HLA-DRB1*04:05 in Epstein-Barr virus-seronegative multiple sclerosis: a Japanese single-center study

Epstein-Barr virus (EBV) infection is now regarded as a near-prerequisite for the development of multiple sclerosis (MS), and EBV-seronegative MS is rare. In the Japanese population, HLA-DRB1*04:05 is a major MS-susceptibility allele, and a previous Japanese study reported that EBV-seronegative MS patients were more likely to carry this allele. However, that study preceded the routine measurement of myelin oligodendrocyte glycoprotein (MOG) antibodies, leaving open the possibility that patients with MOG antibody-associated disease were included.

We retrospectively reviewed 123 consecutive Japanese patients with MS who fulfilled the 2017 McDonald criteria and were negative for both anti-aquaporin-4 and anti-MOG antibodies. Serum anti-Epstein-Barr nuclear antigen (EBNA) antibody and anti-viral capsid antigen (VCA) IgG were measured before the initiation of disease-modifying therapy. HLA-DRB1 genotyping was performed in patients seronegative for both antibodies. The observed number of DRB1*04:05 carriers was compared with published carrier frequencies using an exact binomial test.

Three of 123 patients (2.4%) were seronegative for both anti-EBNA antibody and anti-VCA IgG. All three carried HLA-DRB1*04:05 in the heterozygous state, whereas the second allele differed among them (*14:03, *14:54, and *11:01). DRB1*04:05 was therefore the only allele shared by all three patients. Taking the reported carrier frequency of DRB1*04:05 in Japanese MS (39.6%) as the reference, the probability of observing three carriers among three patients by chance was 0.062 (exact binomial test), which does not reach statistical significance. All were female, with an early age at onset (17, 19, and 26 years) and a low Expanded Disability Status Scale score (2, 0, and 1).

All EBV-seronegative MS patients in this cohort carried HLA-DRB1*04:05. Because the number of seronegative cases is very small, this observation is hypothesis-generating rather than confirmatory: it is compatible with, but does not establish, the possibility that DRB1*04:05 confers resistance to EBV infection or an attenuated humoral response to the virus. Larger, genotyped cohorts are required to determine whether EBV-seronegative MS represents a distinct entity.