Infections and Multiple Sclerosis (MS)

For a long period of time it was believed that MS was caused by an infectious agent. For example, in the early 20th Century it was postulated that MS was caused by the bacterium which causes Syphilis – and MS patients were treated with harsh Arsenical compounds – with all the side effects and no obvious benefit! The infectious hypothesis has never really died but has changed its form over time. In the 1980’s candidate viruses included Measles virus and a “Foamy Virus” (the latter rapidly disproven and shown to be an artifact of the way the viral cultures were done). The Measles hypothesis stems from earlier studies from the 1940’s where mildly elevated Measles antibody levels (as well as levels to other common viruses) were found in the blood of those with MS. Following the antibody saga there was an initial report that genes of the Measles virus could be found in the brain of those with MS. That finding was convincingly disproved in subsequent studies. (It is notable that a rare complication of Measles virus infection is a chronic and progressive brain infection – SSPE. But this is worlds apart from MS and easily differentiated from MS). Other features of MS such as increased CSF immune cells and oligoclonal bands in the CSF (just elevated antibody levels – which originated from foci of immune cells in the CSF pathway) were invoked as indicating an infection; although they could just as easily have arisen from autoimmune inflammation. Many viruses were looked at as possible causes of MS, only to be excluded following careful research.

Then, there were reports of MS following EBV infection. EBV infects virtually every human being and remains mostly latent in our B cells (antibody producing cells) for life. Elevated antibody levels were found in slightly more MS subjects compared with healthy ones. However, this is the flimsiest of evidence on which to base this claim – and the elevated antibody levels to other viruses were ignored in the rush to push the EBV claim. EBV infects children under 2-3yrs in the developing world. It is an asymptomatic infection and mostly goes unnoticed unless an antibody test is done to detect prior exposure to the virus. In contrast, in the developed world, we don’t spend as much time in the dirt in early childhood and as a consequence we typically get EBV infections during our teens. This infection produces “Mono” which is triggered by the virus but the illness is essentially an immune reaction to the virus or triggered by the virus. In fact, many of the more severe cases of “Mono” occur in individuals who subsequently develop an autoimmune disease. The proponents of the EBV hypothesis for MS have unfortunately ignored this fact. Finally, EBV is found in B cells which infiltrate the CNS during the development of MS. However, there is no evidence that the virus is transmitted to CNS cells, including oligodendrocytes (myelin forming cells). So, the EBV infection hypothesis should really be laid to rest.

About the same time as the EBV story the vogue became the claim that Retroviruses caused MS. These viruses are very ancient and function by infecting cells and having their DNA integrated into our DNA (no different from HIV today). Once the viral DNA was integrated, our defenses went to work to get rid of the viruses or inactivate them, leaving traces of Retroviral genes incorporated in our DNA – in fact a good bit of our so called junk DNA is derived from these viruses! (it is hard to believe we are part virus). Some residual retroviral DNA may become activated and produce a gene product (protein or RNA) and this commonly occurs during inflammation and is not specific to, or the cause of MS. I was also involved in studies to determine whether MS was transmissible similar to what are protein transmitted diseases of the brain (e.g. Mad Cow Disease). The brains of chimpanzees were inoculated with tissues from MS subjects and monitored for long periods to see if they developed a brain disease. Nothing happened, ruling out that possibility.

So, what could be the role of viruses in MS?

During the first 20yr of life we are exposed many times to a large variety of infectious agents. This serves to educate the immune system so we develop long-standing resistance to these infections. For example, we only have Measles once either due to the infection itself or vaccination. Part of the process of the immune system becoming educated is the generation of different immune cells which produce a comprehensive, integrated and balanced immune response to any particular agent. Certain inherited variations of immune genes effectively support this process. However, other variations of these same genes may allow a less balanced immune response to develop. It seems that infections during childhood and the teens occur during a vulnerable period for “tuning” the immune system. Having the gene variations which result in a less balanced immune response might predispose to autoimmunity such as MS in the long term. The fact that we see higher antibody levels to viruses (and higher cell immune responses, for example to Measles virus) would imply that the immune response to these viruses is brisker than normal. While this might provide better protection and have survival value against certain viruses, it may also reflect the genesis of MS when it is “under the hood” as well as the immune pathogenesis of ongoing MS. The downside of an inherited overly active immune cell response is that Regulatory T cells (which are important to dampen and balance immune responses) may not develop effectively during the required balancing process. When this process is repeated many times, the net result may be better long-term anti-viral immunity, but greater susceptibility to developing autoimmunity because regulatory check mechanisms are not in place for our own proteins (self-antigens) as well. (This assumes that there are similarities between overactive anti-viral immunity and autoimmunity). Thus infections are an important environmental factor which contributes to the genesis of MS. We know that MS subjects have fewer, particularly respiratory infections (“everyone in the house besides me got an upper respiratory infection”), but often 2-3 weeks after an infection or exposure to one a relapse occurs.  In fact, antecedent infections are the triggers for about 60% of MS relapses. It is the impact of the infection on triggering autoimmunity and not the infection itself which is important. Further, an interesting recent study on lymphocyte circulation in EAE (the animal model of demyelination) demonstrated that immune cells destined to cause myelin damage in the CNS actually circulate through the lungs before they head off for the brain and spinal cord – and some of these cells may even stay in the lungs. While we do not have good supportive evidence at present, this finding may have something to do with what seems to be a predominance of respiratory infections which precede MS relapses. Here the anti-myelin T cells could be easily triggered in the lung by a viral infection.

