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This has been posted before, etc., but just as minor substantiation (of course, there is much more over the last few years that Wesley, Robin and I have found and discussed), but I won't go into it.

This will just help to show how integral norepinephrine and its "defectiveness" contributes to a whole negative chain reaction in MS.

Neurobiol Dis. 2004 Mar;15(2):331-9. Related Articles, Links


Astrocytic beta2-adrenergic receptors and multiple sclerosis.

De Keyser J, Zeinstra E, Wilczak N.

Department of Neurology, University Hospital Groningen, Groningen, The Netherlands. j.h.a.de.keyser@neuro.azg.nl

Despite intensive research, the cause and a cure of multiple sclerosis (MS) have remained elusive and many aspects of the pathogenesis are not understood. Immunohistochemical experiments have shown that astrocytic beta(2)-adrenergic receptors are lost in MS. Because norepinephrine mediates important supportive and protective actions of astrocytes via activation of these beta(2)-adrenergic receptors, we postulate that this abnormality may play a prominent role in the pathogenesis of MS. First, it may allow astrocytes to act as facultative antigen-presenting cells, thereby initiating T-cell mediated inflammatory responses that lead to the characteristic demyelinated lesions. Second, it may contribute to inflammatory injury by stimulating the production of nitric oxide and proinflammatory cytokines, and reducing glutamate uptake. Third, it may lead to apoptosis of oligodendrocytes by reducing the astrocytic production of trophic factors, including neuregulin, nerve growth factor and brain-derived neurotrophic factor. Fourth, it may impair astrocytic glycogenolysis, which supplies energy to axons, and this may represent a mechanism underlying axonal degeneration that is hold responsible for the progressive chronic disability.

Publication Types:
Review

PMID: 15006703 [PubMed - indexed for MEDLINE]

Ok, once again to help substantiate or clarify my viewpoint, if (as previously shown and speculated by recent and prior studies), glutamate and norepinephrine are two of the "substances" (for lack of a better word) that appear to be terribly dysregulated in MS and may contribute to the appearance of MS as a disease itself, then the below may help tie together why treatment of depression associated in MS with SSRIs alone are unlikely to assist to any major degree (which can be seen with the naked eye, that is) with disease modification. That's not saying, though, that even taking an SSRI might not be helpful for MS............they don't scrutinize the effects of any anti-depressant in connection with actual disease modification in MS. Hence, who knows?

And see once again how closely related the two so-called separate diseases really are? (i.e. affective disorders and multiple sclerosis)

NOTE: Just reading the highlighted portions alone will probably show enough.

http://www.medceu.com/course-no-test.cfm?CID=961

Neurotransmitters and Depression

Although numerous monoamine and neuropeptide neurotransmitters have been implicated in the pathophysiology of depression, disturbances in serotonin (5-HT) and NE have been the most extensively scrutinized.

Focus on Serotonin

Serotonin-containing nerve terminals primarily originate in the dorsal raphe nucleus located in the midbrain, and project throughout the forebrain, including the prefrontal cortex. Numerous approaches have suggested the involvement of HT circuit dysfunction in depression. Thus, low levels of the major 5-HT metabolites have been detected in the cerebrospinal fluid (CSF) of depressed and suicidal patients.[22,23] An increased density of 5-HT2 receptors has also been detected in both blood platelets and in the postmortem brain tissue of depressed patients,[24] perhaps a compensatory response to low synaptic 5-HT availability. Perhaps most central to the role of 5-HT in depression is the observation that all selective serotonin reuptake inhibitors (SSRIs) are effective antidepressants. Sex differences in the rate of serotonin synthesis have also been detected using positron-emission tomography (PET). This study demonstrated the rate of serotonin biosynthesis in male brains was 52% higher than that in female brains.[25] The authors speculated this difference may account for the increased prevalence of major depression in females, although much more study is needed before any definitive conclusions can be drawn. Taken together, these and other findings clearly implicate 5-HT neuronal dysfunction in the pathophysiology of depression, although it does not necessarily indicate that 5-HT systems are the primary cause of depression.

Focus on Norepinephrine

Norepinephrine projections originate from a pontine brain region, the locus ceruleus (LC), and like the raphe neurons, these neurons project to the frontal cortex and limbic system. Much evidence implicates norepinephrine circuit involvement in the biology of depression. First, low levels of NE metabolites have been measured in the urine and CSF of depressed patients.[26] Second, an increased density of beta-adrenergic receptors has been observed in postmortem cerebral cortex of depressed suicide victims. Third, alpha2 adrenoreceptor sensitivity is apparently altered in depression, perhaps best exemplified by the blunted growth hormone response after administration of clonidine, an alpha2 agonist.[27] Finally, selective NE reuptake inhibitors are effective antidepressants (ie, desipramine, reboxetine, maprotiline).

