IgG_(4)相关性疾病的临床特征及淋巴细胞亚型分析

Clinical features and lymphocyte subtypes in patients with IgG_(4)-related diseases

目的探讨IgG_(4)相关性疾病(IgG_(4)-RD)患者的临床特征,分析淋巴细胞亚型以及潜在的发病机制及免疫治疗靶点。方法横断面研究。回顾性收集2018年1月至2022年2月在天津医科大学总医院就诊的IgG_(4)-RD患者86例。分析患者的人口学资料、症状和体征、器官受累情况、实验室指标、淋巴细胞亚型、组织病理学表现及治疗情况。结果86例IgG_(4)-RD患者的平均发病年龄为36~87(62±11)岁,其中男性51例(59.3%),女性35例(40.7%),34.9%的患者有过敏史,随访时间为4.8(0.4,14.1)个月。最常见的症状体征为腹痛、颌下腺肿大、泪腺肿大(各占20.9%)。75.6%的患者受累器官超过1个,最常见的受累器官为胰腺(52.3%)、颌下腺(51.2%)和泪腺(34.9%)。18.8%(16/85)伴随嗜酸性粒细胞比例升高,30.0%(24/80)IgE升高,61.2%(52/85)补体C3减低,50.0%(42/84)补体C4减低,72.9%(62/85)IgG升高,58.3%(28/48)IgG1升高,89.5%(77/86)IgG_(4)升高。64.7%(55/85)存在自身抗体阳性,最常见的阳性自身抗体是抗核抗体(ANA)(63.5%)。25.7%(9/35)CD4^(+)T淋巴细胞比例升高,22.9%(8/35)CD4^(+)/CD8^(+)T淋巴细胞比值升高,90.0%(18/20)调节性T细胞(Treg)比例升高。50.0%(11/22)IL-2升高,33.3%(10/30)IL-6升高,16.7%(5/30)IL-10升高。79.2%(42/53)存在大量淋巴浆细胞浸润,67.9%(36/53)存在纤维化,35.8%(19/53)IgG_(4)阳性/IgG阳性浆细胞>40%,且每高倍镜视野IgG_(4)阳性浆细胞>10个,30.2%(16/53)淋巴滤泡增生或异位形成。应用2011年日本研究小组提出的标准对53例具有详尽病理资料的患者进行评价,24.5%(13/53)可确定诊断,3.8%(2/53)很可能诊断,67.9%(36/53)可能诊断,3.8%(2/53)不能诊断。治疗后6个月,EOS%、IgE、IgG、IgG_(4)显著下降,补体C3、C4显著升高(均P<0.05),而且治疗后6个月的IgG_(4)水平与基线时的C4呈负相关,与IgE、IgG_(4)/IgG呈正相关。结论IgG_(4)-RD是一组男性多发,多器官受累,伴随嗜酸性粒细胞、IgE、IgG、IgG1、IgG_(4)升高,补体降低的免疫性疾病。外周血CD4^(+)T淋巴细胞、Treg比例相对升高。糖皮质激素和免疫抑制剂治疗有效,治疗后6个月的IgG_(4)水平与基线时的补体C4水平呈负相关,与IgE水平、IgG_(4)/IgG呈正相关。

Objective To deepen understanding of IgG_(4)-related diseases(RDs),we analyzed the associated lymphocyte subtypes,and explored the pathogenesis and potential immunotherapeutic targets.Methods Eighty-six patients with IgG_(4)-RDs were enrolled,and their clinical characteristics,peripheral lymphocyte subtypes,and disease course were analyzed.Results The mean age of the participants was 36-87(62±11)years;51 were male(59.3%)and 35 were women(40.7%);and 34.9%had a history of allergy.Follow-up lasted 4.8(0.4,14.1)months.The most common symptoms were abdominal pain,and submandibular gland and lacrimal gland swelling(each 20.9%).Sixty-five(75.6%)participants had multiple organ involvement,and the most frequently affected organs were the pancreas(52.3%),submandibular gland(51.2%),and lacrimal gland(34.9%).A high eosinophil count;high IgE,IgG,IgG1,and IgG_(4) concentrations;and low complement C3 and C4 concentrations were present in 18.8%(16/85),30.0%(24/80),72.9%(62/85),58.3%(28/48),89.5%(77/86),61.2%(52/85),and 50.0%(42/84),respectively,of the participants.In addition,64.7%(55/85)were positive for autoantibodies,and the most frequent was anti-nuclear antibody(63.5%).The proportion of CD4^(+)T lymphocytes increased in 25.7%(9/35)of the participants,which was accompanied by an increase in the ratio of CD4^(+)/CD8^(+)T lymphocytes(22.9%,8/35).Importantly,most participants(90.0%,18/20)had a high proportion of regulatory T(Treg)cells.High interleukin(IL)-2,IL-6,and IL-10 concentrations were present in 50.0%(11/22),33.3%(10/30),and 16.7%(5/30),respectively,of the participants.Substantial lymphoplasmacytic infiltration,fibrosis,IgG_(4)-positive plasma cell infiltration,and lymphoid follicle hyperplasia or ectopic formation were present in 79.2%(42/53),67.9%(36/53),35.8%(19/53)and 30.2%(16/53),respectively,of the participants.Fifty-three participants with detailed pathologic data were also further evaluated,of whom 24.5%(13/53),3.8%(2/53),and 67.9%(36/53)had definite,probable,and possible diagnoses;and 3.8%(2/53)could not be diagnosed.Compared with baseline,the percentage of eosinophils and the IgE,IgG,and IgG_(4) concentrations decreased significantly;and the complement C3 and C4 concentrations had increased significantly after 6 months of treatment(all P<0.05).The IgG_(4) concentration after 6 months of treatment negatively correlated with that of C4,and positively correlated with the baseline concentration of IgE and the IgG_(4)/IgG ratio.Conclusion IgG_(4)-RDs are a group of diseases characterized by male predisposition;multiple organ involvement;a high eosinophil count;high IgE,IgG,IgG1,and IgG_(4) concentrations;and a low C3 concentration.Peripheral CD4^(+)T cells and Treg cells are also more abundant.The diseases can be controlled with glucocorticoids and immunosuppressive drugs in the majority of instances.The IgG_(4) concentration after 6 months of treatment negatively correlates with the baseline complement C4 concentration and positively correlates with the IgE concentration and IgG_(4)/IgG ratio,which suggests that IgG_(4)/IgG,IgE,and complement should be closely monitored to evaluate disease activity and the efficacy of treatment in such patients.