Abstract
慢性荨麻疹在临床十分常见，但目前关于慢性荨麻疹的发病机制尚未完全阐明。多数患者因找不到确切病因，造成误诊或治疗不及时。既往研究发现肥大细胞活化是慢性荨麻疹发病的中心环节，遗传、自身免疫、凝血功能紊乱和感染等因素也可能参与慢性荨麻疹的病理生理学过程。随着研究的深入，更多的免疫与非免疫机制在慢性荨麻疹发病中的作用逐步被揭示，如荨麻疹微环境中免疫细胞的相互作用、肠道菌群与代谢、神经免疫、环境因素和激素等。阐明慢性荨麻疹的发病机制有助于发现新的治疗靶点，为临床提供多样化的诊疗思路。
Keywords: 慢性荨麻疹, 发病机制, 自身免疫, 肥大细胞
Abstract
Chronic urticaria is very common in clinic, but its pathogenesis is not fully elucidated. Most patients can’t find the exact cause, resulting in misdiagnosis or delayed treatment. Previous studies have found that mast cell activation is the central link in the pathogenesis of chronic urticaria. Genetics, autoimmune, coagulation disorders, and infection may also be involved in the pathophysiological process of chronic urticaria. With the deepening of research, more immune and non-immune mechanisms have been gradually revealed in the pathogenesis of chronic urticaria, such as the interaction of immune cells in the microenvironment of urticaria, intestinal flora and metabolism, neuroimmunity, environmental factors and hormones. Clarifying the pathogenesis of chronic urticaria will help to find more treatment targets and provide more diversified ideas for clinical diagnosis and treatment.
Keywords: chronic urticaria, pathogenesis, autoimmune, mast cell
慢性荨麻疹(chronic urticaria，CU)表现为反复发作超过6周的风团和瘙痒[1]，伴或不伴血管性水肿，是一种常见的免疫相关性皮肤疾病。CU的全球患病率为0.1%~3.4%，中国人群的患病率为2.6%[2]。由于反复发作，迁延不愈，CU会降低患者及其家属的生活质量[3]。根据有无特定的诱发因素，CU分为慢性自发性荨麻疹(chronic spontaneous urticaria，CSU)和慢性诱导性荨麻疹(chronic inducible urticaria， CIndU)[4]。CSU约占CU的2/3，不同类型CU可合并存在[5]。虽然目前一致认为肥大细胞(mast cell，MC)是其病理生理过程中的关键效应细胞，可通过免疫与非免疫机制被诱导活化，但CU的发病机制复杂，近期研究发现CU发病过程中还涉及多种炎症因子、免疫细胞及免疫微环境等。
1.
CSU的发病机制
1.1. 自身免疫
自身免疫在CSU中起关键作用，是CSU最主要的机制之一。MC通过I型自身免疫反应和IIb型自身免疫反应活化并脱颗粒，2种类型的CSU存在不同的临床特征。
I型自身免疫反应又称自身过敏反应，其特征是具有抗自身抗原的IgE抗体[6]。目前已发现的针对自身抗原的IgE抗体包括抗甲状腺过氧化物酶(thyroid peroxidase，TPO)抗体、抗甲状腺球蛋白(thyroglobulin，TG)抗体、抗双链DNA(double-stranded DNA，dsDNA)抗体、抗白细胞介素(interleukin，IL)-24抗体、抗组织因子(tissue factor，TF)抗体等[6-8]。IgE自身抗体通过其高亲和力受体抗IgE Fc受体(IgE Fc receptor，FcεR)I与相应的自身抗原交联导致MC的活化，激活下游的一系列生化反应，引发CSU[9]。
