首页资讯斑秃的免疫发病机制与靶向治疗进展

斑秃的免疫发病机制与靶向治疗进展

来源：泰然健康网时间：2024年12月07日 23:32

斑秃(alopecia areata,AA)是临床上常见的一种非瘢痕性脱发性疾病,常表现为圆形或者椭圆型的斑片状脱发,严重者出现全秃-头发全部脱落,甚至普秃-累及全身的毛发脱落。作为一种自身免疫性疾病[1],其发病机制涉及多种炎症反应[2-3],发病原因涉及遗传、精神压力、情绪应激、感染等多种因素,治疗面临诸多困难。传统治疗方式如糖皮质激素、免疫抑制剂等对中重度及顽固性斑秃的治疗欠佳,不同的斑秃患者因发病机制不同存在疗效差异,治疗效果很好的普秃患者也面临着斑秃脱发复发的风险[4]。患者常因损容病情、疗效不佳以及疾病复发等加重心理压力,甚至导致焦虑、抑郁[5]。近年来,生物制剂及小分子药物广泛应用于特应性皮炎、银屑病等许多自身免疫性炎症性皮肤病中,取得了较好的临床疗效,靶向治疗也正成为斑秃的重要治疗手段。本文综述斑秃的免疫发病机制,并结合目前靶向治疗在斑秃中的应用现状,探讨靶向治疗斑秃新思路。

1 斑秃的免疫发病机制

1.1 炎症信号通路及相关细胞因子在斑秃发病机制中的作用

包括Th1、Th2、Th17在内的多条炎症信号通路参与AA发病,其中细胞因子的紊乱在AA发病中有重要作用(

表1

),但是其与AA临床严重程度和病程之间的关系,仍有待进一步研究[9-10]。其中IFN-γ是毛囊IP崩溃的关键因子,可诱导细胞MHC-I类分子的表达上调、招募CD8+NKG2D+T细胞的聚集从而破坏毛囊[7-8]。调节T细胞分泌IL-10(也可以由Th1型细胞分泌)和TGF-β。IL-10能抑制T细胞的增殖、炎症细胞因子的生产和降低CD8+T细胞的活性,TGF-β可下调T细胞的MHC-I表达,二者均可以维持IP的免疫抑制环境,发挥“毛囊IP卫士”的作用[11-12]。

表1 细胞因子在AA中的水平变化

Table 1 Changes in cytokine levels in AA

分类 AA患者与健康对照组血清中细胞因子水平变化发病相关细胞因子 Th1型 IFN-γ:升高[6]
IL-2:升高[6-7]
IL-10: 无明显差异[7];升高[8] Th2型 IL-4、IL-13、IL-33和IL-17E/25:升高[9-10] Th17型 IL-17,IL-21,TNF-α:升高[9-10] 维护IP相关细胞因子/分子神经肽/神经激素 P物质[12] 调节T细胞 IL-10:无明显差异[6]; 升高[10]TGF-β:升高[6];降低[10] 神经肽/神经激素降钙素基因相关肽(CGRP)、黑素细胞刺激激素(α-MSH)和血管活性肠肽(VIP)[13] 其他 MIF(巨噬细胞迁移抑制因子)、吲哚胺2,3-双加氧酶(IDO)、血栓反应素1(TSP1)和Red/IK[12,14]

另外,毛囊中的感觉神经末梢分泌各种神经肽和神经激素也参与毛囊IP的崩溃或者维护。毛囊神经末梢分泌的P物质参与IP崩溃,而降钙素基因相关肽(CGRP)、黑素细胞刺激激素(α-MSH)、和血管活性肠肽(VIP)均作为毛囊IP的“安全卫士”,可维持正常IP和恢复毛囊崩溃的IP[13]。

其他细胞因子如巨噬细胞迁移抑制因子(MIF)、吲哚胺2,3-双加氧酶(IDO)、血栓反应素1(TSP1)、和Red/IK等因子也通过免疫调节作用来维护毛囊的免疫特权[11,14]。

1.2 免疫细胞在斑秃发病机制中作用

T细胞及其各种亚型在AA发病中作用突出,体现在AA发病、AA的IP恢复以及AA复发的全过程。首先,CD8+NKG2D+T细胞在AA的发病中起主要作用,Gilhar等人已经证明,NKG2D+/CD56+T细胞、NK细胞即能单独在SCID小鼠上的健康人皮肤移植处诱导AA样皮损[15],这提示了NKG2D受体阳性的T细胞是AA发病的充分条件。另外,树突状表皮T细胞(DETC,也称为γδT细胞)在激活状态下可促进NKG2D表达和IFN-γ分泌而引发毛囊IP破坏[16]。其次,调节T细胞(Tregs)和iNKT细胞(一种非传统的T细胞亚型) 参与毛囊IP的调节,促进AA的恢复。调节T细胞可通过分泌细胞因子TGF-β、IL-10或者高表达CD25(IL-2受体α)消耗IL-2等多种机制来发挥免疫抑制效应[6,17],其免疫抑制功能受损可促进AA发展[6],而在小鼠模型中增加其数量可促进AA皮损恢复[18]。iNKT10细胞可以直接或间接抑制CD8+/NKG2D+T细胞,其激活物-半乳糖神经酰胺(a-GalCer)以IL-10依赖的方式阻止小鼠AA的发展[11]。最后,AA的复发常见在原脱发部位,提示其局部可能具有免疫记忆。一项关于瘢痕性脱发的研究,发现斑秃患者皮损中CD103+CD69+TRM(组织驻留记忆T细胞)细胞出现上调状态[19],并且使用Janus激酶(JAK)信号通路的抑制剂(如tofacitinib)治疗后的AA小鼠,其病变T细胞克隆不会完全消失,直接或间接提示了TRM细胞可能参与AA复发[5]。TRM细胞能够在遇到同源抗原时快速反应,大量分泌AA的重要驱动因子IFN-γ,以及肿瘤坏死因子-α(TNFα))等[20],以此促进AA复发,但是具体机制仍待进一步验证。