Stress, which precipitates depression in vulnerable individuals, produces a number of measurable changes in NE function. Uncontrollable shock, a very potent stressor in animal models, induces activation of NE systems in the locus ceruleus, hypothalamus, hippocampus, and frontal cortex.[28] Chronic stress also produces increases in tyrosine hydroxylase activity (the rate-limiting enzyme involved in NE biosynthesis) in the LC, which may sensitize the system resulting in an enhanced NE system response to subsequent stressor exposure. Similar observations in the LC of depressed patients have been observed in postmortem brain tissue studies.

Finally, a review of the main symptoms of depression suggests that several core symptoms may be modulated at least in part by norepinephrine:

Depressed mood most of the day, nearly every day (possibly 5-HT related as well);
Diminished pleasure in all, or nearly all activities (anhedonia, possibly DA related as well);
Significant weight loss or gain (possibly 5-HT related as well);
Insomnia or hypersomnia nearly every day;
Psychomotor agitation or retardation nearly every day;
Fatigue or loss of energy; and
Diminished ability to think or concentrate.

Evidence in Support of the Catecholamine Hypothesis of Mood Disorders

The extant evidence clearly suggests a role for both NE and 5-HT system dysfunction in the pathogenesis of depression. However, although the evidence indicates both neurotransmitters are involved, it does not necessarily indicate primary causation. Despite the numerous lines of evidence implicating monoaminergic neuronal dysfunction in the pathophysiology of depression, the development of biochemical markers to detect endogenous depression has proven difficult. A recent study used internal jugular venous catheters and arterial lines to assess brain monoamine neurotransmitter activity.[29] This study comprised 19 healthy volunteers and 9 patients with refractory unipolar depression. At rest, the depressed patients demonstrated markedly reduced venoarterial measures of norepinephrine and its metabolites, and homovanillic acid, the major dopamine metabolite, when compared with controls. Of note, venoarterial 5-hydroxyindoleacetic acid concentration, the major 5-HT metabolite, was not reduced in the patients with depressive illness. This study highlights the role of NE circuit dysfunction in refractory depression, and also suggests a role for alteration in DA circuits as well.

The Role of Norepinephrine and 5-Hydroxytryptamine in Mood and Affect

Although drugs that selectively target either the serotonin transporter (SERT) or norepinephrine transporter (NET) are effective antidepressants, their behavioral effects in laboratory animals and man are somewhat distinct. Modulation of brain serotonin levels effects impulsivity, and modulates sexual behavior, appetite, and aggression. Norepinephrine systems seem to directly modulate vigilance, socialization, energy, and overall motivation. Both systems also appear to modulate anxiety, irritability, pain, as well as modulating mood, emotion, and cognitive function. Based on these overlapping yet distinguishable profiles, dual-action agents may provide the broadest spectrum of therapeutic effect across the full range of emotional and physical symptoms of depression.

Rationale for Dual Reuptake Inhibitors

Studies involving depletion of 5-HT or NE have demonstrated that both monoamines are independently involved in the pathophysiology of depression. In patients who respond to an SSRI, 5-HT, but not NE depletion, causes a recurrence of depression symptoms. Conversely, in patients who have responded to treatment with norepinephrine reuptake inhibitors (NRIs), NE, but not 5-HT, depletion causes symptoms to return. Of note, healthy subjects or untreated depressives exposed to the same neurotransmitter depletion regimen do not experience depressive symptoms. These depletion studies clearly highlight the role of 5-HT and NE systems in depression,[30,31] yet transmitter depletion is not sufficient to induce depression in healthy subjects.

As previously discussed, 5-HT and NE systems have unique yet overlapping effects on mood and behavior. Thus, combining selective inhibitors of 5-HT and NE reuptake may target a broader range of depressive symptoms, a notion supported by the currently available evidence. Thus in a series of studies, the Danish University Antidepressant Group, has reported that SSRIs have an advantage in terms of side effects but were less effective when compared with clomipramine, a dual reuptake inhibitor tricyclic antidepressant (TCA).[32] Moreover, a combination of fluoxetine (an SSRI) with desipramine or other TCAs produces a faster and more robust antidepressant response than either alone.[33,34] There is also evidence that venlafaxine, a dual reuptake inhibitor at the higher end of the dose range, may have greater efficacy than selective reuptake inhibitors, particularly fluoxetine.[35-37] A more recent study demonstrated that patients treated with venlafaxine had higher remission rates (45%) relative to both SSRIs (35%) and placebo (25%).[37] ....

