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Two susceptible HLA-DRB1 alleles for multiple sclerosis differentially regulate anti-JC virus antibody serostatus
Mitsuru Watanabe1, Yuri Nakamura1,2,3, Noriko Isobe1,4
1Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
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 (DRB1*15:01 for Caucasians and DRB1*04:05 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-DRB1*15 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-DRB1*15, DRB1*04 carriers had a higher seropositivity rate than non-carriers (84% vs 54%, p = 0.030), and DPB1*04:02 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-DRB1*15 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-DRB1*15-carriers, DRB1*04 was an independent risk factor for the presence of anti-JCV antibody (OR = 5.50, p = 0.023).
Conclusions:
HLA-DRB1*15 is associated with low anti-JCV antibody positive rate and low JCV antibody index, and in the absence of DRB1*15, 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.
Insights
Human leukocyte antigen (HLA) alleles influence JC virus (JCV) antibody status in Japanese multiple sclerosis (MS) patients. HLA-DRB1*15 is linked to lower JCV antibody levels, while DRB1*04 is associated with higher levels in this population.
Area of Science:
- Immunogenetics
- Neuroimmunology
- Viral Immunology
Background:
- Progressive multifocal leukoencephalopathy (PML) is a rare but severe complication of disease-modifying therapies for multiple sclerosis (MS).
- Japanese MS patients on fingolimod exhibit a higher incidence of PML compared to international cohorts.
- Genetic factors, specifically human leukocyte antigen (HLA) class II alleles, may influence susceptibility to JCV infection and PML.
Purpose of the Study:
- To investigate the association between HLA class II alleles and anti-JC virus (JCV) antibody serostatus in Japanese MS patients.
- To determine if HLA alleles modulate the risk of developing anti-JCV antibodies, particularly in patients treated with fingolimod.
Main Methods:
- Study included 128 Japanese MS patients, with 64 on fingolimod.
- Serum anti-JCV antibody positivity and index were measured.
- HLA-DRB1 and -DPB1 alleles were genotyped and analyzed in relation to antibody status.
Main Results:
- HLA-DRB1*15 carriers showed lower anti-JCV antibody positivity and index.
- In the absence of HLA-DRB1*15, DRB1*04 carriers had higher seropositivity rates.
- Fingolimod treatment and duration correlated with increased anti-JCV antibody index; age was positively associated with antibody positivity.
Conclusions:
- HLA-DRB1*15 is associated with reduced anti-JCV antibody levels in Japanese MS patients.
- HLA-DRB1*04 acts as a risk factor for high anti-JCV antibody serostatus in the absence of DRB1*15.
- These findings suggest distinct roles for different HLA-DRB1 alleles in modulating anti-JCV antibody serostatus in MS.
