MSi has been well studied for the last several decades. As a result there are volumes of knowledge about what happens inside the brain of an MS patient, though we are still very unclear on the cause. Any potential "cause" of MS has to fit with the known body of evidence for MS. Interestingly enough there are some similarities between MS on the cellular level and CPn infection and this page will explore that.
As we begin I'd like you to understand that CPn is relatively newly discovered (the 1980's) and new findings are coming out every week in this field. It is also a very different germ in that it behaves in ways that seem "wrong" based on what is "known" about germs. For example, we tend to think of resistence as occuring when a bacteria is exposed to an antibiotic then finds a way to still replicate in the presence of that antibiotic, thus remaining an active infection that we can culture. We do not recognize the kind of resistence that CPn is now proven to be capable of: exposed to an antibiotic it can become persistent, essentially going into hibernation and thus invisible and unaffected by the antibiotic, only to reactivate as soon as the threat of the antibiotic is gone. See THIS PAGE ON PERSISTENCE. Though technical this paper is a wonderful review of the available research on the subject. CPn is an evolutionary coup de gras.
As backgroud for this page, bear with me as I do a quick overview of the CPn lifecycle because it is pertinent to our discussion. CPn is an obligate (it has to) intracellulari ( lives inside of another cell) organsim of eukaryotic cells (cells with a nucleus). It is parasitic in nature meaning it converts the cell's energy mechanisms (mitochondria)for its own uses and leaves the host cell essentially nonfunctional for its original purpose. The elementary body (EB), a tiny hard cell with barbs on it which allow it hook on to potential host cells, is the infective form of CPn. Once contacted, EB'si are carried in the blood floating around looking for a cell to hook into and parasitize. As a CPn EB sticks itself to a cell, it is included, or pulled in, to the cell in a sort of tiny bubble. There, it converts to a reticulate body (RB) which does several things. First, it grows larger by about 2 times and takes over the mitochondria. All the energy the cell can now produce is used to feed the RB which now begins metabolizing and replicating, making new EBs which will look for another new cell to infect. In order to escape detection and death, the CPn covers it's inclusion a lipid bilayer. It also turns off apoptosis in order to increase the life of the cell so its home is safe. At the same time, having an infection in the cell makes it vulnerable to death as the toxic by products of the CPn lifecycle are pushed out of the CPn inclusion and into the cytoplasm of the host cell.
Please also note that CPn was first thought to be a virus because it behaves like one: it floats around and invades your cells themselves, living off of the host cell and unable to metabolize and replicate on its own. Further research showed that it has almost all the usual cellular machinery that bacteria
have. With its own machinery, and a bacterial-size genome (not the tiny gene sequences that viruses have), it can play more tricks than viruses can play. For example, it can convert freely back and forth between these different forms, it can detect "threats" to its survival like antibiotics or gamma interferon, and then go persistent or hibernate in a non metabolic state wherein it is immune to the abxi. The article on persistnce above is very good on this subject.
So let's begin noticing the cellular similarities with a well known concern in MS: The fact that nitric oxide (NO) is high. An example of MS research on this can be found HERE This particular abstract was chosen for two reasons. First it shows that researchers believe that NO is part of the problem in MS, and this fact is so well established that I can't find a reference that establishes it.
So in MS the upregulation of NO is an accepted problem. Frequently we see research focused on potential strategies to reduce the NO and thus spare the nerves. But might that high NO indicate that CPn is present? In this abstract HERE we have the authors showing that the body upregulates NO on purpose to defeat CPn. The organism cannot multiply in the presence of NO. This is the way the body kills unwanted villains like bacteria and viruses, with oxidative metabolites that are harmful to them, then the other immune cells like phagocytes can come in and clean up the debris. Interestingly enough, it is gamma interferon that is responsible for signalling this upregulation(and gamma interferon will come up again later). HERE we have second paper in which cells that can make NO and cells that could not were compared. The NO sufficient cells were regulatory for CPn as we might expect. This is just two of the studies on this subject.
Point two from the abstract on NO in MS above was that LPSi was the agent that the researchers used to damage the oligodendrocytes so that they could study the effect of NO in the MS brain. What is LPS? Lipopolysaccharide is the fragment of the outer cell of a gram negative bacteria. LPS is very toxic to cells in general, and very immunogenic causing a brisk reaction of the immune system, and here we see it is used to induce damage typical of MS damage to oligodendrocytes. LPS comes from a gram negative bacteria like CPn when it dies. This is a very important bit of circumstantial evidence for CPn causing MS. Clearly if CPn, which is a gram negative bacteria, was in the brain and died there would be oligodendrocyte damage similar to MS due to the presence of the LPS fragments released.
