Th1细胞上的T盒转录因子（T-box expressed in T cell，T-bet）［也称为Tbx21（T-box 21）］表达［15］。T-bet诱导增加了IL-12R的表达，为进一步的Th1细胞分化提供了一个正反馈回路。IL-12通过IL-12R激活初始Th1细胞中的STAT4，STAT4转录激活Ⅰ型干扰素表达。
目前针对嗜酸性粒细胞哮喘的单克隆抗体（单抗）有5种被欧洲药品管理局（European Medicines Agency，EMA）和美国食品药品监督管理局（Food and Drug Administration，FDA）批准治疗Th2介导的哮喘。奥马珠单抗（Omalizumab）靶向游离IgE的C端结构域，阻止IgE与肥大细胞、嗜碱性粒细胞、嗜酸性粒细胞、朗格汉斯细胞和树突状细胞上IgE高亲和力受体FcεRI相互作用［34］；美泊利单抗（Mepolizumab）和瑞利珠单抗（Reslizumab）直接中和细胞因子IL-5，从而抑制嗜酸性粒细胞的活化和聚集，这是一种针对嗜酸性粒细胞哮喘的治疗方法［35］；贝那利珠单抗（Benralizumab）与IL-5受体（IL-5 receptor，IL-5R）的α-亚基（IL-5Rα）结合，IL-5Rα通过抗体依赖性细胞毒性破坏表达该受体的细胞，用于治疗严重嗜酸性粒细胞哮喘［36］；度普利尤单抗（Dupilumab）靶向IL-4Rα，因此同时抑制IL-4和IL-13信号转导，用于治疗嗜酸性粒细胞和/或呼出气一氧化氮（fractional exhaled nitric oxide，FeNO）升高的哮喘［37］。这些抗体中，除了瑞利珠单抗是通过静脉注射，其他均为皮下给药。奥马珠单抗适用于过敏性因素导致的中重度持续性哮喘，可以有效控制气促、喘息、胸闷，甚至呼吸困难、呼吸衰竭的发生；瑞利珠单抗让患有不受控制的严重哮喘患者获得明显的肺功能改善；贝那利珠单抗能降低哮喘恶化率、改善肺功能、改善哮喘症状、减少嗜酸粒细胞和减少糖皮质激素的用量；度普利尤单抗治疗中重度不受控制哮喘的疗效显著［38-39］。
WANG Chuanping put forward the theme and framework of the manuscript. ZHAO Yanhong collected relevant literature and wrote the first draft. Both authors participated in further refining and revising the paper. Both authors have read the last version of paper and consented for submission.
利益冲突声明
2位作者声明不存在利益冲突。
COMPETING INTERESTS
Both authors disclose no relevant conflict of interests.
WHITEHEAD G S, THOMAS S Y, NAKANO K, et al. A neutrophil/TGF-β axis limits the pathogenicity of allergen-specific CD4+ T cells[J]. JCI Insight, 2022, 7(4): e150251.
GODWIN M S, JONES M, BLACKBURN J P, et al. The chemokine CX3CL1/fractalkine regulates immunopathogenesis during fungal-associated allergic airway inflammation[J]. Am J Physiol Lung Cell Mol Physiol, 2021, 320(3): L393-L404.
ZUO Z T, MA Y, SUN Y, et al. The protective effects of Helicobacter pylori infection on allergic asthma[J]. Int Arch Allergy Immunol, 2021, 182(1): 53-64.
CANARIA D A, CLARE M G, YAN B, et al. IL-1β promotes IL-9-producing Th cell differentiation in IL-2-limiting conditions through the inhibition of BCL6[J]. Front Immunol, 2022, 13: 1032618.
YU F, LIN Q, ZHANG Z, et al. Therapeutic strategies for the costimulatory molecule OX40 in T-cell-mediated immunity[J]. Acta Pharm Sin B, 2020, 10(3): 414-433.
GEVAERT P, HAN J K, SMITH S G, et al. The roles of eosinophils and interleukin-5 in the pathophysiology of chronic rhinosinusitis with nasal polyps[J]. Int Forum Allergy Rhinol, 2022, 12(11): 1413-1423.
BUCHENAUER L, JUNGE K M, HAANGE S B, et al. Glyphosate differentially affects the allergic immune response across generations in mice[J]. Sci Total Environ, 2022, 850: 157973.