....SSRIs have become the dominant treatment for depression in the United States, predominantly due to their favorable side effect profile compared with that of TCAs. However, SSRIs are not a panacea for the treatment of depression in all patients. One of the major problems with SSRIs is the long lag time before clinical efficacy is seen after initiating treatment. Fortunately, our armament of psychotherapeutic agents and other treatment modalities continues to grow. Newer drugs might provide better strategies for treating depression more quickly and more effectively. More studies are needed, but the current data suggest that agents that target both the NET and SERT may possess greater efficacy, particularly in treatment-resistant and severely depressed patients. ....

Well crumb I guess I'm elected. The infective angle is as always in the background as people get completely focused on the foreground ie the melatonin etc.

I am going to ask you all who are interested in this to accept that there are a number of possible intracellular infections, chlamydia pneumonia, borrelia bergdorferi, mycoplasmas including TB, and even viruses which ar e also intracellular. By expanding the field in this way we have access to enough information to answer the rather obscure questions we come up with. I submit that all of these infections cause similar or more likely nearly identical reactions by the body particularly as it comes to the humeral responses (body wide) vs cellular (which may be more specific for example it is known that the body makes gamma interferon and in CPn infection is specifically catabolizes tryptophan in order to block the CPn as CPn uses it for replication. If you give a petri dish with CPn in it extra tryptophan it increases replication.) It is like we are talking about a bladder infection, the symptoms are the same no matter the infective organism so whether it is pseudomonas or e.coli, same diff physiologically.

Now the physiologic response to CPn I mentioned wherein the body catabolizes or breaks down tryptophan to block the CPn replication plays in to the mel pathway because melatonin is made from tryptophan. Therefore people with CPn infection of the brain will necessarily have depleted stores of tryptophan.

In the above article, " the immunotherapeutic potential of mel"on the melatonin post quoted by Deb you see that mel is mentioned as being

Activation of MEL receptors enhances the release of T-helper cell Type 1 (Th1) cytokines, such as gamma-interferon (gamma-IFN) and IL-2, as well as of novel opioid cytokines. MEL has been reported also to enhance the production of IL-1, IL-6 and IL-12 in human monocytes. These mediators may counteract stress-induced immunodepression and other secondary immunodeficiencies and protect mice against lethal viral encephalitis, bacterial diseases and septic shock. Therefore, MEL has interesting immunotherapeutic potential in both viral and bacterial infections.

So melatonin has a key role in bacterial immunity. Notice also the other cytokines mentioned as they are often mentioned in MS literature as the "smoking autoimmune gun". The other fact I mentioned that tryptophan is decreased by gamma interferon in CPn infection leads to a conclusion that perhaps the CPn infected person is in fact somwhat hampered by this in the arena of fighting the bug as mel stores will be decreased. If you are interested in the possibility of CPn in MS brains this accounts for the well known decrease in mel in MSers

on another front the question is does HPA overactivity mean there is dysregulation of the system in pwMS. Well, crud only if you come at it with an attitude that it has to be true that the dysregulation is the problem
in other words autoimmuniuty

Abstract:


Attenuation by Reactive Oxygen Species of Glucocorticoid Suppression on Proopiomelanocortin Gene Expression in Pituitary Corticotroph Cells
Koichi Asaba, Yasumasa Iwasaki, Masanori Yoshida, Masato Asai, Yutaka Oiso, Toyoaki Murohara and Kozo Hashimoto
Departments of Clinical Pathophysiology (K.A., Y.I.) and Internal Medicine (M.Y., M.A., Y.O., T.M.), Nagoya University Graduate School of Medicine and Hospital, Nagoya 466-8550, Japan; and Second Department of Internal Medicine (K.A., K.H.), Kochi Medical School, Nankoku, Kochi 783-8505, Japan

Abstract

Up-regulation of hypothalamo-pituitary-adrenal axis is maintained during acute inflammation and/or infection, in the face of sustained elevation of plasma glucocorticoid hormone. Inflammatory stress is usually associated with high plasma cytokine levels and increased generation of reactive oxygen species (ROS) as well. In this study, we examined the effect of ROS on the negative feedback regulation of glucocorticoid in hypothalamo-pituitary-adrenal axis using AtT20 corticotroph cells in vitro. When the cells were treated with H2O2, glucocorticoid suppression on the proopiomelanocortin gene promoter activity was attenuated in a dose-dependent manner. H2O2 also inhibited the ligand-stimulated nuclear translocation of glucocorticoid receptor. The released glucocorticoid suppression by H2O2 was not observed when the cells were cotreated with antioxidants. Together, these results suggest that increased ROS generation in the oxidative redox state attenuates the glucocorticoid negative feedback system, at least in part, by interfering with the nuclear translocation of glucocorticoid receptor and eliminating the repression on proopiomelanocortin gene expression.