除T细胞以外,树突状细胞(DCs)中的浆细胞样DC(pDCs)也能分泌I型IFN从而启动毛囊自身免疫反应[21]。肥大细胞在AA患者皮损中表现为促炎表型,可通过脱颗粒和增加与CD8+T细胞的接触促进炎症反应[12]。

2 生物制剂治疗AA及其潜在靶点

2.1 Th1型

2.1.1 IFN-γ

IFN-γ作为Th1型细胞因子,是AA发病的关键因子。目前阻断IFN-γ作用通路的研究主要有2个方面:1.阻断IFN诱导型趋化因子(CXCL9/10/11)及其受体CXCR3,可抑制CD8+NKG2D+T细胞向AA小鼠模型中迁移,从而抑制AA的发展[22];2.细胞因子信号传导抑制剂3(SOCS3)-可以阻断产生IFN-γ的CD8+T细胞在AA皮损中的积累[23]。虽然以上两个方面可作为生物治疗AA的潜在靶点,但是由于IFN-γ作为Th1型炎症通路的关键信号因子,临床上尚无应用于治疗的生物制剂。

2.1.2 低剂量IL-2

IL-2在AA患者的血清中水平升高,但是多项研究表明IL-2在血清中的水平与AA患者的病情严重程度、疾病持续时间无关[7,24]。然而,低剂量IL-2能够通过募集Tregs细胞而增加其数量,从而有望治疗重度AA。一项包含5例受试者的前瞻性研究通过皮下注射IL-2,实现了4名受试者的血清Tregs细胞数量增加和毛发再生,而样本量更大的多中心前瞻性安慰剂对照研究虽证实了低剂量IL-2对Tregs细胞的招募效果,却没有实现受试者毛发再生[25-26]。低剂量IL-2对AA的治疗作用研究需要进一步明确IL-2对Tregs细胞的招募作用的机制和其对Tregs细胞功能的影响。

2.2 Th2型

度普利尤单抗(Dupilumab)是一种通过结合IL-4R受体a亚基(IL-4和IL-13共有的受体亚基)从而抑制Th2型炎症反应的单克隆抗体。目前该药物广泛应用于特应性皮炎(AD)。在其临床应用过程中,多项病例报告/系列发现,Dupilumab治疗AD的同时,可能缓解AA,也可能诱发AA样脱发甚至加重AA[27]。一项关于Dupilumab治疗AA的随机、安慰剂对照临床研究表明,在治疗的24周后,Dupilumab的治疗反应与血清总IgE水平相关,IgE水平越高,对Dupilumab治疗反应越好[28]。出现以上度普利尤单抗治疗AA的临床效果差异性的原因究其根本在于AA患者的临床表型差异性:在血清中IgE水平高的AA患者中,Th2炎症通路可能在AA的发病中占据着相对较重要的地位,当使用Dupilumab阻断该炎症通路,AA能得到缓解;然而对于非以Th2型炎症反应为主的AA患者,抑制该通路不仅达不到治疗效果,反而加强了Th1炎症反应,从而诱发或者加重AA。值得注意的是,有学者认为,度普利尤单抗治疗AD过程中脱发的诱发或者AA加重(同TNF-α抑制剂引起的脱发一样)是由于药物反应所致,药物诱导了皮脂腺的萎缩和非瘢痕性的脱发[29]。度普利尤单抗治疗AA需要明确的临床评价指标,IgE水平是否可以做为该指标,需要进一步的临床随机对照试验证实。

2.3 Th17型

2.3.1 TNF-α抑制剂

TNF-α抑制剂治疗AA并没有在临床上取得较好的疗效,相反,其可能加重或者诱发AA。一项20例病例的前瞻性研究表明依那西普在治疗中度至重度斑秃、全秃或全身性脱发中无效[30]。阿达木单抗治疗AA的3例病例报告也提示其不能诱导毛发的再生[31]。甚至,有病例报告提示在阿达木单抗治疗银屑病后出现了斑秃[32]。出现这些结果的原因可能与TNF-α失去对浆细胞样树突状细胞所产生的干扰素的抑制有关[33],也可能是上文所述的药物反应。但同时,也有阿达木单抗成功治疗了斑秃的案例,治疗效果不一致可能与AA复杂的发病机制和AA患者个体差异有关。

2.3.2 IL-17抑制剂

IL-17抑制剂包括了司库奇优单抗(Secukinumab)、依奇珠单抗(ixekizumab )和布罗达鲁单抗(brodalumab,)。鉴于IL-17在AA中的重要作用,其在靶向治疗AA上颇有潜力,但目前尚缺乏有力的临床随机对照试验证实它在促进毛发再生中的作用。一项包括11名受试者的RCT表明在接受24周皮下注射苏金单抗治疗的AA患者的毛发无明显再生[34]。同时,也有病例报告表明在司库奇优单抗治疗银屑病合并全秃患者时,患者毛发有一定程度再生,停药后毛发再次脱落[35]。与之相反,有个案报道的银屑病患者经过司库奇优单抗治疗后出现多毛[36]。以上IL-17抑制剂治疗AA成功或者失败的例子不能完全说明其有效和无效,需要样本量更大的RCT来证实。

2.3.3 IL-12/23抑制剂

乌司奴单抗(Ustekinumab)是抑制IL-12/23的共有P40亚基的的全人源化单克隆抗体,IL-12、IL-23分别是诱导T细胞向Th17细胞、Th1细胞分化的重要细胞因子。乌司奴单抗主要应用于中重度斑块状银屑病。在Emma Guttman-Yassky的病例系列报告中,3例经乌司奴单抗治疗的患者在20周后出现不同程度的毛发再生,且患者皮肤活检中炎症标志物水平也降低[37]。但是,Ortolan LS等人进一步小鼠试验表明,中和IL-12、IL-23的共有P40亚基和IL-23的特异性P19亚基不会抑制AA的发展;并且4例AA患者使用乌司奴单抗治疗均失败[38]。此外,也有病例报告显示在乌司奴单抗治疗银屑病期间出现了AA的发展[39]。总体来说,目前尚无临床随机对照研究来证明乌司奴单抗在治疗AA的临床效果。