IIb型自身免疫反应的特征是具有抗IgE的IgG自身抗体和/或抗FcεRI的IgG自身抗体[6]。FcɛRI与补体C5a受体均在MC和嗜碱性粒细胞上表达，且被证实在IgG-抗FcɛRI介导的脱颗粒中发挥作用[10]。IIb型自身免疫反应CSU的诊断标准[11]：1)自体血清皮肤试验(autologous serum skin test，ASST)阳性；2)体外嗜碱性粒细胞组胺释放试验(basophil histamine release assay，BHRA)或嗜碱性粒细胞活化标志物阳性；3)针对抗IgE的IgG自身抗体和/或抗FcεRI的IgG自身抗体的免疫测定阳性。PURIST研究[12]的结果表明，约88%的CSU患者至少具有3个IIb型自身免疫反应CSU诊断标准中的1个，不到10%的CSU患者3个标准全部符合，并且这些患者往往表现为更严重的病情、低水平的总IgE和高水平的TPO抗体。此外，研究[13]发现针对FcεRIα的IgM和/或IgA自身抗体可能有助于IIb型自身免疫反应，并且IgM-抗FcɛRIα水平升高与外周血嗜碱性粒细胞计数和嗜酸性粒细胞计数降低有关，是CSU疾病高活动性的标志。
多种自身免疫性疾病可与CSU伴发，最常见的是桥本甲状腺炎(≥21%)和白癜风(2%)[14]。CSU患者合并自身免疫性疾病与女性、自身免疫性疾病家族史以及甲状腺功能减退/亢进的发生率较高有关，并且自身免疫性疾病与IIb型自身免疫反应CSU有关。此外，全基因组关联研究[15]结果显示CSU与自身免疫性疾病之间具有遗传重叠，CSU的易感遗传因素主要通过与自身免疫特征的关联来表现。
1.2. 免疫细胞与炎症因子网络的相互作用
1.2.1. MC活化是CSU的中心环节
MC是CSU的关键效应细胞[4]。MC来自骨髓造血祖细胞，随后迁移到外周组织，并在干细胞因子(stem cell factor，SCF)和IL-3的影响下进行终末分化[16]。MC存在3种亚型：MCT(胰蛋白酶阳性但乳糜酶阴性)、MCTC(胰蛋白酶和乳糜酶均阳性)和MCC(胰蛋白酶阴性但乳糜酶阳性)[17-18]。MCT通常见于肠、肺和鼻等的黏膜组织，必需依赖T细胞才能增殖，MCT数量增加通常与过敏性疾病有关；MCTC主要位于皮肤和胃肠道黏膜下，增殖不依赖于淋巴细胞；MCC可见于腋窝淋巴结、肺黏膜和肠黏膜组织，由于较少被关注，MCC的功能及其在疾病中的作用机制尚不明确，有待进一步研究[18-19]。
MC主要由针对自身变应原的IgE或FcεRI α链的自身抗体通过FcεRI激活，胸腺基质淋巴细胞生成素(thymic stromal lymphopoietin，TSLP)、血浆衍生外泌体、IL-33、IL-4、IL-13、IL-5、补体C5a和MAS相关G蛋白偶联受体-X2(Mas-related G-protein coupled receptor-X2，MRGPRX2)也可激活MC[20-21]。MC活化后释放的各种介质可导致感觉神经激活、血管扩张、血浆外渗以及参与荨麻疹的细胞募集，引起CSU的症状和体征(皮肤瘙痒和血管水肿)[22]。研究发现腺苷[23]、动力相关蛋白1(dynamin-related protein 1，Drp1)[24]和琥珀酸受体1(succinate receptor 1，SUCNR1)[25]也可调节MC的活性，但Drp1和SUCNR1在CSU中的这种作用有待验证。CSU患者的血浆腺苷水平升高，并且腺苷水平可预测重度CSU患者对非镇静H1抗组胺药的无应答者[23]。
1.2.2. 嗜碱性粒细胞和嗜酸性粒细胞参与CSU
嗜碱性粒细胞与MC一样，可以产生组胺、白三烯和细胞因子等，参与CSU风团的诱导。嗜碱性粒细胞还表达FcεRI，可被抗FcεRI自身抗体激活[26]。在CSU患者中经常观察到外周血嗜碱性粒细胞减少，可能是嗜碱性粒细胞从循环迁移到组织的结果[27-28]。奥马珠单抗可能通过降低嗜碱性粒细胞上FcεRI和IgE的密度，使嗜碱性粒细胞从外周血迁移到组织的数量减少，外周血嗜碱性粒细胞增多，从而达到治疗CSU的作用[29]。而血液循环中嗜碱性粒细胞数量降低则提示CSU患者对奥马珠单抗反应不佳[30]。
嗜酸性粒细胞表达低亲和力的IgE受体FcεRII/CD23，可被IgG-抗FcεRII/CD23结合并激活[31]。嗜酸性粒细胞可能通过3种方式参与CU发病：1)产生SCF，促进组织中MC的募集和局部成熟；2)嗜酸性粒细胞蛋白主要碱性蛋白、嗜酸性粒细胞阳离子蛋白和嗜酸性粒细胞过氧化物酶可促进MC脱颗粒；3)活化后表达TF，TF是凝血级联反应中凝血酶的主要激活因子[32]。此外，研究[33]发现10%的CSU患者出现嗜酸性粒细胞减少症，且与IIb型自身免疫反应、疾病高活动度和治疗反应差有关。
1.2.3. T细胞在CSU中起调节作用
辅助性T(T help，Th)1/Th2和Th17相关细胞因子的水平在CSU中显著升高，并与疾病的活动度相关[34-35]。Th1反应通常与ASST阳性有关[34]，但在Prosty等[36]的研究中，ASST阳性和ASST阴性患者之间的Th1细胞丰度评分没有差异；Th2细胞产生IL-4、IL-5和IL-13等多种细胞因子，可刺激IgE的产生及诱导MC、嗜碱性粒细胞和嗜酸性粒细胞的激活[37]。Th17通过分泌细胞因子IL-6促进MC的增殖，并诱导其趋化[38]。调节性T细胞(regulatory cells，Tregs)靶向许多不同的免疫细胞亚群和组织，可防止炎症反应过度并支持组织修复和稳态[39]。体内外证据表明Tregs通过OX40-OX40配体信号抑制MC脱颗粒[40]。研究[41]表明，血液循环中CD4+CXCR5+细胞比例、滤泡辅助性T(T follicular helper，Tfh)细胞比例和Tfh/滤泡调节性T细胞的比值异常均与CSU严重程度呈正相关，提示这些细胞可能参与CSU发病的免疫机制。