HYPOTHALAMO-PITUITARY-ADRENAL (HPA)-AXIS IS activated by a variety of stresses, and the resultant increase in adrenal glucocorticoid (GC) hormone mediates body defense responses by its antistress effect (1). In addition to the well-known physical or mental stresses, inflammation and/or infection are known to activate HPA axis as well, through the so-called immune-endocrine interaction (2). Indeed, plasma GC level is elevated after infectious/inflammatory stress, which in turn exerts a suppressive effect on the immune function to prevent the overactivation of the system.

If the high GC suppresses the activated immune system, it may also inhibit HPA axis through the well-known negative feedback effect. Nonetheless, the activation of HPA axis is maintained until the inflammation/infection subsides, and thus there should be some mechanism by which GC suppression of neuroendocrine regulation is reduced or abolished in the face of high plasma GC levels.

It is well known that systemic or local generation of reactive oxygen species (ROS) is increased during inflammation and/or infection with increased cytokine production (3, 4, 5), which influences the redox regulation of various intracellular signaling systems. In this study, we have hypothesized that GC suppression of pituitary ACTH expression is somehow reduced so that the set point of negative feedback is shifted to allow continuous stimulation of GC secretion under a high plasma GC level. We especially focused on the effect of ROS on GC receptor (GR) function, because recent studies suggest an impaired function of GR during oxidative stress through redox regulation (6, 7, . We found that the impaired nuclear translocation of GR is observed in corticotrophs under high hydroxyradical generation, which may account for the reduced or eliminated effect of glucocorticoid on the expression of the proopiomelanocortin (POMC) gene that encodes ACTH.

Ok so these guys see the HPA activation is part of response to the illness.


The HPA axis is simply part of your body. TO me it is like we've been say "the HEART is involved in exercise! Yes, it goes UP in exercise" ANd someone else comes along and says "but wait, the heart rate is going up also in SHOCK! It's true look at these references" and someone else notices that heart rate seem different in MS so we are trying to draw a correlation between this and disease. We cannot. The HPA is involved in every single thing just like your heart is. It's involved in infection, stress, psychogenic stress, physiologic stress (like an operation) even dysregulation of other endocrine systems (low blood sugar). It is nothing that you can point to and say AHA! any more than an increased heartrate
means much. Does this mean it cannot be the core issue? Possibly not, after all, there is a disease called atrial fibrillation wherein the heart rate goes up for no reason and that IS the problem, but just because the heart rate is up does not mean it is atrial fibrillation. Just becasue the HPA has been frequently fingered in MS literature does not mean itis the cause of MS and not a bystander activated by the real cause. For me as a nurse I really get nutty with the focusing in on a particular angle and getting all over excited about it. To me it is obvious that MS Is a whole body problem, not a one system issue. Psychneuroimmunology makes it VERY clear that the immune system and the part of our being that we consider emotional or "psyche" use THE SAME EXACT NEUROTRANSMITTERS, therefore to the extent the immune system is activated the "psyche" is also impacted. But immune activation is obviouly necessary in ANY infection.

Also it is well known that in any illness of any kind people have more depression. http://www.news.uiuc.edu/news/04/0727depression.html I'm afraid like the Vandy people I do not buy the affective disorder notion of ms, I see the affective components as a nataural side effect of what's going on chemically speaking. In order for that to be the problem it would have to be true that the dysregulation of the cytokines and other factors noted were altered for no reason and that this alteration was at the root of MS. I contend that the dysregulated and abnormal cytokine picture seen is a normal response to infection, and the depression and other affective alterations are in fact simply a side effect of the problem, just like a fever is a side effect. We could get all excited about fevers and say hey, how did the HPA stimulate this fever! Lets get the brain to stop that by turning it down, then the person will be well This assumes the fever is the cause of the person's illness, it is not. It is the germ and that must be gone for the person to be well . The fever in fact is part of the healing system and useful (also impacts mood of course)

As far as glutamate, how might that be upregulated in infection, EBV, CPN Bb or other putative mechanism in the MS brain? Do I not accept that this is out of whack?

