Antibody reactivity against EBNA1 and GlialCAM differentiates MS patients from healthy controls, 2025,Neda Sattarnezhad et al

Significance
Multiple sclerosis (MS) is an autoimmune disease of the brain and spinal cord, leading to disability in young adults. Infection with Epstein–Barr virus (EBV) is a prerequisite for developing the disease.
We previously demonstrated that antibody responses against the virus protein EBV nuclear antigen 1 (EBNA1) cross-react with brain proteins of MS patients and contribute to the disease. Here, we confirm in a large cohort of MS patients and controls that the presence of these antibodies increases the risk for MS, and we correlate them with the major genetic risk factor for MS.
A combination of multiple antibodies and the genetic risk factor increases the risk for MS in an additive fashion.

Abstract
Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system (CNS), which is linked to Epstein–Barr virus (EBV) infection, preceding the disease. The molecular mechanisms underlying this connection are only partially understood. We previously described molecular mimicry between the EBV transcription factor EBV nuclear antigen 1 (EBNA1) and three human CNS proteins: anoctamin-2 (ANO2), alpha-B crystallin (CRYAB), and glial cellular adhesion molecule (GlialCAM).

Here, we investigated antibody responses against EBNA1 and GlialCAM in a large cohort of 650 MS patients and 661 matched population controls and compared them to responses against CRYAB and ANO2.

We confirmed that elevated IgG responses against EBNA1 and all three CNS-mimic antigens associate with increased MS risk. Blocking experiments confirmed the presence of cross-reactive antibodies and molecular mimicry between EBNA1 and GlialCAM, and accompanying antibody responses against adjacent peptide regions of GlialCAM suggest epitope spreading. Antibody responses against EBNA1, GlialCAM, CRYAB, and ANO2 are elevated in MS patients carrying the main risk allele HLA-DRB1*15:01, and combinations of HLA-DRB1*15:01 with anti-EBNA1 and anti-GlialCAM antibodies increase MS risk significantly and in an additive fashion.

In addition, antibody reactivities against more than one EBNA1 peptide and more than one CNS-mimic increase the MS risk significantly but modestly.

Overall, we show that molecular mimicry between EBNA1 and GlialCAM is likely an important molecular mechanism contributing to MS pathology.
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I have no way to assess the quality of this study, but this kind of work gets me more excited about DecodeME and SequenceME. And while it’s probably too late for my family member with very severe MS, they might be able to help others in the future.

 

authors: Stanford
Journal: PNAS.
cases: 650
controls:661.
p-values: some very low indeed.

tl;dr this study is more likely than most to have found something that is true.

That is exciting since what they have found looks relevant and novel.