1.2.4. 免疫细胞相互作用共同促进CSU的发生和发展
CU的发病机制涉及包括免疫细胞在内的多种细胞(如血管内皮细胞、神经元)的共同参与(图1)。先天免疫和适应性免疫在CSU中存在极其复杂的相互作用，MC是先天免疫和适应性免疫之间的重要纽带[42]：活化的MC通过释放炎症介质和趋化因子[组胺、前列腺素D2、基质金属蛋白酶-9和趋化因子C-X-C模体配体(C-X-C motif ligand，CXCL)1/2等]促进嗜酸性粒细胞、嗜碱性粒细胞、中性粒细胞和T细胞向皮肤迁移[43-46]，来自MC的IL-4、TSLP是先天淋巴样细胞的共刺激细胞因子[47]；嗜碱性粒细胞和T细胞产生IL-4可影响MC的趋化[48-49]；单核细胞通过趋化因子C-C模体配体2(C-C motif ligand 2，CCL2)/单核细胞趋化蛋白-1(monocyte chemotactic protein 1，MCP-1)作用于MC和嗜碱性粒细胞，促进其激活[50]；巨噬细胞可通过分泌IL-6促进MC增殖和成熟，并释放干扰素-λ1(interferon-λ1，IFN-λ1)调节T细胞的发育[51, 52]；B细胞产生的IgE/IgG抗体与MC和嗜碱性粒细胞的FcεRIα结合并导致一系列的活化反应[53]，来自嗜碱性粒细胞的IL-4和IL-6可增强B细胞的存活和增殖[54]；内皮细胞产生的SCF影响MC的发育和成熟，通过迁移抑制因子激活巨噬细胞，通过IL-6、IL-18、肿瘤坏死因子(tumor necrosis factor，TNF)-α和脂肪因子与中性粒细胞相互作用参与CSU的发病[55]；免疫细胞和神经元之间同样存在强烈的相互作用[56-57]。
图1.
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免疫细胞在CSU患者外周血和组织中的相互作用
Figure 1 Interaction of immune cells in peripheral blood and tissue of patients with CSU
Innate immunity and adaptive immunity play extremely complex interactions in CSU through soluble inflammatory factors, microvesicles or cell-to-cell contact. Endothelial cells can participate in the maturation or activation of immune cells through various cytokines, and immune cells in peripheral blood migrate under the action of chemokines released by mast cells. There is a complex interaction between neurons and immune cells in itching and inflammation. CSU: Chronic spontaneous urticaria; IL: Interleukin; MMP-9: Matrix metalloproteinase-9; CXCL: C-X-C motif ligand; CCL2: C-C motif ligand 2; TF: Tissue factor; MCP-1: Monocyte chemotactic protein 1; PGD2: Prostaglandin D2; SCF: Stem cell factor; VCAM-1: Vascular cell adhesion molecule 1; VEGF: Vascular endothelial growth factor; C5a: Complement 5a; MIF: Migration inhibitory factor; IFN-λ1: Interferon-λ1; LTE4: Leukotriene E4; TSLP: Thymic stromal lymphopoietin; MBP: Major basic protein; ECP: Eosinophil cationic protein; EPO: Eosinophil peroxidase; NGF: Nerve growth factor; SP: Substance P; CGRP: Calcitonin gene-related peptide; ILC2: Group 2 innate lymphocytes; GM-CSF: Granulocyte-macrophage colony-stimulating factor.
