Department of Physiology, School of Medicine, National and Kapodistrian University of Athens, M. Asias 75, 11527 Athens, Greece.
First Department of Neurology, School of Medicine, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece.
J Neurol Sci. 2024 Jun 15;461:123046. doi: 10.1016/j.jns.2024.123046. Epub 2024 May 12.
Progressive multifocal leukoencephalopathy (PML) is a potentially life-threatening complication among Multiple Sclerosis (MS) patients under natalizumab treatment, with serum anti-JCV antibody titers being used for stratification risk. Given the critical role of interferon (IFN)/B-cell activating factor (BAFF) axis in humoral immune responses against viruses, we explored whether it is involved in the generation of serum anti-JCV antibodies among these patients.
162 consecutive patients with relapsing-remitting MS under natalizumab treatment were included. Serum anti-JCV antibodies were measured at baseline, as well as 12 and 24 months after treatment initiation. Type I and II IFN-inducible genes and BAFF expression were quantitated in peripheral blood by qRT-PCR. Moreover, BAFF rs9514828, rs1041569, and rs9514827 gene variants were assessed by RFLP-PCR.
While type I and II IFN inducible gene expression were not associated with anti-JCV serum titers, the latter were significantly correlated with BAFF gene expression. Of interest, the TTT haplotype of the studied BAFF variants was more frequently detected in male, but not female anti-JCV (+) MS patients compared to anti-JCV (-) counterparts at baseline, as well as at 12 months and 24 months of natalizumab treatment. Measures of clinical validity/utility for the BAFF TTT haplotype showed 88% specificity, 45%, positive predictive value, and sensitivity of 70% for the discrimination of anti-JCV (+) male MS patients after 24 months of treatment.
Our study suggests an implication of the BAFF axis in the production of serum anti-JCV antibodies. Additionally, the BAFF TTT haplotype derived from the rs9514828, rs1041569, and rs9514827 variants may represent a novel risk factor for anti-JCV seropositivity and indirectly for PML development among male MS patients treated with natalizumab.
在接受那他珠单抗治疗的多发性硬化症（MS）患者中，进行性多灶性白质脑病（PML）是一种潜在的致命并发症，血清抗 JCV 抗体滴度用于分层风险。鉴于干扰素（IFN）/B 细胞激活因子（BAFF）轴在针对病毒的体液免疫反应中的关键作用，我们探讨了它是否参与了这些患者血清抗 JCV 抗体的产生。
纳入 162 例接受那他珠单抗治疗的复发缓解型 MS 患者。在治疗开始时、治疗开始后 12 个月和 24 个月时测量血清抗 JCV 抗体。通过 qRT-PCR 定量检测外周血中 I 型和 II 型 IFN 诱导基因和 BAFF 的表达。此外，通过 RFLP-PCR 评估 BAFF rs9514828、rs1041569 和 rs9514827 基因变异。
虽然 I 型和 II 型 IFN 诱导基因的表达与抗 JCV 血清滴度无关，但后者与 BAFF 基因表达显著相关。有趣的是，与抗 JCV（-）MS 患者相比，在基线以及接受那他珠单抗治疗 12 个月和 24 个月时，研究中 BAFF 变异的 TTT 单倍型在男性而非女性抗 JCV（+）MS 患者中更频繁地检测到。在治疗 24 个月后，BAFF TTT 单倍型对男性抗 JCV（+）MS 患者的区分具有 88%的特异性、45%的阳性预测值和 70%的敏感性，是一种有效的临床诊断标志物。
我们的研究表明，BAFF 轴在血清抗 JCV 抗体的产生中起作用。此外，来自 rs9514828、rs1041569 和 rs9514827 变异的 BAFF TTT 单倍型可能是男性 MS 患者接受那他珠单抗治疗后抗 JCV 血清阳性和间接 PML 发展的新的危险因素。