Nope, I do not. Once again we act like this kind of reaction in the body is "abherrent" somehow and that we "know" it sould not be like that. Who says?

Here I will lean on research in the HIV positive field becasue the little there is in the CPn world is associated with alzheimers and you must accept the idea that CPn causes AD, and while I could make a good case for that (more evidence there than in MS)I do not want to for this. That HIV is a virus, so for the 'EBV is probably it' crowd this lends some interesting insights:

Brain Pathology Volume 13 Issue 2 pp. 211-222
Regulated Expression of Sodium-dependent Glutamate Transporters and Synthetase: a Neuroprotective Role for Activated Microglia and Macrophages in HIV Infection?
Authors:
Gabriel Gras; Fabrice Chrétien; Anne-Valérie Vallat-Decouvelaere; Gwenaelle Le Pavec; Fabrice Porcheray; Christophe Bossuet; Cathie Léone; Patricia Mialocq; Nathalie Dereuddre-Bosquet; Pascal Clayette; Roger Le Grand; Christophe Créminon; Dominique Dormont; Anne-Cécile Rimaniol; Françoise Gray
Abstract:
It is now widely accepted that neuronal damage in HIV infection results mainly from microglial activation and involves apoptosis, oxidative stress and glutamate-mediated neurotoxicity. Glutamate toxicity acts via 2 distinct pathways: an excitotoxic one in which glutamate receptors are hyperactivated, and an oxidative one in which cystine uptake is inhibited, resulting in glutathione depletion and oxidative stress. A number of studies show that astrocytes normally take up glutamate, keeping extracellular glutamate concentration low in the brain and preventing excitotoxicity. This action is inhibited in HIV infection, probably due to the effects of inflammatory mediators and viral proteins. Other in vitro studies as well as in vivo experiments in rodents following mechanical stimulation, show that activated microglia and brain macrophages express high affinity glutamate transporters. These data have been confirmed in chronic inflammation of the brain, particularly in SIV infection, where activated microglia and brain macrophages also express glutamine synthetase. Recent studies in humans with HIV infection show that activated microglia and brain macrophages express the glutamate transporter EAAT-1 and that expression varies according to the disease stage.

So here we have evidence that the body in viral infection loses the ability to regulate glutamate. Someone might say hey wait a minute Marie, how can you say that HIV is the same as CPn in MS? I can't say for sure how they are the same how different because no one has looked, although in AD ther eis evidence of this same glutamate issue as well as the CPn connection. What is obvious here is that there is a normal biological reason for glutamate to be upregulated in an infective process that we all understand and accept.

As for the idea that if we interevene and change these things, for example reducing the glutamate levels assuming that will fix MS, I say that if it is high in response to a infective organism, stop that and you stop the glutamate upregulation. Simple as that. IF you do not the organism what ever it is remains active and we have the usual "NEW MS DRUG!" `issue of 'well golly! it worked in EAE I don't know what happened....'
That's my take on it from the infective angle. Do I KNOW this is the cause of MS, no I do not, it could even be a cofactor but the more I do like this discovering that the so called "abherrent immune system" is in fact known to "do whatever" in infection as well, the more I say, crud this has been missed.
It is fun to do this kind of thing Thank you for asking for the infective angle
marie

If only I could say it to you personally: that was really wonderful! Thank you. We should all get together and send you to medical school, though maybe you could just take the boards and be done with it. You are brilliant AND reasonable.

Roca

Marie--

How do cpn and infections account for and/or explain the brain and spinal cord atrophy that's present in people with MS?

Thanks

Sharon

Thanks for asking. I am mildly uncomfortable with the abx apologist role, but will offer the information from the best understanding I have accepting that the connection to MS is more circumstantial than proven and stating that to you up front. IT is not proven of course but it is an interesting theory becasue on many levels it answers the conundrums of MS. The difficulty some researchers have culturing it in MS brains is a problem for the acceptance of this idea as "proven" though there are some serious questions about how the cultures ought to be done in the brain. I speculate here with the caveat that this is not medical advice, but a theoretical model.

Well, since we know that MS whatever it is causes loss of neural tissue I have always assumed it eventually adds up to a noticable atrophy. ie nerves die, the brain is made up of nerves, ergo the brain shrinks (atrophies).

