Demystifying Multiple Sclerosis Etiology: Molecular Mimicry and The Role of Epstein-Barr Virus - Episode 4
Ahmed Obeidat, MD, PhD, comments on other viruses that have been linked to the development of multiple sclerosis and discusses how they can be both protective and detrimental.
Scott Newsome, DO: Let’s jump to other viruses. Ahmed, there have been other viruses implicated in MS [multiple sclerosis], not just pathological but also protective. Do you want to give a few comments about that? If we’re going to think about viruses in the context of MS in general, it’s important to consider other viruses, especially those that may have a protective effect.
Ahmed Obeidat, MD, PhD: As we think about multiple sclerosis in relation to viruses, this is an issue that people have looked at over the years. When I was an attending resident at the NIH [National Institutes of Health Clinical Center Grand Rounds], I doing a rotation, and Professor [John] Kurtzke said that MS is caused by an infection. This is 1 of the theories behind the epidemiological distribution of MS.
Viruses are something we think about as we think about multiple sclerosis. When I think about multiple sclerosis in relation to viruses, there was work looking at other herpesviruses, including herpes simplex viruses and meta-analyses showing some increased providence of it in people living with MS. At CMSC [Consortium of Multiple Sclerosis Centers Annual Meeting] there wasn’t an increase in our patient population, but we saw an increase in the EBV serology. We didn’t see this in herpes simplex 1 or 2 when compared with non-MS neuroimmunology that we can control. People have other autoimmune diseases, but they don’t have MS. There was some distinction there with our small cohort.
I’m also intrigued by people who live with HIV or AIDS but also live with MS. It’s very rare to see this combination. People think [that those] infected with retroviruses may not develop multiple sclerosis. The main cell that HIV targets is CD4. Those cells can die. The immune system will try to make more, and time is the differentiation. But we can’t keep up with the rate of distraction with the virus. Those patients may be at a lower risk of developing MS; we don’t know. Is it the chicken or the egg? People have even looked at the role of antiretroviral therapy. Is this something that will work in MS? Some clinical trials look at this.
The other virus I think about is CMV, or cytomegalovirus. This virus targets the CD8, which is cytotoxic T cells. Those cells cannot result in premature aging of the cells. They cannot talk about the concept of immune signal cells in people who may be infected with CMV. They may be early immune signal cells. That’s another virus that has a relationship to the immune system.
One other interesting virus is SARS-CoV-2 the virus that causes COVID-19. We hear about the long COVID-19 syndrome. Maybe there’s some immune dysregulation in the innate and adaptive immune system related to the virus in the long term. This is still a matter of research. The viruses and the immune system are intertwined. Those viruses can modify, change, dysregulate, or even restore some regulation of the immune system in patients who may have immune dysregulation.
We can go on and on about those viruses and the immune system, but those are the ones I think about as I think about MS, the immune system, and the viruses.
Lawrence Steinman, MD: Could I interject with an interesting anecdote? You mentioned HIV being known to attack CD4. It’s widely held that anti-CD20 therapies [have been successful]. We like to think of MS as B-cell disease, and this is further kindled by EBV, which infects B cells. About 35 years ago, a group decided to try anti-CD4 therapy to treat MS. There was something called AIDS at the time, which turned out to be HIV, and we were petrified of lowering the CD4 count much below 50% because there were all sorts of opportunistic infections. Unlike what we’re doing with the abandon in anti-CD20 therapy to lower the CD20 count to about 90%, sometimes 95% or 99%, we stopped at about 50%, and we did not hit the primary end point.
A covariate analysis showed, however, that there was a strong correlation between the reduction of GAD [gadolinium] activity if the count was lowered. Some people who mounted a very strong reduction, and they had really good outcomes. Anti-CD4 never gained a place in the armamentarium we have, and for a very good reason. But when we talk about MS as a B-cell disease, we have to remember that you can’t have a B-cell disease without CD4-helper T cells.
Amit Bar-Or, MD, FRCPC: We had thought of MS as a T-cell–mediated disease. We should be transitioning to it being not a B-cell–mediated disease but a disease of cellular interactions. There are interactions between B cells and T cells, myeloid cells, and perhaps others that can explain much of what we think about in terms of MS pathophysiology.
With respect to EBV, if you think of MS pathophysiology, you can think of initiating mechanisms and what’s involved in the development of the disease. Propagating mechanisms don’t necessarily have to be the same as initiating mechanisms. In MS, we think of at least 2 types of biological processes that can contribute to injury. There’s the relapse-related biology, which are peripheral immune cell interactions that result in inappropriate activation or insufficient regulation and trafficking, vs CNS [central nervous system]–compartmentalized inflammation that we increasingly think is involved in progressive disease.
As we think of EBV, where it may be acting on MS pathophysiology, and where and how we may want to intervene, it’s worth considering separately that EBV is strongly implicated as necessary but insufficient for the development of MS. The question is, is it responsible for every MS attack? Perhaps through B-cell activation, B-cell and T-cell interactions, or other mechanisms. And by virtue of being in the CNS, is it also responsible for propagating CNS-compartmentalized inflammation and injury of progressive disease? At the extreme, it’s responsible for everything, from the beginning to relapsing and progressive disease. But I wouldn’t lump it all together. We need to think of those separately and each case on its own.
Transcript Edited for Clarity