DROGHINI H R, ABONIA J P, COLLINS M H, et al. Targeted IL-4Rα blockade ameliorates refractory allergic eosinophilic inflammation in a patient with dysregulated TGF-β signaling due to ERBIN deficiency[J]. J Allergy Clin Immunol Pract, 2022, 10(7): 1903-1906.
MATSUDA M, TABUCHI Y, NISHIMURA K, et al. Increased expression of CysLT2 receptors in the lung of asthmatic mice and role in allergic responses[J]. Prostaglandins Leukot Essent Fatty Acids, 2018, 131: 24-31.
HIGAZI H M K I, HE L, FANG J, et al. Loss of Jak2 protects cardiac allografts from chronic rejection by attenuating Th1 response along with increased regulatory T cells[J]. Am J Transl Res, 2019, 11(2): 624-640.
WANG F P, YANG Y H, LI Z X, et al. Mannan-binding lectin regulates the Th17/Treg axis through JAK/STAT and TGF-β/SMAD signaling against Candida albicans infection[J]. J Inflamm Res, 2022, 15: 1797-1810.
XIONG D K, SHI X, HAN M M, et al. The regulatory mechanism and potential application of IL-23 in autoimmune diseases[J]. Front Pharmacol, 2022, 13: 982238.
DELLA B C, ANTICO A, PANOZZO M P, et al. Gastric Th17 cells specific for H+/K+-ATPase and serum IL-17 signature in gastric autoimmunity[J]. Front Immunol, 2022, 13: 952674.
ZHANG B B, ZENG M N, ZHANG Q Q, et al. Ephedrae Herba polysaccharides inhibit the inflammation of ovalbumin induced asthma by regulating Th1/Th2 and Th17/Treg cell immune imbalance[J]. Mol Immunol, 2022, 152: 14-26.
LI X L, LUCK M E, HERRNREITER C J, et al. IL-23 promotes neutrophil extracellular trap formation and bacterial clearance in a mouse model of alcohol and burn injury[J]. Immunohorizons, 2022, 6(1): 64-75.
WU M D, LAI T W, JING D, et al. Epithelium-derived IL17A promotes cigarette smoke-induced inflammation and mucus hyperproduction[J]. Am J Respir Cell Mol Biol, 2021, 65(6): 581-592.
ZHOU Q L, WANG T Y, LI M, et al. Alleviating airway inflammation by inhibiting ERK-NF-κB signaling pathway by blocking Kv1.3 channels[J]. Int Immunopharmacol, 2018, 63: 110-118.
STEWART E, WANG X M, CHUPP G L, et al. Profiling cellular heterogeneity in asthma with single cell multiparameter CyTOF[J]. J Leukoc Biol, 2020, 108(5): 1555-1564.
CHEN Q, NIAN S J, YE Y C, et al. The emerging roles of T helper cell subsets and cytokines in severe neutrophilic asthma[J]. Inflammation, 2022, 45(3): 1007-1022.
WU Z W, MEHRABI NASAB E, ARORA P, et al. Study effect of probiotics and prebiotics on treatment of OVA-LPS-induced of allergic asthma inflammation and pneumonia by regulating the TLR4/NF-kB signaling pathway[J]. J Transl Med, 2022, 20(1): 130.
HUANG K, REN H Y, LIN B Y, et al. Protective effects of Wuwei Xiaodu Drink against chronic osteomyelitis through Foxp3+CD25+CD4+ Treg cells via the IL-2/STAT5 signaling pathway[J]. Chin J Nat Med, 2022, 20(3): 185-193.
ONO M. Control of regulatory T-cell differentiation and function by T-cell receptor signalling and Foxp3 transcription factor complexes[J]. Immunology, 2020, 160(1): 24-37.
HINKS T S C, ZHOU X Y, STAPLES K J, et al. Innate and adaptive T cells in asthmatic patients: relationship to severity and disease mechanisms[J]. J Allergy Clin Immunol, 2015, 136(2): 323-333.
KORKMAZ E T, AYDıN O, MUNGAN D, et al. Can dose reduction be made in patients with allergic bronchopulmonary aspergillosis receiving high-dose omalizumab treatment?[J]. Eur Ann Allergy Clin Immunol, 2022. DOI: 10.23822/EurAnnACI.1764-1489.261.