I'll go this way, I'll make the case for CPn infection of neural cells, then make the case for cell death in any CPn affected cells.

Does CPn infect neural tissue:
<shortened url>
this reference in in regards to alzheimers disease and it's connection to CPn. I qoute

identified C. pneumoniae within pericytes, microglia, and astroglia. Further immunolabelling studies confirmed the organisms' intracellular presence primarily in areas of neuropathology in the AD brain. Thus, C. pneumoniae is present, viable, and transcriptionally active in areas of neuropathology in the AD brain.

So here is evidence by this author that the cells of the AD brain were infected with CPn I could of course have offered the Vanderbilt University work suggesting it is found in MS brains also, but wanted to use different refs showing the specific neural cells

here <shortened url> is a reference in relation to mice that shows that intranasal infection with CPn established a persistent (low level but active) infection still present 3 months later, and that with this infection the mice developed CPn in the brain also.

I offer that these suggest that CPn has an affinity for brain cells as well as the blood vessel cells and respiratory cells that EVERYONE accepts everyhwere ( this is just not a debatable thing it's well accepted. the CDC considers CPn an emerging pathogen in atherosclerosis- in other words there's enough evidence it is considered a matter of time until it's proven) The links to asthma are very well established also. We KNOW this pathogen goes into the lungs and can establish a persistent inflammatory infection (it's not acute pneumonia, it is a low level infection that results in permanent colonization and what we call "asthma". Completely proven? not yet, there are still some people producing "no we did not find it papers" but not too many, and mainly 'Gee we treated asthma with abx but did not get better asthma outcomes' sugggesting not that the CPn was not there but that the abx were inadequate) So why not the brain? The above references suggest it can be the brain. In fact the perivascular nature (near blood vessels) of MS plaques taken along with the affinity CPn has for blood vessels makes one even more suspicious. Here we have a known respiratory pathogen that in SOME people (not everyone has athersclerosis) colonizes the blood vessels resulting in scarring and plaques there. Why not the brain also?

So what happens to a cell infected by CPn?
This easy reference to read enlightens us on the basics of CPn function in
the body
http://gsbs.utmb.edu/microbook/ch039.htm
I'll quote from it now;

The chlamydiae are a small group of nonmotile coccoid bacteria that are obligate intracellular parasites of eukaryotic cells. Chlamydial cells are unable to carry out energy metabolism and lack many biosynthetic pathways; therefore they are entirely dependent on the host cell to supply them with ATP and other intermediates. Because of their dependence on host biosynthetic machinery, the chlamydiae were originally thought to be viruses; however, they have a cell wall and contain DNA, RNA, and ribosomes and therefore are now classified as bacteria.

I think it's interesting they were thought to be viruses in the beginning.
Notice that these bugs hide inside the cell and take it over like viruses do.

The cell cannot function as it should then. IT uses all it's energy to do the work of the CPn, not what it is assigned to do (make myelin perhaps? who knows, if a myelin making cell had CPn in it it would not be able to do that, would it?) and it enventually dies- see the table on the quoted reference cell death is at the end.
additionally it would have inflammation

Chlamydial infections are characterized by chronic inflammation

sound like any disease you know?

All chlamydial infections induce IgM, IgG, IgA, and IgE antibodies, but these antibodies do not prevent reinfection. Although secretions from trachomatous eyes contain specific antitrachoma IgG and IgA antibodies, these antibodies do not impede the infection. Moreover, antibodies that bind to C trachomatis elementary bodies do not impair their infectivity in cell cultures

(but there is inflammation as we've already established)

The initial infection usually occurs in childhood, and the active disease eventually appears (mostly by 10 to 15 years of age (and else where in tha article it says that people may develop symptoms years after leaving a CT endemic area .MR)

SO chlamydiae are very slow insidious infections, not one that is a dramatic 'get sick get over it' in a giant reactive frenzy of illness. Nope, this is a quiet slow and stealthy infection in which antibodies do not impair infectivity and which may take years to show scarring and permanent damage.

Cultured chlamydiae are sensitive to interferon, which is produced by cultured cells infected with chlamydiae

hmmmm. how about that. I just threw that in for fun cause it was there.
this reference is a easy to read for the lay person's paper on CPn. If you are interested there is much more in depth material to be read on the subject, this paper is the easy not too deep version/overview.

