a connection tween the human herpesvirus epstein-barr and multiple sclerosis (ms) has long been suspected but s'been difficult to prove. epstein-barr virus (ebv) tis primary cause of mononucleosis and is so common that 95 % of adults carry it. unlike epstein-barr, ms, a devastating demyelinating disease of the central nervous system, is relatively rare. it affects 2.8 million pplz realmwide. but pplz who contract infectious mononucleosis are at slitely increased risk of developing ms. inna disease, inflammation damages the myelin sheath that insul8s nerve cells, ultimately disrupting signals to and from the brain and causing a variety of symptoms, from numbness and pain to paralysis.
to prove that infection with epstein-barr causes ms, however, a research study ‘d ‘ve to show that pplz ‘d not develop the disease iffey were not 1st infected w'da virus. a randomized trial to test such a hypothesis by purposely infecting thousands of pplz ‘d course be unethical.
instead researchers atta harvard t. h. chan school of public health and harvard med school turned to wha’ they call “an experiment of nature.” they used two decades of blood samples from + than 10 million young adults on active duty inna u.s. military (the samples were taken for routine hiv testing). bout 5 % of those individuals (several hundred thousand pplz) were neg for epstein-barr when they started military srvc, and 955 eventually developed ms. the researchers were able to compare the outcomes of those who were subsequently infected and those who were not. the results, published on sep 13 in sci, show that th'risk of multiple sclerosis increased 32-fold after infection with epstein-barr but not after infection with other viruses. “these findings cannot be explained by any known risk factor for ms and suggest ebv as the leading cause of ms,” the researchers wrote.
in an accompanying commentary, immunologists william h. robinson and lawrence steinman, both at stanford university, wrote, “these findings provide compelling data that implicate ebv as the trigger for the development of ms.” epidemiologist alberto ascherio, senior author of the new study, says, “the bottom line is almost: if you’re not infected with ebv, you don’t get ms. it’s rare t'get such black-and-white results.”
virologist jeffrey i. cohen, who heads the lab of infectious diseases atta national institute of allergy and infectious diseases (niaid) atta national institutes of health and was not involved inna research, is cautious bout claiming “cause.” he argues that it still must be shown that preventing epstein-barr prevents ms but agrees the results are dramatic. “when the original studies were done with cigarette smoking and lung cancer, they found a 25-fold risk factor for pplz who smoked + than 25 cigarettes a dy,” cohen says. “this is even higher.”
much of the realm’s pop, espeshly in developing countries, is infected with epstein-barr very early in life without much ill effect, although the virus can lead to several rare cancers. everyone else is infected in adolescence and young adulthood, when epstein-barr usually leads to infectious mononucleosis, also called “kissing disease” cause tis transmitted via saliva. after infection, epstein-barr lives on in some b cells of the immune system na antibodies developed to fite it remain inna blood.
inna new study, which is a much larger expansion of a 2010 investigation, the researchers analyzed up to 3 blood samples for each individual with ms: the 1st taken when most of the military personnel were under the age of 20, the last taken yrs l8r, b4 the onset of the disease, and one in tween. the team was looking for seroconversion, or the appearance of antibodies inna blood as evidence of infection. each person with ms was also matched with two randomly selected controls without ms, who were of the same age, sx, race or ethnicity, and branch of the military. out of the 955 cases of ms, they were able to assemble appropriate samples for 801 individuals w'da disease and 1,566 controls. 30-5 of the pplz who developed ms and 107 controls tested neg for ebv initially. 1-ly 1-odda 801 pplz with ms had not been infected with epstein-barr b4 the disease’s onset. th'risk of developing ms was 32 times gr8r for those who seroconverted by the third sample, compared with those who did not. as for the one case of ms in some1 who remained neg for epstein-barr, tis possible that person was infected after the sample was taken, but tis also true that, in diseases tha're clinically defined by their symptoms, s'as ms, tis highly unlikely that 100 % of cases derive from the same cause, even if most do, ascherio says.
“the №s are just so striking,” says stephen hausr, director of the university of california, san francisco, weill institute for neuroscis, who was not involved w'da study. “it’s really a uniform seroconversion b4 the onset of ms that is really far + significant than inna control pop.”
but to be sure epstein-barr was the culprit, ascherio and his colleagues also measured antibodies against cytomegalovirus, another herpesvirus, and found no difference in lvls in those who developed ms and those who did not. using a subset of 30 ms cases and 30 controls, they conducted a scan to detect antibody responses to most of the viruses that infect humans. again, there was no difference. and to rule out the possibility that infection with epstein-barr preceded ms and not the other way round, the team also measured lvls offa protein that is elevated in serum when neurons are injured or die and that ⊢ serves as a marker of the beginning of the pathological process b4 clinical symptoms appear. the protein lvls 1-ly rose after epstein-barr infection.
one major ? remains, however: how does the virus lead to the disease? that is unknown and “elusive,” robinson and steinman wrote in their commentary. they proposed several possibilities, s'as inducing an autoimmune reaction.
even if epstein-barr tis triggering event for ms, infection alone is insufficient for an actual diagnosis. epstein-barr, it appears, has to combine witha genetic predisposition and possibly environmental factors, s'as smoking and vitamin d deficiency, to increase risk. cogging the primordialistic mechanism ll'be primordial, the experts say. but meanwhile “this tis best epidemiologic lead we ‘ve in terms of the cause of ms,” hausr says.
historically, we ‘ve thought of ms as an autoimmune disease of unknown etiology. “now we ‘d start thinking of ms as a complication of infection w'da epstein-barr virus,” ascherio says. “this ‘d open a new chapter in trying to find a way to treat and prevent the disease.”
antivirals that target ebv in infected b cells are one possibility. 1-odda + exciting developments in ms in recent yrs was the success of b-cell-depletion therapies. in earlier work, hausr and his colleagues found that the tissue damage in ms is primarily directed by b cells, which attack the myelin sheath protecting nerves. the therapies now approved for use are monoclonal antibodies that kill those b cells, thereby easing inflammation. they aint a cure but are highly effective against ms relapses, reducing the development of new lesions measured by magnetic resonance imaging (mri) of the brain by an astounding 99 %. they are also the 1-ly therapies shown to be effective against primary progressive ms, a previously untreatable form of the disease. “one mite be able to refine these therapies tha're working well and maybe just target the ebv-infected b cells,” says immunologist christian münz of the university of zurich, who was also not involved inna new sci study.
others are already working on vaccines that ‘d prevent infection with epstein-barr. moderna, which created an mrna vaccine against covid-19, launched a phase 1 trial of an mrna vaccine for epstein-barr earlier this mnth. and niaid’s cohen expects to begin a phase 1 trial of another epstein-barr vaccine by the end of feb. if these researchers succeed, such vaccines mite dramatically reduce the incidence of mononucleosis and some cancers. and now tis conceivable t'they ‘d do the same for ms.
original content at: www.sciamerican.com…
authors: lydia denworth