1.3. 神经-免疫机制
在CSU中，神经元通过释放神经肽如P物质和降钙素基因相关肽(calcitonin gene- related peptide，CGRP)等来调节MC的功能，可能导致血管扩张、血浆外渗；免疫细胞释放的炎症介质和细胞因子[如组胺、IL-31和神经生长因子(nerve growth factor，NGF)]等作用于神经元，可导致神经源性炎症和瘙痒症状[56-57]。MRGPRX2在皮肤MC上高度表达，可由神经肽如P物质激活，并导致MC释放组胺[58]，进而引起CSU患者皮肤反应性的增高[59]。另有研究[60]发现CSU患者的焦虑与抑郁风险是对照组的6倍，CSU对焦虑或抑郁的影响与瘙痒和睡眠障碍有关，有效缓解瘙痒可以促进自然睡眠，从而改善CSU患者的情绪[61]。
1.4. 肠道菌群通过代谢和免疫调控参与CSU的发病
近年来，肠道菌群与CSU之间的关联逐渐受到关注。研究发现CSU患者和健康对照组之间肠道微生物群的α多样性[62]和β多样性[63]存在差异。通过16S核糖体RNA(ribosomal RNA，rRNA)基因测序发现CSU和皮肤划痕症(symptomatic dermographism，SD)患者由于有益菌(主要是产短链脂肪酸菌)的减少，导致短链脂肪酸的生成减少而有害代谢产物(脂多糖)的产生增加[64]，从而通过促进Th2细胞的分化，IgE的产生激活MC，参与CSU的发病。研究[65]发现CU患者血浆脂质代谢特征与健康对照组不同：CU患者血浆磷脂酰丝氨酸、磷脂酰乙醇胺和磷脂酰甘油水平显著升高，而磷脂酰胆碱水平显著下降。以上研究表明CSU患者肠道微生物群组成和代谢物的紊乱以及它们之间的相互作用可能参与了CSU的发病。此外，笔者所在研究组[66]发现毛螺菌科及其下属类群是抗组胺药治疗应答者和无应答者肠道微生物群的主要差异，应答者的毛螺菌科丰度高于无应答者，提示毛螺菌科是抗组胺药在CSU患者中的疗效预测标志。
1.5. 其他机制
部分CSU患者存在家族史，提示遗传因素在CSU的发病中可能存在潜在作用。研究[67]通过飞行质谱法对ORAI钙释放激活钙调节因子1(ORAI calcium release-activated calcium modulator 1，ORAI1)多态性进行基因分型，发现ORAI1基因单核苷酸多态性(single nucleotide polymorphism，SNP) rs12320939和rs3741596与CSU易感性相关，ORAI1基因编码的Orai1参与MC脱颗粒、白三烯分泌、组胺释放以及TNF-α分泌。补体C5a受体1(complement component 5a receptor 1，C5AR1)-1330T等位基因与CSU易感性相关，可作为CSU的危险因素[68]，Fcε受体Ia(Fc epsilon receptor Ia gene，FCER1A) rs2298805等位基因与CSU风险和总IgE血清浓度有关[69]。成年CSU患者与成年健康参与者存在不同的全基因组DNA甲基化谱[70]，表明表观遗传学可能参与CSU的发生和发展。miRNA-196a2位点SNP可能与CSU存在关联，rs11614913位点SNP可能会增加CSU的发病风险[71]。此外，研究[72]发现经地氯雷他定治疗后出现镇静的患者中，组胺受体H1(histamine receptor H1，HRH1) rs901865 G等位基因的频率明显高于rs901865 A等位基因，提示HRH1基因多态性可能与CSU患者地氯雷他定治疗后的镇静副作用有关。
环境因素可能参与CSU的发病，Wang等[73]发现细颗粒物(particulate matter 2.5，PM2.5)通过Gadd45b/促分裂原活化蛋白激酶4(mitogen-activated protein kinase 4，MEKK4)/c-Jun氨基末端激酶(c-Jun N-terminal kinase，JNK)途径调节活性氧的产生，促进IgE介导的MC活化。此外，人类广泛暴露于全氟和多氟烷基物质(per- and polyfluoroalkyl substances，PFAS)环境中，PFAS可能通过食物和饮用水被人体吸收[74]，通过因果中介分析发现IL-4是全氟庚酸与CSU相关性的部分中介(14.8%)，血清中的PFAS水平升高与CSU发病风险增加相关[75]。因此，持续暴露在不利环境因素中可能会导致CSU的发病并加剧其病情。
非免疫学致病因素也参与CSU的发病。例如屋尘螨可能穿过皮肤屏障，直接触发神经元释放P物质，导致MC脱颗粒[76]；性激素可能通过遗传[77]、微生物[78]和环境因素[79]的复杂网络导致女性的CSU患病率较男性高。此外，研究[80]发现凝血-补体系统可通过下游的MC和/或嗜碱性粒细胞激活轴参与CSU的发病。维生素D[81]、金黄色葡萄球菌[82]、热激蛋白[83]和硫醇/二硫化物稳态[84]等也被发现通过各种机制参与CSU的发生。
2.