So, if the cell dies eventually then is not replaced (clearly the infection should this be a factor in MS woud impact other cells nearby and eventually the repairative ability would be impacted as fewer healthy cells are available to do repair.) thus atrophy would occur it seems to me, as well as scarring and inflammation and chronic activation of the immune system. IL-15, gamma interferon, nitric oxide, potnetially glutamate as above on and on. These alterations in the immune system are plausibly nothing more than reactions to CPn as it is known that they are upregulated in CPn infection-----dang I cant get the quote to work mid paper so heres a quote:------------------------------------------------------

C. pneumoniae has also been shown to induce cytokines such as IL-1ß, IL-6, IL-8, IL-12, TNF-, IFN-, and intercellular adhesion molecule-1 in various systems such as human peripheral blood mononuclear cells, alveolar macrophages, and various mouse cell models (11, 16, 19, 22, 39). The possible relationship between C. pneumoniae and atherosclerosis led to many studies of the cytokine effects of infection on human endothelial cells and smooth muscle cells in which IL-6, IL-8, and monocyte chemotactic protein-1 were shown to be readily induced by infection and activation of NF-B was shown to be a requirement for monocyte chemotactic protein-1 gene expression (6, 32, 33, 37, 40). C. pneumoniae infection can also stimulate the production of anti-inflammatory cytokines such as IL-10, which can down regulate the expression of major histocompatibility complex class I molecules (5, 16). Interestingly, C. pneumoniae-infected epithelial cells and peripheral blood mononuclear cells are resistant to apoptosis induced by chemicals or death receptors, and this resistance is at least partially due to IL-10 induction (12, 38). Thus, the overall effect of cytokine release by host cells following C. pneumoniae infection is likely to be determined by complex interactions between beneficial and detrimental cytokine actions End quote----------------------------------------------------------------------

Wow, look at that immune system wide alterations and abnormalities, and note the similarity to MS observed cytokine upregulation Found here http://iai.asm.org/cgi/content/full/71/2/614

You might bring up the notion that older people then should be the ones diagnosed with ms IF CPn plays a role, but not really. Notice that kids are the ones with the trachoma age 10-15 for average, yet while enedemic in those areas, not everyone gets trachoma (the CT eye disease); some people resist it somehow even though as quoted above the presence of antigens does not impair infectivity this suggest there is some other resistive factor in the individual that is as yet undefined. MS is less common but all that means to me is that this is a less common complication of this illness depending on many factors for everything to fall into place "just right" for it to happen. 95% of polio victims were so mildly ill they did not know they had it. 5% had what we think of as "Polio" A very rare few died.

It is an interesting possibility in the arena of MS though not proven
Thank you for asking
Marie

BRAVO!! BRAVO!!

Rica

Marie,

How do you kill off CPn? Or is it malignant? Does the body produce antibodies against it? Sorry if you had already specified. I read through your last two postings, but may have missed it. I think you make a very strong case for the infectious theory.

I noticed on one document you referenced that it said you could "control" with tetracyclines, but does that erradicate, or limit proliferation of the bacteria?

Flagyl/metronidizole is a bactericidal antibiotic and is used to get rid of CPn totally. It tends now to be taken in pulses of about five days every three weeks, to give some respite from it. Have a look through the various postings in the regimens section. The body does produce antibodies. Testing for antibodies is one way of testing for infection, but no method is foolproof. Have a look in the treatment and physician's sections of CPn Help to find out more.

Sarah

Thank you for asking Viper. I will once again remind you that this is theoretical but here are the details as I understand them; Anyone reading this will need to see their doctor and discuss it. I am only a nurse.

There is debate in the field as to whether or not CPn can be eradicated completely from the body, but microbiology is growing in understanding constantly. I subscribe to the NIH and get the new chlamydia research emailed every week. There are about 4 papers A WEEK on the germ, how it behaves in the body and what it can do and how to fight it.

As understanding grows, so too do strategies to beat it.

Right now this is known:
--perisistence is an non replicating, non metabolizing state (hibernation if you will) which reverts to active, infective states later
--it becomes persistent in several kinds of situations including-
immune system attack via gamma interferon
subinhibitory doses of abx ie the blood level is too low to keep from
replicating for example you miss a dose or just are taking too low
--CPn has an affinity for immune system cells and it goes into the actual bacteria fighting cells of your system subverting the cell for it's own purposes. Like HIV this is a problem becasue you are not fighting with a full army so to speak. CPn gets a hold of the individual cell tuning it into a CPn factory. You immune system slowly become less and less effective as more and more cells are taken over.

