What can we learn from studying infections in MSers? #MSBlog #MSResearch
“The paper below may be old but it is as relevant today as it was back in 1994 when it was published. Infections, in particular viral infections, trigger relapses. You are more than twice as likely to have a relapse in the week prior to, or the 5 weeks after, an infection. The infections in this paper were mainly symptomatic upper respiratory infections due to viruses, so the risk may be much higher if we could count so called minor or asymptomatic infections.”
“What do I mean by asymptomatic infections? We are continuously being exposed to new viruses that infect us but don’t cause symptoms. An example of this is the JC virus that causes PML in MSers on natalizumab. When we initially become infected with the JC virus it does not cause any symptoms; it simply gets into our body and stays there. In the majority of us this is fine and it is only if we become immunocompromised do we have a chance of this virus mutating and causing PML. Similarly, for the majority of us when we get infected with Epstein-Barr virus (EBV) it does not cause symptoms; only the minority of us get glandular fever or infectious mononucleosis. The same applies for the another herpes virus called CMV or cytomegalovirus; asymptomatic infection is the rule. What is interesting about the herpes viruses is that they become latent in the body and reactivate every now and then. These reactivations of latent viruses are usually asymptomatic but are strong enough to stimulate the immune system and may trigger relapses. In fact there is some weak evidence that this may be the case.”
“When I did my PhD I studied an marke of immune activation on a daily basis in MSers over many months. I found that immune activation usually preceded the occurrence of new MRI lesions by a few weeks. Please remember that new MRI lesions are the equivalent of subclinical relapses. I therefore proposed in my thesis that latent viral reactivations may be the factor responsible for this immune activation, which then triggers MS disease activity. This is the reason why I became so interested in the viral MS hypothesis. These viral reactivations don’t have to apply to exogenous viruses only, i.e. viruses that come from outside the body, but could also apply to endogenous viruses, i.e. viruses that reside in our bodies or genome. The latter is referring to human endogenous retroviruses (HERVs). This is one of the hypotheses that is underpins the Charcot Project. Can we treat MS by reducing endogenous viral reactivation (HERVs)? Can we treat MS by preventing reactivation of latent herpes viruses, in particular EBV?”
“The observation of infections triggering relapses is not limited to viral infections, but also applies to bacterial infections, in particular urinary tract infections. This is why I am on a mission to improve the management of bladder problems in MSers with the aim of preventing or reducing bladder infections. There is some emerging evidence that MSers with recurrent bladder infections do worse than MSers without bladder infections.”
“So you can see there is still a lot we don’t know about MS. The role of infections is just one aspect we need to study in more detail. Who knows by doing this we may pin down the cause of MS? I am already a believer in EBV being the cause. I am convinced that if we can stop people becoming infected with EBV we will prevent them getting MS and that if we treat MSers with drugs that eliminate EBV from their bodies we will stop MS in its tracks. As I have said before once you have become infected with EBV it remains latent inside B cells; drugs that target B cells by transiently depleting them are the most effective drugs we have (alemtuzumab, rituximab, ocrelizumab, mitoxantrone, cladribine, bone marrow transplantation). What about natalizumab and fingolimod? Natalizumab stops B cells crossing from the blood into the brain and spinal cord and fingolimod traps B cells in lymph nodes. What all these drugs have in common is the B cell. My money is therefore on B cells and EBV as being the therapeutic target in treating MS.”
Panitch HS. Influence of infection on exacerbations of multiple sclerosis. Ann Neurol. 1994;36 Suppl:S25-8.
Background: Exacerbations of MS are triggered by exogenous events, the best documented being viral upper respiratory infections (URIs), which can stimulate secretion of cytokines such as interferon-gamma (IFN-gamma) by immune cells.
Methods: In conjunction with a recent clinical trial of systemic interferon-beta (IFN-beta) in relapsing-remitting MS, we studied the occurrence of viral infections and their correlation with MS attacks. Thirty MSers kept daily logs, noting URI symptoms in themselves, family members, and co-workers. MSers were examined every 3 months, or whenever an attack of MS occurred, and were tested for antibodies to common upper respiratory pathogens.
Results: A strong correlation was found between MS attacks and URIs. There were 168 URIs in 2,792 MSer-weeks, including 996 weeks at risk (the interval beginning 1 week before and ending 5 weeks after onset of URI symptoms) and 1,796 weeks not at risk. Nearly two-thirds of attacks occurred in periods at risk. Attack rates were 2.92 per year in weeks at risk compared to 1.16 per year in weeks not at risk, a significant difference (p < 0.001). High-dose interferon reduced the frequency of MS attacks, but had no effect on the number of URIs.
Conclusions: Although a specific virus could not be incriminated, we concluded that URIs of presumed viral origin are an important trigger of MS attacks, and that treatment with IFN-beta reduces the attack rate, but not by preventing URIs. Rather, it may modulate responses to viral infection that would otherwise lead to immune activation and clinical symptoms.