3 小分子药物靶向治疗AA现状

3.1 JAK抑制剂

JAK通路是某些干扰素和白介素类细胞因子的共同下游通路,通过抑制此通路,不仅可以阻断IFN-γ信号传导,还可以阻断其他细胞因子介导的炎症反应。JAK抑制剂治疗AA颇具潜力。

3.1.1 非选择性JAK抑制剂

非选择性JAK抑制剂在临床上可应用于治疗AA的有托法替尼(tofacitinib)、鲁索替尼(ruxolitinib)、巴瑞替尼(baricitinib)。托法替尼是JAK1/3抑制剂,鲁索替尼、巴瑞替尼是JAK1/2抑制剂,它们在临床试验中显示出良好的治疗效果及安全性[40-41]。需注意的是目前少有临床试验证实儿童口服JAK抑制剂的疗效和安全性,但有研究证实了外用JAK抑制剂在AA儿童患者中的疗效。一项针对6名儿童患者的研究中,使用1%~2%浓度的托法替尼和鲁索替尼外用制剂进行治疗后,6例患者中有4例出现毛发再生[42]。

据各种临床研究显示,使用JAK抑制剂最常见的不良反应是上呼吸道感染,头痛,痤疮,疲劳等,实验室检查指标上少数患者可出现肝酶异常、脂质异常,白细胞计数减少等,未见严重不良反应[43]。但是停药后复发是目前治疗面临的重要问题,预防疾病复发可予药物的维持治疗,可以选择口服药物维持,或者改用外用药物,但目前尚缺乏明确具体维持治疗方案的研究[40,43]。在选择口服或者外用给药方面,需考虑患者皮损的累及范围及年龄,同时考虑长期使用药物的不良反应。一般来说,局限性的AA和儿童患者选择外用制剂更好,以求更高的局部浸润浓度和更好的安全性,虽然并没有明确的研究证实外用制剂和口服用药在不良反应上的差别。对皮损广泛且成年AA患者来说,口服用药是更好的选择。Phan等[43]的研究也显示,口服JAK抑制剂比局部外用治疗效果好。

3.1.2 选择性JAK抑制剂

选择性JAK抑制剂有更高的选择性和安全性。一些选择性JAK抑制剂已经应用于临床,如选择性JAK1抑制剂厄帕替尼(upadacitinib)已获批上市用于治疗类风湿关节炎(RA)。一些选择性Jak抑制剂治疗AA进入II-III期临床阶段[44]。

3.2 T细胞调剂

阿巴西普(Abatacept)是细胞毒性T淋巴细胞相关抗原 4(Cytotoxic T lymphocyte associate protein-4,CTLA-4)和部分IgG1(CTLA-4Ig)组成的融合蛋白。其可阻断T细胞上CD28的共刺激作用,从而广泛抑制T细胞,减少关键炎症细胞因子如FN-γ、TNF-α的产生[45]。目前有一项开放标签单臂临床试验显示了阿巴西普对AA的治疗潜力[46]。

3.3 磷酸二酯酶(PDE4)抑制剂

阿普斯特(Apremilast)是一种口服磷酸二酯酶4(PDE4)抑制剂,其可通过升高细胞内cAMP水平,降低TNF-α、IL-12、17、23等多种细胞因子的表达,提高IL-10等的表达,降低炎症反应水平,从而治疗AA。目前少量小样本临床研究证实了其对AA患者毛发再生的作用[47]。

4 结语与展望

AA的发病机制比较复杂,涉及众多炎症通路和免疫细胞,这造成了不同AA患者的异质性,也为靶向治疗AA取得满意的疗效带来了一定的困难。但是,在进一步明确AA发病机制基础上的靶向治疗,可为提升AA患者疗效带来更多可能。因此,针对AA发病机制的研究和针对AA发病过程中失衡的细胞因子或者免疫细胞的靶点药物研究仍需深入开展。关于AA的靶向治疗可以考虑同时将阻断炎症通路和恢复毛囊IP的治疗相结合,这样更可能在AA患者自身异质性的情况下,达到理想的治疗效果和防止复发的效果。

=2" class="main_content_center_left_zhengwen_bao_erji_title main_content_center_left_one_title" style="font-size: 16px;">{{custom_sec.title}}{{custom_sec.content}}[1]SIMAKOU T

BUTCHER J P

REID S

, et al. Alopecia areata:a multifactorial autoimmune condition[J]. J Autoimmun, 2019, 98:74-85.

ITO N

TAKIGAWA M

, et al. The hair follicle and immune privilege[J]. J Investig Dermatol Symp Proc, 2003, 8(2):188-194.

GILHAR A

PAUS R

. Alopecia areata as a model for T cell-dependent autoimmune diseases[J]. Exp Dermatol, 2012, 21(6):477-479.

JABBARI A

DAI Z

, et al. High-throughput T cell receptor sequencing identifies clonally expanded CD8+ T cell populations in alopecia areata[J]. JCI insight, 2018, 3(19):e121949.doi:10.1172/jci.insight.121949.

MARKS D H

MANATIS-LORNELL A

, et al. Association between alopecia areata, anxiety, and depression: a systematic review and meta-analysis[J]. Am Acad Dermatol, 2019, 1:S0190-9622(19)30890-4.doi:10.1016/j.jaad.2019.05.086.

SHARMA V K

. T-helper and regulatory T-cell cytokines in the peripheral blood of patients with active alopecia areata[J]. Br J Dermatol, 2013, 169(3):543-548.