David Wheldon is a microbiologist, in American terms, an MD whose specialty is germs. His wife had MS and he felt the theory for CPN put forth by the team at VU plausible so he spent a week if I rememeber right studying the best approach for killing it in spite of the fact it was thought it might not be eradicable. He reasoned that like TB we would have to

1.Stop replication with bacteriostatic agents
bacteria replicate by using proteins to build a new infective unit. A certain combo of proteins are needed to replicate for any germ. Antibiotics that are bacteriostatic block one or another protein used for this purpose, stopping replication. Eventuallyy the bacteria will learn to replicate without that particular protein and this we call resistence. In the case of CPn and also Tuberculosis (TB) you use a number of agents, the cell is essentially stuck unable to work so impaired. SO there it is stuck and unable to reproduce itself hanging out inside your cell and unable to create resistence becasue it's stalled on two fronts. It is essentially frozen there. Some will die under this condition, others will simply be in hibernation. In the case of normal germs the body simply cleans up using your immune system, but becasue CPn is hiding out inside your cells not floating around in the blood visible they are stealth pathogens and not cleaned up. Therefore bacteriostatic agents are not enough

2. Kill the intracellular frozen forms stalled by bacteriostatic agents
this is the flagyl treatment so often referred to. If you look you will find little research indicating CPn can be killed by flagyl as it kills anaerobic germs which CPn is not considred to be. HOwever it is an anaerobe when it is stalled by bacteriostatic agents- in this case it is stuck halfway between elementary body and reticular body becasue it does not have the protein it needs to finish and get to be a funcitonal RB. As an RB it is aerobic because it uses your cell's mechanisms for respiration (aerobic means using oxygen anaerobic not)but before it can complete this process of metamorphosis, it is anaerobic, which you have created witht he bacteriostatic drugs. At this point Dr Wheldon realized it would likely be sensitive to flagyl becasue of it's anaerobic situation. Thus the bactericidal (kills bacteria) flagyl is "pulsed"; you take it once a month for 5 days to kill the actual intracellular bacteria. People get loss of function during this time. Obviously if the bacteria was in the brain and it was killed the cell will die also resulting in inflammaiton of the area becasue this is not apoptosis it is necrotic cell death and it is right next to your brain cell.

IMHO This is the dicey part of treatment. It will be somewhat harmful to the cells of the brain assuming that this is it, but the germs themselves are harmful as they are inflammatory. IT's not better to leave them there in other words, if they exist (reminding you this is theoretical) But if they do not exist the drugs should not make you have inflammation and reactions of any kind as abx are considered relatively safe. (Minocycline in fact is antinflammatory and is sometimes given for its immunomodulatory property to people with MS and RA that based on the theory that MS and RA are autoimmune . In fact many abx have some immunomodulatory properties.) If this theory is true then the person undergoing treatment will have less and less reaction to flagyl with time as the bacterial load is reduced and areas are cleaned up. This has been reported by Sarah. Anecdotal? absolutely, but someone has to do it first.

Some people have noted if they plateau and stop gaining new ground they get new levels of reaction and new gains in health by using another protocol after time( see Gibbledegook's abx log), for example adding INH (often used in TB)to the profile. THis drug is hard on the liver and must be monitored closely and a peson would be a fool to drink alcohol while on it.

This is experimental. Potential problems are side effects from the drugs
for example c. difficile which can cause colitis as an over growth bacteria in the intestines, or for example liver problems particularly with azithromycin and INH, or possibly peripheral neuropathy from the Flagyl though that takes high doses and long term treatment usually to appear...by long term I mean day after day not pulsed. It would be very hard to tell PN from MS symptoms for the average person. This should not be a problem because the pulsed nature and lesser doses used in this approach should be Ok but your doc will assess this if needed. many with HIV take high doses for long periods.

To couteract some of the potential side effects there are numerous supplements (like probiotics to couteract c.difficile) outlined to be taken. See CPn Help.org or david wheldon's site

No one knows if the long term oucome is going to be complete freedom from CPn and abx if this is related to MS. Sarah is now at the 2.5 year mark and feels no different on abx than she does off them, indicating there is no inflammation in her brain as a reaction to the death of CPn as people early in treatment suffer (I fall down more ) and suggesting she is free from CPn in her brain. I will not go into the endotoxin reactions because it's beyond the scope of your question. She takes abx now once every 2 months for a week along with flagyl for 5 days, and remains well functioning and still slowly improving. Going from the original 7-8 edss to a 2 is significant as she was SPMS.

So the answer we can hope it will be completely eradicable, but we do not know yet.
marie
this is not to be construed as medical advice. It is highly speculative and theoretical.