Lawrence Steinman, MD, discusses his recent publication, which demonstrated the causal link between Epstein-Barr virus and multiple sclerosis, highlighting key findings and conclusions.
Scott Newsome, DO: Larry, your group’s study clearly broke down in a mechanistic way how EBV [Epstein-Barr virus] could be related to MS [multiple sclerosis]—a causal link, not just an epidemiological link. Could you describe your study, how it differs also from the prior studies, and how it may complement? Is there anything you want to tell the audience that you feel is quite relevant?
Lawrence Steinman, MD: I’ll tell you the points in favor and against how EBV and that molecular mimicry may play a role. It certainly plays a role in the triggering but may also play a role in propagation. Just to review, there’s a piece of the EBNA1 that resembles a protein in the white matter of the brain called GlialCAM. There are about 6 or 7 amino acids in a row that are identical. Some beautiful structural studies with x-ray diffractions showed how the clonal antibodies in the spinal fluid recognize that segment of EBNA1. It’s a segment that’s very rich in prolines, but nearby in the segment are serines. If those serines are phosphorylated, then the binding gets even stronger.
One interesting thing is that phosphorylation is triggered by kinases. There are various kinases that showed up in … Jiwa’s studies. They were considered minor hits. In other words, they weren’t anything resembling HLA class 2. Nevertheless, whether you have a certain kinase may make the difference between you having EBV, mono, or that bifurcation where you didn’t even know you had EBV but ended up with MS. Those phosphorylation steps are important.
In the paper, we looked at other clonal expansions. There was a signal for a measles clonal expansion, an antimeasles clonal expansion, an antirubella, and an anti–varicella zoster—the famous MRZ reactions. One enigma is why, in MS and a few other diseases—neurosyphilis was the first that was studied in the 1950s with agarose gels, and they saw an expansion of immunoglobulin—do we have these clonal expansions? Are we meant to say that the only clonal expansion that makes a difference is the 1 reacting to EBNA1 in EBV? That’s a big unknown. There’s a lot to learn.
Most of us would have reasoned that those clonal expansions would sooner or later give us an aha answer. Along the way, there’s been some great work by many people all over the world. One clonal expansion, just to be clear, reacted to a certain part of the myelin basic protein. That may still play a role in progression of disease. I’ll call attention to 1 other remarkable finding: with the Karolinska [Institutet] group, Tomas Olsson and colleagues studied a molecule called anoctamin-2. In their initial studies, they didn’t look so much at anoctamin-2 in the spinal fluid. They looked at anoctamin-2 antibodies. They found out that anoctamin-2 is a molecular mimicry of EBNA1, and it’s a chloride channel.
Interestingly GlialCAM is called the chaperone. It’s a close accompaniment of a chloride channel. Here we have 2 molecular mimics within a very small region of EBNA1, and not far away is the molecular mimic to myelin basic protein. This was work from the Oklahoma Medical Research Foundation. Is that area of EBNA1 a hot spot? I’m conflating a lot of issues. Is the EBNA1 molecular mimic the only thing important? Are other clonal expansions important or not? That has to be resolved.
Let me add 1 more piece of information that shows how imperfect this story is. In our study, we saw that about 25% to 30% of patients have anti-GlialCAM antibodies in the blood. In the studies on anoctamin-2, Olsson and the Karolinska group showed that it was 14%. Even if you add those 2 together, only about 40% of people who have those antibodies. From our COVID-19 vaccines, we’re all a little wiser about what having an antibody in the peripheral blood means to long-term immunity. We heard early on from people saying the antibody in the blood is evanescent; it goes away. The good news is your immunity doesn’t wane nearly as much as the decay of your peripheral antibody to the SARS-CoV-2 [severe acute respiratory syndrome coronavirus 2] spike protein.
The snapshots of what the GlialCAM anoctamin-2 antibody levels are in the blood may only be a snapshot of part of the response. T cells have to be studied in more depth. But those are some of the major unresolved questions. I covered a lot of things, both the pros and the cons.
Scott Newsome, DO: I have a question. Given what you just said, what caught my attention is sampling. When you take the sample in the continuum, you may get different things within the blood. When you decide with a study as you did, how do you decide when you take the blood sample? Do you do it in early stage, later stage, a mix, relapse, not relapsing?
Lawrence Steinman, MD: Here’s the most encouraging answer. We’ve been on the phone, and we have collaborations for longitudinal studies on all those types of patients teed up with Alberto Ascherio’s group and with the Karolinska group. I invite everyone on this call to join in. We have to have a full-court press with lots of samples. Studying the disease longitudinally is going to be really important and, when possible, sampling both the blood compartment and the CNS [central nervous system] compartment.
Transcript Edited for Clarity