Lets go deeper into this subject with THIS paper which discusses the microglial activation in the CNSi by LPS. This paper shows that it is the microglia specifically that must respond to LPS damage of the nerves, and it also says plainly that LPS causes " injury to oligodendrocytes and myelini as occurs in periventricular leukomalacia and multiple sclerosis", a direct replication of the information above. This work also says the oligodendrocyte precursor cells were damaged by the LPS. Since OPC's are another known concern in MS, LPS damage to brain tissue is a good match for MS damage. Also, note that microglial activation opens the BBBi and allows peripheral immune cells like B-cells and T-cells in to the area to aid in cleanup.
HERE is an abstract and link to an older paper that discusses the activation of microglia in the CNS in MS and EAE. This supports both the idea that microglial activation is normal in infection, as well as presenting the notion that microglial activation is the damaging feature of MS. These authors suggest that if we could turn off the microglial activation, the MS brain could be spared. But obviously if the brain is responding to pathogen by turning on microglia to fight the germ, ridding the brain of that pathogen "turns off" microglial activation, and it does this without leaving the brain open to opportunistic infections like PML. It leaves your brain's pathogen surveillance system intact.
Another well known fact in MS is that there is upregulation of cox 2 prostaglandins which are inflammatory.HERE is one paper showing that this is true in MS. HERE is another, this one also tying it in to the oligodendrocytes, which when injured send out the Cox 2 signal which results in caspase 3 activation and death. The speculated conclusion of this paper is that it is the cox 2 that causes MS oligodendrocyte damage. It supposedly does this by cox 2 upregulating by itself (autoimmune theory) and thus starting the cascade we call MS.
HERE is a paper that shows that cox 2 is upregulated by the body on purpose in CPn infection. Actually, cox 2 upregulation can be inferred from the previous discussion on the LPS damage because it is stated that damaged oligodendrocytes will send out this chemical signal. Once again we see natural, expected immune reactions to infection occuring that mirror the known cellular/chemical profile in MS.
I mentioned gamma interferon above. In early studies (the 1970's) of the interferon drugs, pwMS got rapidly worse when taking gamma interferon. Yet we just showed that gamma interferon regulates CPn growth by being responsible for upregulating NO. Isn't this opposing the CPn theory? In fact in those early trials the patients given gamma interferon had myalgia, fevers, and arthralgia, and while gamma interferon itself may have caused this directly, this triad of symptoms is also common to endotoxini reaction. No patient of the seven who had worsening had residual symptoms and every patient had a flare up of symptoms already known to them, suggesting pseudoflare (common in fevers, and familiar to people using the CPn protocols here as an endotoxin reaction)not a true exacerbation which would be involvement of a new area of the brain. The reference for this information is HERE titled "Experimental allergic encephalomyelitis: a misleading model of multiple sclerosis." by Sriram S and Steiner I in the Annals of Neurology Dec 2005. You have to get the whole citation to read the material about the gamma interferon I mention as it is not discussed in the abstract. Might it be true these people had transient worsening due to endotoxin as the gamma interferon via nitric oxide and tryptophan depletion killed some of the CPn load? It is unusual for people to have worsening with no residual deficits. This author also mentions that gamma globulin results in an upregulation of gamma interferon without exacerbation in MS ptients. Circumstantial but possibly important information supporting the idea that gamma interferon may not be the profoundly negative influence it was thought to be.
Tryptophan is of interest in MS also and has a role in CPn regulation. In the Eur J Neurol. 2005 Aug;12(8):625-31 there was a paper titled "Interferon-beta affects the tryptophan metabolism in multiple sclerosis patients" authored by Amirkhani A, et al found HERE In this work it is clear that the tryptophan pathway is altered in MS and that beta interferon plays a role in mediating this. But in CPn the body, again via the gamma interferon pathway, catabolizes tryptophan in order to deny this amino acid to the CPn which needs it to replicate. See this HERE from our own archives. So tryptophan is altered in MS, but it is altered by the body in response to CPn also. Tryptophan is important because it is necessarly for making melatonin and serotonin in the brain, two important neurotransmitters associated with mood and immune function. Without adequate amounts a person is prone to depression and poor sleep, both known problems in MS.
Speaking of beta interferon, it also hampers CPn apparently. HERE is a citation titled "Role of Interferon-Stimulated Gene Factor 3 and Beta Interferon in HLA Class I Enhancement in Synovial Fibroblasts upon Infection with Chlamydia trachomatis " by Jürgen Rödel, et al. Perhaps the modest improvement seen with beta interferon use in people with MS could be related to this mechanism.
