Association of B-cell activating factor gene variants with serum anti-JCV antibody positivity in male patients with multiple sclerosis under natalizumab treatment: Implications for progressive multifocal leukoencephalopathy risk stratification

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 fa...

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Bibliographic Details
Published in:Journal of the neurological sciences 2024-06, Vol.461, p.123046, Article 123046
Main Authors: Skarlis, Charalampos, Papadopoulos, Vassilis, Raftopoulou, Sylvia, Mavragani, Clio P., Evangelopoulos, Maria-Eleftheria
Format: Article
Language:English
Subjects:
B-cell activating factor (BAFF) gene variants
JCV
John Cunningham virus
Multiple sclerosis (MS)
Natalizumab
Progressive multifocal leukoencephalopathy (PML)
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Summary: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. •Peripheral blood BAFF gene expression significantly correlates with anti-JCV serum titers in MS patients.•The BAFF TTT haplotype significantly associates with anti-JCV seropositivity in male MS patients treated with natalizumab.•The BAFF TTT haplotype may represent a novel risk factor for JCV seropositivity and, consequently, PML in male MS patients.
ISSN:0022-510X
1878-5883
1878-5883
DOI:10.1016/j.jns.2024.123046