Alteration in T-lymphocyte function and cytokines secreted by T-cell subsets has been proposed in the immunopathogenesis of alopecia areata (AA). The role of T-helper and regulatory T-cell cytokines in the pathogenesis of active AA has not been established.To assess the role of hallmark cytokines of T-helper cells (Th1, Th2 and Th17) and regulatory T cells (Tregs) in the pathogenesis of AA, and its clinical correlation.Fifty-one patients with AA and 45 age- and sex-matched healthy control subjects were included in the study. Serum interleukin (IL)-2, interferon (IFN)-γ, IL-10, IL-13, IL-17A and transforming growth factor (TGF)-β1 were measured by enzyme-linked immunosorbent assay in both groups. Correlation of serum cytokine levels with age, sex, disease subtype and duration, number of patches on the scalp, associated autoimmune disorders and atopy was studied.The serum cytokine levels of IL-2, IFN-γ, IL-13 and IL-17A were significantly increased, and serum TGF-β1 levels were significantly decreased (P < 0·05) in patients with AA compared with controls. Serum IL-2 levels were significantly different among AA subgroups (P < 0·05). IL-2 levels were positively correlated with the total disease duration and the number of patches on the scalp.The increased levels of serum IL-2, IFN-γ, IL-13 and IL-17A suggested altered T-helper cell function, and reduced serum TGF-β1 levels suggested a defect in Treg function. Therefore, enhanced T-cell-mediated immunity and breakdown of immune tolerance due to deficiency in Tregs may facilitate the occurrence of AA.© 2013 The Authors BJD © 2013 British Association of Dermatologists.

CAVALJUGA S

OVCINA-KURTOVIC N

, et al. Serum levels of interleukin-2 in patients with alopecia areata: relationship with clinical type and duration of the disease[J]. Skin Appendage Disor, 2018, 4(4):286-290.

Background: Alopecia areata (AA) is a disease characterized by focally, nonscarring hair loss on the scalp or any hair-bearing surface. The etiology is unknown, although the evidence suggests that AA is an immunologically mediated disease. In the pathogenesis of AA, Th1 immune response is predominant. A special cytokine profile is created by Th1 cells, which disturbs the natural balance of the cytokine networks and leads to inflammatory reaction and follicle damage. Objective: The aim of our study was to evaluate serum concentrations of IL-2 in patients with AA and healthy subjects. We also examined a possible association between serum levels of IL-2, disease severity, and duration of AA. Methods: Sixty patients with AA and 20 healthy controls were enrolled in the study. Serum concentrations of IL-2 were measured using enzyme-linked immunoassay techniques. Results: Comparison of mean values of IL-2 has showed that serum concentrations of this cytokine are significantly higher in serum samples of AA patients in relation to the control group (22.2 ± 1.19 vs. 21.1 ± 2.68 pg/mL, respectively; p = 0.0142). No correlations were found between clinical type, duration of the disease, and serum levels of IL-2. Conclusion: Our findings support the evidence that elevation of serum IL-2 is associated with AA. The exact role of serum IL-2 in AA should be additionally investigated in future studies.

SINGH Y

GUPTA A

, et al. The profile of cytokines (IL-2, IFN-γ, IL-4, IL-10, IL-17A, and IL-23) in active alopecia areata[J]. J Cosmet Dermtol, 2020, 19(1):234-240.

MCDONALD E

MOFFAT F

, et al. Alopecia areata is characterized by dysregulation in systemic type 17 and type 2 cytokines, which may contribute to disease-associated psychological morbidity[J]. Br J Dermatol, 2020, 182(1):130-137.

Alopecia areata (AA) is a common autoimmune disease, causing patchy hair loss that can progress to involve the entire scalp (totalis) or body (universalis). CD8 NKG2D T cells dominate hair follicle pathogenesis, but the specific mechanisms driving hair loss are not fully understood.To provide a detailed insight into the systemic cytokine signature associated with AA, and to assess the association between cytokines and depression.We conducted multiplex analysis of plasma cytokines from patients with AA, patients with psoriatic arthritis (PsA) and healthy controls. We used the Hospital Anxiety and Depression Scale (HADS) to assess the occurrence of depression and anxiety in our cohort.Our analysis identified a systemic inflammatory signature associated with AA, characterized by elevated levels of interleukin (IL)-17A, IL-17F, IL-21 and IL-23 indicative of a type 17 immune response. Circulating levels of the type 2 cytokines IL-33, IL-31 and IL-17E (IL-25) were also significantly increased in AA. In comparison with PsA, AA was associated with higher levels of IL-17F, IL-17E and IL-23. We hypothesized that circulating inflammatory cytokines may contribute to wider comorbidities associated with AA. Our assessment of psychiatric comorbidity in AA using HADS scores showed that 18% and 51% of people with AA experienced symptoms of depression and anxiety, respectively. Using linear regression modelling, we identified that levels of IL-22 and IL-17E are positively and significantly associated with depression.Our data highlight changes in both type 17 and type 2 cytokines among people with AA, suggesting that complex systemic cytokine profiles may contribute both to the pathogenesis of AA and to the associated depression. What's already known about this topic? NKG2D CD8 T cells cause hair loss in alopecia areata (AA) but the immunological mechanisms underlying the disease are not fully understood. AA is associated with changes in levels of interleukin (IL)-6, tumour necrosis factor-α, IL-1β and type 17 cytokines. Psychiatric comorbidity is common among people with AA. What does this study add? People with AA have increased plasma levels of the type 2 cytokines IL-33, IL-31 and IL-17E (IL-25), in addition to the type 17 cytokines IL-17A, IL-21, IL-23 and IL-17F. Levels of IL-17E and IL-22 positively predict depression score. What is the translational message? AA is associated with increased levels of multiple inflammatory cytokines, implicating both type 17- and type 2 immune pathways. Our data indicate that therapeutic strategies for treating AA may need to address the underlying type 17- and type 2 immune dysregulation, rather than focusing narrowly on the CD8 T-cell response. An immunological mechanism might contribute directly to the depression observed in people with AA.© 2019 British Association of Dermatologists.

MOON H N

LEW B L

, et al. Role of T helper 17 cells and T regulatory cells in alopecia areata: comparison of lesion and serum cytokine between controls and patients[J]. J Eur Acad Dermatol Venereol, 2018, 32(6):1028-1033.

