两种易患多发性硬化症的 HLA-DRB1 等位基因与芬戈莫德一起，对抗 JCV 抗体血清阳性状态具有不同的调节作用。

Two susceptible HLA-DRB1 alleles for multiple sclerosis differentially regulate anti-JC virus antibody serostatus along with fingolimod.

机构信息

Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Department of Neurology, Brain and Nerve Center, Fukuoka Central Hospital, International University of Health and Welfare, 2-6-11 Yakuin, Chuo-ku, Fukuoka, 810-0022, Japan.

出版信息

J Neuroinflammation. 2020 Jul 9;17(1):206. doi: 10.1186/s12974-020-01865-7.

DOI:10.1186/s12974-020-01865-7

PMID:32646493

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7350631/

Abstract

BACKGROUND

Progressive multifocal leukoencephalopathy (PML) caused by JC virus (JCV) is a rare but serious complication of some disease-modifying drugs used to treat multiple sclerosis (MS). Japanese MS patients treated with fingolimod were reported to be 10 times more likely to develop PML than equivalent patients in other countries. The strongest susceptibility human leukocyte antigen (HLA) class II alleles for MS are distinct between races (DRB115:01 for Caucasians and DRB104:05 and DRB1*15:01 for Japanese); therefore, we investigated whether HLA class II alleles modulate anti-JCV antibody serostatus in Japanese MS patients with and without fingolimod.

METHODS

We enrolled 128 Japanese patients with MS, in whom 64 (50%) were under fingolimod treatment at sampling, and examined the relationship between HLA class II alleles and anti-JCV antibody serostatus. Serum anti-JCV antibody positivity and index were measured using a second-generation two-step assay and HLA-DRB1 and -DPB1 alleles were genotyped.

RESULTS

HLA-DRB115 carriers had a lower frequency of anti-JCV antibody positivity (57% vs 78%, p = 0.015), and lower antibody index (median 0.42 vs 1.97, p = 0.037) than non-carriers. Among patients without HLA-DRB115, DRB104 carriers had a higher seropositivity rate than non-carriers (84% vs 54%, p = 0.030), and DPB104:02 carriers had a higher anti-JCV antibody index than non-carriers (3.20 vs 1.34, p = 0.008) although anti-JCV antibody-positivity rates did not differ. Patients treated with fingolimod had a higher antibody index than other patients (1.46 vs 0.64, p = 0.039) and treatment period had a positive correlation with antibody index (p = 0.018). Multivariate logistic regression analysis revealed that age was positively associated, and HLA-DRB115 was negatively associated with anti-JCV antibody positivity (odds ratio [OR] = 1.06, p = 0.006, and OR = 0.37, p = 0.028, respectively). Excluding HLA-DRB115-carriers, DRB1*04 was an independent risk factor for the presence of anti-JCV antibody (OR = 5.50, p = 0.023).

CONCLUSIONS

HLA-DRB115 is associated with low anti-JCV antibody positive rate and low JCV antibody index, and in the absence of DRB115, DRB1*04 carriers are associated with a high antibody positive rate in Japanese, suggesting the effects of two susceptible HLA-DRB1 alleles on anti-JCV antibody serostatus differ.

摘要

背景

JC 病毒（JCV）引起的进行性多灶性白质脑病（PML）是一些用于治疗多发性硬化症（MS）的疾病修正药物的罕见但严重的并发症。接受芬戈莫德治疗的日本 MS 患者发生 PML 的风险比其他国家的等效患者高 10 倍。与种族相比，MS 最强的易感人类白细胞抗原（HLA）II 类等位基因是不同的（白种人为 DRB115:01，日本人则为 DRB104:05 和 DRB1*15:01）；因此，我们研究了 HLA II 类等位基因是否调节日本 MS 患者有无接受芬戈莫德治疗时的抗 JCV 抗体血清状态。

方法

我们纳入了 128 名日本 MS 患者，其中 64 名（50%）在采样时正在接受芬戈莫德治疗，并检测了 HLA II 类等位基因与抗 JCV 抗体血清状态之间的关系。使用第二代两步检测法测量血清抗 JCV 抗体的阳性率和指数，并对 HLA-DRB1 和-DPB1 等位基因进行了基因分型。

结果

与非携带者相比，HLA-DRB115 携带者的抗 JCV 抗体阳性率较低（57% vs 78%，p=0.015），抗体指数也较低（中位数 0.42 vs 1.97，p=0.037）。在没有 HLA-DRB115 的患者中，DRB104 携带者的血清阳性率高于非携带者（84% vs 54%，p=0.030），而 DPB104:02 携带者的抗 JCV 抗体指数高于非携带者（3.20 vs 1.34，p=0.008），尽管抗 JCV 抗体阳性率没有差异。接受芬戈莫德治疗的患者的抗体指数高于其他患者（1.46 vs 0.64，p=0.039），治疗时间与抗体指数呈正相关（p=0.018）。多变量逻辑回归分析显示，年龄与抗 JCV 抗体阳性呈正相关，而 HLA-DRB115 与抗 JCV 抗体阳性呈负相关（比值比[OR]分别为 1.06，p=0.006 和 OR 为 0.37，p=0.028）。排除 HLA-DRB115 携带者后，DRB1*04 是抗 JCV 抗体存在的独立危险因素（OR 为 5.50，p=0.023）。