KORN S, BOURDIN A, CHUPP G, et al. Integrated safety and efficacy among patients receiving benralizumab for up to 5 years[J]. J Allergy Clin Immunol Pract, 2021, 9(12): 4381-4392.e4.
CAMPISI R, CRIMI C, NOLASCO S, et al. Real-world experience with dupilumab in severe asthma: one-year data from an Italian named patient program[J]. J Asthma Allergy, 2021, 14: 575-583.
BUSSE W W, BLEECKER E R, et al. Long-term safety and efficacy of benralizumab in patients with severe, uncontrolled asthma: 1-year results from the BORA phase 3 extension trial[J]. Lancet Respir Med, 2019, 7(1): 46-59.
NAIR P, PIZZICHINI M M M, KJARSGAARD M, et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia[J]. N Engl J Med, 2009, 360(10): 985-993.
KIM T H, KISHIMOTO M, WEI J C, et al. Brodalumab, an anti-interleukin-17 receptor A monoclonal antibody, in axial spondyloarthritis: 68-week results from a phase 3 study[J]. Rheumatology (Oxford), 2023, 62(5): 1851-1859.
WOODS R H. Potential cerebrovascular accident signal for risankizumab: a disproportionality analysis of the FDA Adverse Event Reporting System (FAERS)[J]. Brit J Clinical Pharma, 2023, 89(8): 2386-2395.
EUSEBIO M, KUNA P, KRASZULA L, et al. The relative values of CD8+CD25+Foxp3brigh Treg cells correlate with selected lung function parameters in asthma[J]. Int J Immunopathol Pharmacol, 2015, 28(2): 218-226.
SCHREIBER T H, WOLF D, TSAI M S, et al. Therapeutic Treg expansion in mice by TNFRSF25 prevents allergic lung inflammation[J]. J Clin Invest, 2010, 120(10): 3629-3640.
YU S Q, JIN L, CHE N, et al. Dendritic cells modified with Der p1 antigen as a therapeutic potential for allergic rhinitis in a murine model via regulatory effects on IL-4, IL-10 and IL-13[J]. Int Immunopharmacol, 2019, 70: 216-224.
... 树突状细胞（dendritic cell，DC）是“专业的”抗原呈递细胞（antigen-presenting cell，APC）.肺部气道的DC捕获吸入的过敏原，将其转化为抗原肽.DC上主要组织相容性复合物（major histocompatibility complex class，MHC）Ⅱ类分子携带抗原肽呈递给有抗原特异性T细胞受体（T cell receptor，TCR）的幼稚CD4+辅助性T0细胞（helper T cell 0，Th0细胞），并与DC上的共刺激分子［例如CD80、CD86、OX-40L（OX-40 ligand）］和相关细胞因子一起刺激Th0细胞分化为效应Th细胞.效应Th细胞产生大量细胞因子，直接或间接驱动不同的哮喘亚型.目前已经发现至少5种不同的Th细胞亚群［Th1、Th2、Th9、Th17和滤泡性辅助性T细胞（follicular helper T cell，Tfh细胞）］，其与调节性T细胞（regulatory T cell，Treg细胞）受损在哮喘病理生理中发挥着至关重要的作用［4］. ...
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... DC上的MHC Ⅱ类分子呈递低剂量抗原有利于Th0细胞分化为Th2细胞，但还需要DC上共刺激分子如OX-40L才能实现最佳启动.Th2细胞的主要转录因子GATA-3（GATA binding protein 3）被激活将诱导白细胞介素-2（interleukin 2，IL-2）产生，IL-2表达反过来激活分化的Th2细胞中信号转导和转录激活因子5（signal transducer and activator of transcription 5，STAT5），STAT5与GATA-3结合诱导TCR依赖性IL-4转录，这种内源性产生的IL-4将继续激活STAT5并决定Th2细胞的命运［5］. ...
... 高剂量抗原激活DC产生增量IL-12和驱动Th1细胞分化.高剂量抗原诱导性强的TCR直接激活Th1细胞上的转录因子STAT1，而被激活的STAT1进一步诱导Th1细胞上的T盒转录因子（T-box expressed in T cell，T-bet）［也称为Tbx21（T-box 21）］表达［15］.T-bet诱导增加了IL-12R的表达，为进一步的Th1细胞分化提供了一个正反馈回路.IL-12通过IL-12R激活初始Th1细胞中的STAT4，STAT4转录激活Ⅰ型干扰素表达. ...