Alopecia areata (AA) is an organ-specific autoimmune disease with T-cell-mediated attack of hair follicle autoantigens. As T helper 17 (Th17) cells and T regulatory (Treg) cells are crucially involved in the pathogenesis, the role of Th17 and Treg cytokines has not been studied yet.To determine whether AA is associated with alterations in lesional and serum Th17 and Treg cytokines and studied whether they were associated with clinical type.Scalp skin samples from 45 patients and eight normal controls were obtained for PCR specific for IFN-γ, TNF-α, TGF-β, IL-1, IL-2, IL-4, IL-10, IL-12A, IL-13, IL-17, IL-22 and IL-23. Serum cytokines were measured from 55 patients and 15 normal controls using ELISA.Lesional IL-17 and IL-22 were significantly increased in patient group. Moreover, positive correlations were shown between lesional IL-17, IL-22 and disease severity. Serum IL-1, IL-17, TNF-α and TGF-β were significantly increased, and positive correlation was shown between serum IL-17 and disease severity.These results showed significantly high Th17 cytokines in both lesion and serum in AA patients, which may highlight a functional role of these cytokines in the pathogenesis of AA.© 2017 European Academy of Dermatology and Venereology.

KEREN A

GINZBURG A

, et al. iNKT cells ameliorate human autoimmunity: lessons from alopecia areata[J]. Autoimmun, 2018, 91:61-72.

MCELWEE K

GILHAR A

, et al. Hair follicle immune privilege and its collapse in alopecia areata[J]. Exp Dermatol, 2020, 29(8):703-725.

Anagen stage hair follicles (HFs) exhibit "immune privilege (IP)" from the level of the bulge downwards to the bulb. Both passive and active IP mechanisms protect HFs from physiologically undesired immune responses and limit immune surveillance. IP is relative, not absolute, and is primarily based on absent, or greatly reduced, intra-follicular antigen presentation via MHC class I and II molecules, along with prominent expression of "no danger" signals like CD200 and the creation of an immunoinhibitory signalling milieu generated by the secretory activities of HFs. Perifollicular mast cells, Tregs and other immunocytes may also contribute to HF IP maintenance in healthy human skin. Collapse of anagen hair bulb IP is an essential prerequisite for the development of alopecia areata (AA). In AA, lesional HFs are rapidly infiltrated by NKG2D + T cells and natural killer (NK) cells, while perifollicular mast cells acquire a profoundly pro-inflammatory phenotype and interact with autoreactive CD8+ T cells. Using animal models, significant functional evidence has accumulated that demonstrates the dominance of the immune system in AA pathogenesis. Purified CD8+T-cell and NK cell populations alone, which secrete fγ, suffice to induce the AA phenotype, while CD4+T-cells aggravate it, and Tregs and iNKT cells may provide relative protection against AA development. While IP collapse may be induced by exogenous agents, inherent IP deficiencies might confer increased susceptibility to AA for some individuals. Thus, a key goal for effective AA management is the re-establishment of a functional HF IP, which will also provide superior protection from disease relapse.© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

DRAKE L A

SENNA M M

, et al. Alopecia areata: a review of disease pathogenesis[J]. Br J Dermatol, 2018, 179(5):1033-1048.

Alopecia areata is a disorder that results in nonscarring hair loss. The psychological impact can be significant, leading to feelings of depression and social isolation. Objectives In this article, we seek to review the pathophysiological mechanisms proposed in recent years in a narrative fashion.We searched MEDLINE and Scopus for articles related to alopecia areata, with a particular emphasis on its pathogenesis.The main theory of alopecia areata pathogenesis is that it is an autoimmune phenomenon resulting from a disruption in hair follicle immune privilege. What causes this breakdown is an issue of debate. Some believe that a stressed hair follicle environment triggers antigen presentation, while others blame a dysregulation in the central immune system entangling the follicles. Evidence for the latter theory is provided by animal studies, as well investigations around the AIRE gene. Different immune-cell lines including plasmacytoid dendritic cells, natural killer cells and T cells, along with key molecules such as interferon-γ, interleukin-15, MICA and NKG2D, have been identified as contributing to the autoimmune process.Alopecia areata remains incurable, although it has been studied for years. Available treatment options at best are beneficial for milder cases, and the rate of relapse is high. Understanding the exact mechanisms of hair loss in alopecia areata is therefore of utmost importance to help identify potential therapeutic targets.© 2018 British Association of Dermatologists.

KILANI R T

LI Y

, et al. Fibroblast cell-based therapy prevents induction of alopecia areata in an experimental model[J]. Cell Transplant, 2018, 27(6):994-1004.

Alopecia areata (AA) is an autoimmune hair loss disease with infiltration of proinflammatory cells into hair follicles. Current therapeutic regimens are unsatisfactory mainly because of the potential for side effects and/or limited efficacy. Here we report that cultured, transduced fibroblasts, which express the immunomodulatory molecule indoleamine 2,3-dioxygenase (IDO), can be applied to prevent hair loss in an experimental AA model. A single intraperitoneal (IP) injection of IDO-expressing primary dermal fibroblasts was given to C3H/HeJ mice at the time of AA induction. While 60-70% of mice that received either control fibroblasts or vehicle injections developed extensive AA, none of the IDO-expressing fibroblast-treated mice showed new hair loss up to 20 weeks post injection. IDO cell therapy significantly reduced infiltration of CD4 and CD8 T cells into hair follicles and resulted in decreased expression of TNF-α, IFN-γ and IL-17 in the skin. Skin draining lymph nodes of IDO fibroblast-treated mice were significantly smaller, with more CD4 CD25 FoxP3 regulatory T cells and fewer Th17 cells than those of control fibroblast and vehicle-injected mice. These findings indicate that IP injected IDO-expressing dermal fibroblasts can control inflammation and thereby prevent AA hair loss.

SCHRUM A G

ETZIONI A

, et al. Alopecia areata: animal models illuminate autoimmune pathogenesis and novel immunotherapeutic strategies[J]. Autoimmun Rev, 2016, 15(7):726-735.