So how did this immune imbalance arise?

One possibility is that there is a natural selective advantage for an individual to survive infections to adulthood to be able to reproduce. And, this possibility may be even more important for women than men. (Don’t forget that historically as many as 50% of individuals died during childhood, mostly of infections). So, survival from infections was a big biological issue for much of human history. Women also have a more active immune system than men which also has survival value in itself (a similar situation is seen in equatorial regions where people in Africa have a larger infectious load and consequently more active immune responses – below). Having a more active immune system may be like living on the edge as far as autoimmunity is concerned – and we do know that overall women predominantly develop autoimmune diseases – probably because they start with a more active immune system with weaker checks and balances.

Ironically, the high infectious load in Equatorial Africa was of a nature to stimulate the immune system to develop heightened protective immunity, but to also concurrently aid the development of regulatory T cells to create balance. This may be part of the reason why indigenous Africans (in contrast to Europeans or their descendants) seldom develop MS despite having brisker immune responses overall.

As large cities began to develop and persist from the Middle Ages on, particularly in Europe, epidemic infections became more prevalent. (For example, Measles virus outbreaks mostly occur in urban areas with a minimum of 200-500,000 people). One thing that drives natural selection is infections – we are at constant war with pathogens – with pathogens trying to subvert or evade our immune system, and our immune system developing defensive strategies against them in response. In part, the way we improve our viral resistance as a species is to develop gene mutations – which happened especially in immune genes in humans over time. There is evidence that certain gene variations (mutations) associated with MS were probably created to improve resistance to infections but unfortunately resulted in increased susceptibility to autoimmunity in general, and in MS in particular. These mutations were generated about the same time that European cities began to grow although this process has probably continued for hundreds of years since that time.

One consequence of having an imbalance between the responder T cells (effector T cells) and regulatory T cells in MS is that when someone with MS is exposed to a viral infection the signaling molecules that are made to alert and activate effector cells may also activate the cells which respond to putative myelin self-antigens (proteins). When these myelin-reactive effector T cells are triggered as part of the overall resistance pattern to an infection they might outstrip the regulatory T cells designed to control them, resulting in an excessive immune response which results in demyelination.  There is also evidence that in certain circumstances, regulatory T cells actually lose their suppressive function and join the other guys (effector T cells) adding fuel to the fire.

Do infections have anything to do with the fact that MS has become more frequent recently?

Yes, it absolutely does. And, it has a lot to do with the kind of environment we have created with urbanization.

For the last 10,000 years we lived in an intimate relationship with animals (and seemingly most importantly cattle). For example, early houses were built with the first floor as a barn for animals; and people lived on the second floor above. As a result, there was constant exposure to cattle, their droppings, and their environment. Some of the bacteria (and possibly other factors) in this environment seem to beneficially modulate the human immune system, preventing the long-term development of allergies and autoimmunity. Exposure to this environment in the first six months of life seems to be sufficient to imprint a lasting protection from allergies and autoimmunity. This effect has been studied especially in the developing immune system in infants and toddlers. The benefit from a farm environment in reducing allergies and autoimmunity is the result of promoting and enhancing regulatory T cell development and function.

With urbanization and the relatively recent cleaning of our environment (sanitation, clean water, vaccinations etc.) we live longer but our immune systems have lost the long-term benefit of early micro-organism exposure which tunes and improves regulatory T cell function. It likely accentuates the down side of viral infections in those with genetically inherited immune variations which predispose to MS. Minimizing epidemic infections has also removed the immune system from the positive immune balancing benefit from “helpful” pathogen exposure of regulatory T cells. The environmental change due to urbanization and its impact on allergy and autoimmunity has been called the “Hygiene Hypothesis”.

It is notable that with urbanization of rural communities in Africa and elsewhere, there has been a spike in the development of allergies and autoimmunity. This phenomenon seems to be the result of losing the kind of environment necessary to induce a balanced development of our immune systems. Further, an interesting epidemiologic study was done in Crete where the effects of urbanization on the development of MS were studied. It was found that the movement of young women in their twenties from rural to urban environments increased the occurrence of MS in these women. Again, it is possible that this situation reflects the loss of ongoing immune protection from living in a farm environment in these individuals.

Therefore, while viruses do not directly cause an infection called MS they do have a profound influence on the development and balance of immune responses. The interactions of certain viruses with the immune system in genetically susceptible individuals may predispose to the development of MS as well as acting as triggers for relapses. The major focus of our research at MSRI is to study the immune system and especially the balance between effector and regulatory T cells to uncover fundamental immune mechanisms which cause MS.

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