CIndU发病机制研究进展
CIndU的确切发病机制仍不清楚，但MC的激活、脱颗粒以及随后的炎症介质的释放被认为是关键因素，其中组胺在所有类型的CIndU中都发挥致病作用[85]。肠道生态失调及代谢异常可能参与SD的发生[64, 86]，过敏性炎症和免疫失衡在SD中可能也很关键[87]。另外，最近发现了SD的新变种——食物加重SD和食物依赖性SD[88]。除组胺外，胆碱能性荨麻疹的发病可能还涉及胆碱能药物(如乙酰胆碱)、汗液过敏、自体血清因子(如抗IgE的IgG抗体)、汗腺导管闭塞和少/无汗症[89]，其中少/无汗症可能与汗腺中毒蕈碱乙酰胆碱受体M3(M3 muscarinic acetylcholine receptor，CHRM3)和乙酰胆碱酯酶低表达有关[90]。冷凝集素和冷球蛋白与寒冷性荨麻疹的发病和病程有关[91]，最近，Kulthanan等[92]发现了食物依赖性寒冷性荨麻疹，食物摄入对其他类型的CIndU的影响值得进一步探讨研究。热性荨麻疹的发病机制尚不明确，潜在的触发因素包括温水浴、热空气和阳光照射[93]。日光性荨麻疹的研究十分有限，众多假设(如光过敏、紫外线介导的免疫抑制和遗传/环境因素影响日光性荨麻疹等)有待进一步验证[94]。Zhao等[95]发现来自中国或德国的115例年轻参与者的振动性血管性水肿总体患病率超过14.4%，比预测的更为常见，并且与黏附类G蛋白偶联受体(adhesion G protein-coupled receptor E2，ADGRE2)基因突变无关。水源性荨麻疹的机制已有几种假设：1)水与皮脂或皮脂腺的相互作用；2)涉及水溶性表皮抗原；3)水是表皮或真皮抗原的载体[96]。真皮和皮下组织中的MC被认为是延迟性压力性荨麻疹的关键细胞驱动因素[97]。接触性荨麻疹可由IgE或T细胞介导的免疫反应或非免疫反应引起[98]。
3. 结 语
目前对CU发病机制的研究越来越深入，MC的激活和脱颗粒是CSU发生的核心，自身免疫(IgE/IgG自身抗体)、细胞相互作用(包括免疫细胞在内的多种细胞如MC、嗜酸性粒细胞、嗜碱性粒细胞、T细胞、内皮细胞和神经元等通过炎症因子、微囊泡或细胞间接触发挥复杂的相互作用)、神经-免疫(通过皮肤瘙痒感觉神经介导的组胺依赖和组胺非依赖性瘙痒信号通路)、肠道微生物群(通过代谢和免疫紊乱)、遗传环境因素、凝血补体级联的激活等机制相互关联共同参与CSU的发病。在CIndU中，类似MC激活的机制包括自身过敏和/或自身免疫，可能起到一定作用。进一步的研究应侧重于鉴定MC和嗜碱性粒细胞的激活因子，阐明精神或心理疾病对CU的影响机制，确定不同疾病类型及其生物标志物，以发现更多潜在的治疗靶点，为CU的临床治疗提供新思路和新手段。
基金资助
国家自然科学基金(82173424，81974476)。
This work was supported by the National Natural Science Foundation of China (82173424, 81974476).
利益冲突声明
作者声称无任何利益冲突。
作者贡献
王佳怡 论文构思、撰写与修改；李捷 论文构思、指导与修改。所有作者阅读并同意最终的文本。
原文网址
http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/2023101602.pdf
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