One of the most common human autoimmune diseases, alopecia areata (AA), is characterized by sudden, often persisting and psychologically devastating hair loss. Animal models have helped greatly to elucidate critical cellular and molecular immune pathways in AA. The two most prominent ones are inbred C3H/HeJ mice which develop an AA-like hair phenotype spontaneously or after experimental induction, and healthy human scalp skin xenotransplanted onto SCID mice, in which a phenocopy of human AA is induced by injecting IL-2-stimulated PBMCs enriched for CD56+/NKG2D+ cells intradermally. The current review critically examines the pros and cons of the available AA animal models and how they have shaped our understanding of AA pathobiology, and the development of new therapeutic strategies. AA is thought to arise when the hair follicle's (HF) natural immune privilege (IP) collapses, inducing ectopic MHC class I expression in the HF epithelium and autoantigen presentation to autoreactive CD8+ T cells. In common with other autoimmune diseases, upregulation of IFN-γ and IL-15 is critically implicated in AA pathogenesis, as are NKG2D and its ligands, MICA, and ULBP3. The C3H/HeJ mouse model was used to identify key immune cell and molecular principles in murine AA, and proof-of-principle that Janus kinase (JAK) inhibitors are suitable agents for AA management in vivo, since both IFN-γ and IL-15 signal via the JAK pathway. Instead, the humanized mouse model of AA has been used to demonstrate the previously hypothesized key role of CD8+ T cells and NKG2D+ cells in AA pathogenesis and to discover human-specific pharmacologic targets like the potassium channel Kv1.3, and to show that the PDE4 inhibitor, apremilast, inhibits AA development in human skin. As such, AA provides a model disease, in which to contemplate general challenges, opportunities, and limitations one faces when selecting appropriate animal models in preclinical research for human autoimmune diseases. Copyright © 2016 Elsevier B.V. All rights reserved.

GHERARDINI J

PAPPELBAUM K

, et al. Resident human dermal γδT-cells operate as stress-sentinels: lessons from the hair follicle[J]. J Autoimmun, 2021, 124:102711.doi:10.1016/j.jaut.2021.102711.

ZIRAK B

RODRIGUEZ R S

, et al. Regulatory T Cells in skin facilitate epithelial stem cell differentiation[J]. Cell, 2017, 169(6):1119-1129.

The maintenance of tissue homeostasis is critically dependent on the function of tissue-resident immune cells and the differentiation capacity of tissue-resident stem cells (SCs). How immune cells influence the function of SCs is largely unknown. Regulatory T cells (Tregs) in skin preferentially localize to hair follicles (HFs), which house a major subset of skin SCs (HFSCs). Here, we mechanistically dissect the role of Tregs in HF and HFSC biology. Lineage-specific cell depletion revealed that Tregs promote HF regeneration by augmenting HFSC proliferation and differentiation. Transcriptional and phenotypic profiling of T and HFSCs revealed that skin-resident Tregs preferentially express high levels of the Notch ligand family member, Jagged 1 (Jag1). Expression of Jag1 on Tregs facilitated HFSC function and efficient HF regeneration. Taken together, our work demonstrates that Tregs in skin play a major role in HF biology by promoting the function of HFSCs.Copyright © 2017 Elsevier Inc. All rights reserved.

HARRIS J E

RICHMOND J M

. Resident memory T cells in autoimmune skin diseases[J]. Front Immunol, 2021, 12:652191.doi:3389/fimmu.2021.652191.

GORDON C L

CHRISTO S N

, et al. Local heroes or villains: tissue-resident memory T cells in human health and disease[J]. Cell Mol Immunol, 2020, 17(2):113-122.

Tissue-resident memory T (T) cells are increasingly associated with the outcomes of health and disease. T cells can mediate local immune protection against infections and cancer, which has led to interest in T cells as targets for vaccination and immunotherapies. However, these cells have also been implicated in mediating detrimental pro-inflammatory responses in autoimmune skin diseases such as psoriasis, alopecia areata, and vitiligo. Here, we summarize the biology of T cells established in animal models and in translational human studies. We review the beneficial effects of T cells in mediating protective responses against infection and cancer and the adverse role of T cells in driving pathology in autoimmunity. A further understanding of the breadth and mechanisms of T cell activity is essential for the safe design of strategies that manipulate T cells, such that protective responses can be enhanced without unwanted tissue damage, and pathogenic T cells can be eliminated without losing local immunity.

DAI J

SINGH S

. Plasmacytoid dendritic cells and type I IFN: 50 years of convergent history[J]. Cytokine Growth Factor Rev, 2008, 19(1):3-19.

XING L

CERISE J

, et al. CXCR3 blockade inhibits T cell migration into the skin and prevents pevelopment of alopecia areata[J]. J Immunol, 2016, 197(4):1089-1099.

Alopecia areata (AA) is an autoimmune disease of the hair follicle that results in hair loss of varying severity. Recently, we showed that IFN-γ–producing NKG2D+CD8+ T cells actively infiltrate the hair follicle and are responsible for its destruction in C3H/HeJ AA mice. Our transcriptional profiling of human and mouse alopecic skin showed that the IFN pathway is the dominant signaling pathway involved in AA. We showed that IFN-inducible chemokines (CXCL9/10/11) are markedly upregulated in the skin of AA lesions, and further, that the IFN-inducible chemokine receptor, CXCR3, is upregulated on alopecic effector T cells. To demonstrate whether CXCL9/10/11 chemokines were required for development of AA, we treated mice with blocking Abs to CXCR3, which prevented the development of AA in the graft model, inhibiting the accumulation of NKG2D+CD8+ T cells in the skin and cutaneous lymph nodes. These data demonstrate proof of concept that interfering with the Tc1 response in AA via blockade of IFN-inducible chemokines can prevent the onset of AA. CXCR3 blockade could be approached clinically in human AA with either biologic or small-molecule inhibition, the latter being particularly intriguing as a topical therapeutic.

JIN Y Q

WU W

. SOCS3 treatment prevents the development of alopecia areata by inhibiting CD8+ T cell-mediated autoimmune destruction[J]. Oncotarget, 2017, 8(20):33432-33443.

YÜCESOY S N

COŞKUN E

, et al. Evaluation of the level of serum interleukins (IL-2, IL-4, IL-15 andIL-17) and its relationship with disease severity in patients with alopecia areata[J]. An Bras Dermatol, 2021, 96(5):551-557.