Many features of MS are actually known features of EAE with the authors ASSUMING that MS has this same feature. For example, caspase 3 is a regulator of apoptosis (organized cell deathi) and is seen to be upregulated in EAE. There has been speculation that caspase 3 itself may be at fault in MS, the logic being that if there was extra caspase 3 floating around it would mistakenly kill off perfectly good nerves and thus cause MS. While we do see CNS cells dying, they also would die from being infected and as discussed above, this will result in caspase 3 activation secondary to cox 2 activation caused by LPS. And all of this would cause the body to respond to the area with inflammation and immune cells to clean up the dead tissue. So it is not necessarily true that caspase 3 activation is secondary to anything other than natural response to pathogen. The Prineas and Barnett paper cited earlier also looked at caspase3 in the areas of apoptotic nerve cells. They found very little.
And here we have this PDF file which is a review of the pathology of the MS lesion found HERE Note that the author of the review of the pathology of an MS lesion draws a very clear parallel between the MS brain and viral infection, saying the cellular immunopathology is the same while also noting that EAE is not the same as MS. This again supports and repeats the information offered on the page "MS and the CPn Model" which establishes that there is significant research showing MS is not autoimmune. Additionally, remember that CPn is very similar to viruses because it is an intracellular organism. Once again we have support for the notion that MS is not autoimmune and a clue that the cytokinei profile we see in MS is indistinguishable from a natural reaction to a pathogen, and here on this page we are showing research that directly ties the same cytokines to CPn.
Another angle to MS which is considered an autoimmune clue which people frequently point out is that MS has been shown to have various upregulated genesi. Doesn't that prove that pwMS have a problem gene that causes this abherrent reaction? Well, no it does not. The average person thinks a gene is like your eye color- it is what it is and it cannot be different. But genes turn on and off all the time and this is called upregulation and down regulation, and they do this in reaction to the environment. HERE is an abstract that outlines a couple of kinds of gene upregulation in response to CPn infection. In this case the macrophages i(an immune system cell) have upregulated some genes and down regulated others.
In another example of genetic changes, HERE is a paper that shows how CPn itself changes and upregulates a whole bunch of its genes in persistent states vs acute infection, this giving it the flexibility to do the many things it is capable of doing and making it so difficult a pathogen to eliminate.
In order to be fair it is obvious that some genes such as your HLA type impacts the way your body responds to germs. It is possible that some people with some genetic profiles respond to CPn in such a way that persistence is more likely in that individual. It would be narrow to assume that a genetic type could cause autoimmunity, but not that it could cause an atypical reaction to a bacteria.
So this page is focused on the fact that many known features of MS are also known physiological reactions to CPn infection, remembering that infections of many kinds likely have a similar if not identical profile. This is not unexpected as it has been amply pointed out by many authors that MS resembles, on a cellular level, a reaction to an infective process. The fly in the ointment has been the inability to culture anything consistently, though the known fact that CPn is possibly unculturable in the persistent state might easily account for the "we found it" and the "we tried to replicate their work and did not find it" back and forth nature of the MS/CPn research to date.
It is interesting to note that while CPn is known to live in human cells, is known to cause cellular inflammatory reactions to that cellular infection, is known to cause immune reactions and cellular death and that it is very hard (and some say impossible)to culture and complicated to kill in persistent state, we still have people who debate whether or not it is a "problem" suggesting perhaps CPn's presence is innocuous for human beings. And we also have people seeing cell death, immune response and inflammation, and who are unable culture any germs at the site continue to insist that this immune response has to be the body attacking itself for no good reason (autoimmunity)seemingly oblivious to the possibility of an intracellular infection like CPn and ignoring the limitations of current ability to find these bacteria.
At this point in time it is not proven one way or the other. We really need a test every competant researcher can do which shows the presence of CPn in MS brains to get to that level of understanding. This is all circumstantial evidence for the presence of CPn in MS brains. But also note there is nothing that is excludes the possibility of it either and the evidence indicates that if CPn WERE in a brain it would: upregulate NO, cause oligodendrocyte damage via LPS identical to MS damage, cause the cox 2 prostaglandin to be made which would signal caspase 3 and apoptosis, would damage the nerves and cause death, would cause microglial activation, would catabolize tryptophan. Since this profile of changes mirrors MS, we have a smoking gun in CPn for being involved in MS.
This is speculative and based on currently available research which may not be all inclusive, or which may not apply to you directly. It is posted here for informational and purposes. This page may be added to or revised as new material comes up......