LE DUFF F

BUTORI C

, et al. Effects of low-dose recombinant interleukin 2 to promote T-regulatory cells in alopecia areata[J]. JAMA Dermatol, 2014, 150(7):748-751.

An impaired inhibitory function of circulating CD4+CD25+ regulatory T (Treg) cells was reported to play a key role in alopecia areata (AA). We report the first use to our knowledge of low-dose interleukin 2 for treating severe AA by promoting the recruitment of Treg cells.We conducted a prospective open pilot study in 5 patients with severe AA resistant to previous systemic treatments. Subcutaneous interleukin 2 (1.5 million IU/d) was administered during 5 days, followed by three 5-day courses of 3 million IU/d at weeks 3, 6, and 9. The primary outcome was the evolution of the Severity of Alopecia Tool (SALT) score, evaluated by 2 independent investigators on standardized photographs. Lesional skin biopsy specimens and peripheral blood lymphocyte phenotype were analyzed. The median SALT score went from 82 (range, 63-100) at baseline to 69 (range, 28-100) at 6 months. Immunochemical analysis revealed the appearance or a notable increase in Treg cell count in 4 of 5 patients at the end of the treatment compared with baseline. No serious adverse event was reported.The partial regrowth achieved in 4 of 5 patients and the recruitment of Treg cells in lesional skin support the interest of promoting Treg cells for treating AA. Further investigations are now required to confirm and to optimize the design in order to enhance the Treg cell response.clinicaltrials.gov Identifier: NCT01840046.

BOUAZIZ J D

FONTAS E

, et al. Low-Dose IL-2 for treating moderate to severe alopecia areata: a 52-week multicenter prospective placebo-controlled study assessing its impact on T regulatory cell and NK cell populations[J]. J Invest Dermatol, 2021, 141(4):933-936.

陈静, 张守民. 斑秃合并特应性皮炎免疫学特性及治疗研究进展[J]. 中国麻风皮肤病杂志, 2022, 38(5):343-346.

RENERT-YUVAL Y

BARES J

, et al. Phase 2a randomized clinical trial of dupilumab (anti-IL-4Rα) for alopecia areata patients[J]. Allergy, 2022, 77(3):897-906.

NAPOLITANO M

FERRILLO M

, et al. Dupilumab and alopecia: a janus effect[J]. Dermatol Ther, 2019, 32(5):e13023.

SIU K

ALEXIS A F

, et al. Etanercept does not effectively treat moderate to severe alopecia areata: an open-label study[J]. J Am Acad Dermatol, 2005, 52(6):1082-1084.

In this prospective, open-label pilot study, we evaluated the safety and efficacy of etanercept, a TNF-alpha inhibitor, in the treatment of moderate to severe alopecia areata, alopecia totalis, or alopecia universalis. Seventeen otherwise healthy adults with moderate to severe alopecia areata were enrolled. The primary outcome measure was the extent of hair regrowth during and after the end of treatment as evaluated by the Severity of Alopecia Tool (the SALT score). After between 8 and 24 weeks of continuous treatment with etanercept 50 mg given subcutaneously twice weekly, significant regrowth of hair was not shown in any of the subjects treated. Based on these results, etanercept appears to be ineffective in treating subjects with treatment-refractory, moderate to severe alopecia areata, alopecia totalis, or alopecia universalis.

BISSONNETTE R

. Safety and efficacy of adalimumab for the treatment of severe alopecia areata: case series of three patients[J]. J Cutan Med Surg, 2012, 16(4):257-260.

Current therapeutic options for extensive alopecia areata (AA) often lead to disappointing results.To study the efficacy and safety of adalimumab in patients with severe AA.This was a prospective, open-label, single-center, pilot study. Three subjects of the planned 10 were enrolled and received two weekly subcutaneous (SC) loading doses of adalimumab 80 mg followed by 40 mg SC every week for 6 months. Patients were evaluated for efficacy and safety on a monthly basis.Enrolment in this trial was stopped following publication of studies showing no improvement in patients with AA treated with tumor necrosis factor α antagonists. One patient had a favorable response to adalimumab, whereas the two other patients had no benefit from the therapy. Adalimumab was well tolerated by patients with AA.Adalimumab was well tolerated in patients with AA but did not induce clinically significant hair regrowth.

LIN A

TRABOULSI C

, et al. Treatment of crohn's disease and concomitant alopecia areata with tofacitinib[J]. ACG Case Rep J, 2021, 8(11):e00690.

SUZUKI T

SAKABE J I

, et al. Plasmacytoid dendritic cells as a possible key player to initiate alopecia areata in the C3H/HeJ mouse[J]. Allergol Int, 2020, 69(1):121-131.

Alopecia areata (AA) is a tissue-specific autoimmune disease, and interferon (IFN)-γ has been regarded as the key cytokine in the pathogenesis of AA. The clinical observation that AA can occur after viral infection or IFN-α administration implies that IFN-α-producing plasmacytoid dendritic cells (pDCs) may be involved in the AA pathogenesis.We generated AA in C3H/HeJ mice by intradermal injection of T cells derived from lymph nodes of AA-bearing syngeneic mice and stimulated IL-2, IL-7, and IL-15. Distribution of IFN-γ producing pDCs were immunohistochemically analyzed. Realtime PCR were also demonstrated to detect the expression of IFN-γ mRNA. Hair follicles were cultured with IFN-α in order to calculate the hair elongation. Imiquimod was employed to induce catagen stage. PDCs were injected into C3H/HeJ mice to initiate AA.In this mouse, IFN-α-producing pDCs densely infiltrated around HFs in not only AA lesional but also vicinity of AA lesion. Importantly, intradermal injection of pDCs induced AA lesions. Finally, IFN-α inhibited hair elongation of murine vibrissae and upregulated MHC class I and CXCL10 levels in vitro.These findings suggest that IFN-α-producing pDCs initiate AA by inducing apoptosis and increasing Th1/Tc1 chemokine production such as CXCL10, that accumulates Th1/Tc1 cells and result in autoimmune reactions against hair follicles.Copyright © 2019 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.

NIA J K

HASHIM P W

, et al. Efficacy and safety of secukinumab treatment in adults with extensive alopecia areata[J]. Arch Dermatol Res, 2018, 310(8):607-614.

CAVANI A

CANZONA F

, et al. Mild therapeutic response of alopecia areata during treatment of psoriasis with secukinumab[J]. Eur J Dermatol, 2020, 30(5):602-603.

MAGNANO M

PATRIZI A

, et al. Generalized hypertrichosis due to secukinumab in a patient with moderate psoriasis: a case of serendipity or zemblanity?[J]. Dermatol Ther, 2019, 32(3):e12894.

UNGAR B

NODA S

, et al. Extensive alopecia areata is reversed by IL-12/IL-23p40 cytokine antagonism[J]. J Allergy Clin Immunol, 2016, 137(1):301-304.

KIM S R

CROTTS S

, et al. IL-12/IL-23 neutralization is ineffective for alopecia areata in mice and humans[J]. J Allergy Clin Immunol, 2019, 144(6):1731-1734.

BENETON N

REYGAGNE P

, et al. Alopecia areata developing during ustekinumab therapy: report of two cases[J]. Eur J Dermatol, 2013, 23(6):912-913.

FENG S

SUN B

, et al. Benefit and risk profile of tofacitinib for the treatment of alopecia areata: a systemic review and meta-analysis[J]. J Eur Acad Dermatol Venereol, 2020, 34(1):192-201.

Recent insights showed the possibility of using JAK inhibitors for the treatment of alopecia areata (AA). Most of the previous articles evaluated the overall efficacy of existing JAK inhibitors rather than evaluating one of them alone. Currently, the benefit and risk profile of tofacitinib for the treatment of AA is still not clear.To estimate the safety and efficacy of tofacitinib in patients with AA based on summarizing the clinical outcomes.The systematic review and meta-analysis was performed according to PRISMA guidelines. ROBINS-I (Risk of Bias in Non-randomized Studies-of Interventions) was used for quality assessment.We enrolled 14 studies including six clinical trials and eight observational studies with 275 patients. The result of meta-analysis showed that tofacitinib has reasonable effectiveness in patients with AA. The pooled good/complete hair regrowth rate of tofacitinib treating patient with AA was 54.0% (95% CI: 46.3%-61.5%), and the pooled rate of partial response in patients with AA taking tofacitinib was 26.1% (20.7-32.2%). Approximately a quarter of patients had experience of relapse, most of which was reported due to discontinuation of tofacitinib. In terms of toxicity, reported adverse effects included only mild symptoms. Upper respiratory infection, headache and acne were the most common adverse events.Tofacitinib seems to be a promising drug for the treatment of AA with only mild adverse effects. More thorough larger sized randomized clinical trials are required to further assess the safety and clinical efficacy of tofacitinib for the treatment of AA.© 2019 European Academy of Dermatology and Venereology.

KO J

FORMAN S

. et al. Efficacy and safety of the oral janus kinase inhibitor baricitinib in the treatment of adults with alopecia areata: phase 2 results from a randomized controlled study[J]. J Am Acad Dermatol, 2021, 85(4):847-853.

DENIRO K L

BRICHTA L

, et al. Topical janus kinase inhibitors for the treatment of pediatric alopecia areata[J]. J Am Acad Dermatol, 2017, 77(1):167-170

SEBARATNAM D F

. JAK inhibitors for alopecia areata: a systematic review and meta-analysis of the european academy of dermatology and venereology[J]. J Eur Acad Dermatol Venereol, 2019, 33(5):850-856.

There have been a number of case reports and small clinical trials reporting promising outcomes of Janus Kinase (JAK) inhibitors tofacitinib, ruxolitinib and baricitinib for alopecia areata (AA). The majority of the literature to date is based on small volume data, with a lack of definitive evidence or guidelines. To determine the expected response of AA to JAK inhibitor therapy and factors which influence response and recurrence rates. A systematic review and meta-analysis was performed according to PRISMA guidelines. From 30 studies and 289 cases, there were 72.4% responders, good responders 45.7% and partial responders 21.4%. Mean time to initial hair growth was 2.2 ± 6.7 months, and time to complete hair regrowth was 6.7 ± 2.2 months. All 37 recurrences occurred when treatment was ceased after 2.7 months. Oral route was significantly associated with response to treatment compared to topical therapy. No difference was found between paediatric and adult cases in proportion of responses. There is promising low-quality evidence regarding the effectiveness of JAK inhibitors in AA. Future large-sized randomized studies are required to confirm findings.© 2019 European Academy of Dermatology and Venereology.

李梦丽, 卢诚, 万慧阳, 等. 小分子Janus激酶抑制剂的研究进展[J]. 中国新药杂志, 2021, 30(23):2178-2188.

GUTTMAN-YASSKY E

. A novel therapeutic paradigm for patients with extensive alopecia areata[J]. Expert Opin Biol Ther, 2016, 16(8):1005-1014.

SALLEE B N

WANG E H C

, et al. An open-label study evaluating the efficacy of abatacept in alopecia areata[J]. J Am Acad Dermatol, 2021, 84(3):841-844.

刘伊雯, 王磊, 周君浩, 等. 斑秃的药物治疗研究进展[J]. 中国皮肤性病学杂志, 2022, 36(7):841-845.

{{custom_citation.content}}https://doi.org/{{custom_citation.doi}}https://www.ncbi.nlm.nih.gov/pubmed/{{custom_citation.pmid}}{{custom_citation.url}}本文引用 [{{custom_ref.citedCount}}]摘要{{custom_citation.annotation}}{{custom_ref.label}}{{custom_citation.content}}https://doi.org/{{custom_citation.doi}}https://www.ncbi.nlm.nih.gov/pubmed/{{custom_citation.pmid}}{{custom_citation.url}}本文引用 [{{custom_ref.citedCount}}]摘要{{custom_citation.annotation}}