MS as an evasion of immunity
V1.4Different mechanisms underly MS
The MS timeline shows a double peak in the graph of age of onset where a first peak appears around the age of mid 20’s and a second peak in the early 40’s. Of course we know about RR and the progressive phase, but this fact provides an indication that a two stage process is at work with different underlying mechanisms. One mechanism wanes with time, the other increases with time.
When at mid age, any new acute problems occur, this will result in more severe symptoms because the second process that causes the steady progression in the background has advanced further and if one has not already been diagnosed during the RR phase because symptoms were relatively mild, one gets diagnosed at this stage.
A detailed inspection of disability progression charts would also suggest that two largely independent mechanisms are underlying. And they may work at different places.
In the beginning, the herpes virus including herpes simplex, Varicella Zoster Virus (VZV) and Epstein-Barr Virus (EBV) spreads through the Virchow-Robin spaces in meningeal follicles, the lymphatic system and stem cells including OPCs and bone marrow.
In the RR phase, VZV/HERV in combination with toxins and/or “adjuvants” causes vasculopathies, microbleedings, endothelial inflammation, and lesion in the white matter. VZV also evades T-cell immunity but over time the immune system learns and RR wanes. VZV is believe to cause the inflammation in RR; immunologists know that VZV is an inflammatory virus. Demyelination is seen as collateral damage.
In the second phase – the progressive phase – a different mechanism is at work. An unbridled diffusion of EBV infected and immortalised B cells is seen which cause high oxidative stress. It is believed that this is a EBV/HERV related stimulation of B-cell growth and that this is a natural and healthy reaction of the immune system to prevent neoplasia/cancer. EBV would be the beneficiary. Immunologist know that EBV is an onco virus. Because of changes in innate immunity above 60 years of age, B-cell growth stops above 60 and no new cases of MS are reported but more cancers.
As we shall see in the next sections, this picture of VZV involvement in RR MS and EBV involvement in progressive MS is confirmed by epidemiological analysis. Epidemiological studies don’t lie. If framed within right boundaries, they just tell us what we see in the population and that can’t be wrong.
MS is thus a loss of epi-genetic control on HERV with VZV possibly in combination with toxins triggering cellular inflammation with an initial VZV evasion of T-cell immunity (RR), and; with EBV stimulating B-cells growth leading to huge oxidative stress and progressive mitochondrial failure. In other words, MS is caused by HERV/VZV with a herpes evasion of T-cell immunity and a deficient humoral immunity (B-cells).
Both mechanisms may assail the body in different places including the brains with white matter lesions in the first phase as well as grey matter loss including in the spinal column in the second phase. In addition, a herpetic neuralgia may cause muscles to loose weight and sensitivity [PHN]. The effect on our mobility is then the result of a degrading serial pathway from brains to muscle cells and sensors.
Varicella zoster virus vasculopathies: diverse clinical manifestations, laboratory features, pathogenesis, and treatmenthttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2814602/
Antivirus immune activity in multiple sclerosis correlates with MRI activityhttp://www.ncbi.nlm.nih.gov/pubmed/25939660
Evolutionary Aspects of Human Endogenous Retroviral Sequences (HERVs) and Diseasehttp://www.ncbi.nlm.nih.gov/books/NBK6235/
Varicella Zoster Virus and Relapsing Remitting Multiple Sclerosishttp://www.hindawi.com/journals/msi/2011/214763/
Pathogenesis and Current Approaches to Control of Varicella-Zoster Virus Infectionshttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3811230/Human immune response to herpes viruses
The multiple layers of the human immune response present a challenge to viruses, which must survive and multiply within a host for a sufficient period of time to allow successful transmission to susceptible individuals. Given the large proteomes and comparatively low polymerase error rate of human herpesviruses, antiviral immunity at first glance appear to have the upper hand. Nonetheless, herpesviruses manage prolonged incubation periods following initial infection, with systemic dissemination and prolonged secretion, often from multiple sites. In contrast to the similarly large poxviruses, the ability to subsequently establish persistent infection is a hallmark of the human herpesviruses. To enable this lifestyle, the herpesviruses devote a significant proportion of their genome coding capacity to the expression of immuno-evasins, a collection of molecules that disrupt normal immune physiology. Each human herpesvirus studied has evolved elegant cell biological solutions to problems posed by the immune response.
Innate immunity, an evolutionarily conserved and relatively non-specific system of pattern recognition molecules hardwired in the genome, cytokines such as interferons, phagocytes and natural killer (NK) cells, represents the first line deployed against microbial invaders, including herpesviruses. The clonal expansion of B- and T- lymphocytes that bear antigen-specific receptors for viral epitopes underlies the adaptive antiviral immune response, laying the groundwork for a highly pathogen-specific defense. Such specificity comes at a price – lymphocyte proliferation requires time to unfold, and innate immunity, in particular NK-cell activity, limits the initial herpesvirus spread. Indeed, NK cell immune deficiencies result in dramatic infection by several herpesviruses. There is significant cross-talk between the innate and adaptive systems, and preliminary pathogen recognition by the innate immune system directly contributes to the development of adaptive immunity. Further, the eventual adaptive response utilizes branches of the innate system for crucial effector function.
Innate and adaptive immunity act in concert to allow recovery from acute herpesvirus infection. Adaptive immunity then allows for lifelong immunological memory, affording both control of persistent herpesvirus infection and protection against reinfection. Once present, virus-specific CD4+ T-lymphocytes then coordinate the adaptive antiviral response, directing the production of virus-specific immunoglobulin by B-lymphocytes, the antiviral activity of CD8+ T-lymphocytes and NK cells, and further stimulating the activity of phagocytic cells.
Through millennia of coevolution, herpesviruses have largely reached a state of equilibrium with their human hosts. At the cost of a large proportion of their coding capacity, herpesviruses perturb adaptive immunity to achieve persistent infection, in general with remarkably little collateral damage to their hosts. However, lapses in T-cell immunity, such as by immunosuppressive agents or by coinfection with other pathogens such as Human Immunodeficiency Virus, can lead to significant herpesvirus-associated pathology.
Human herpesvirus genome size and polymerase fidelity place constraints on epitope mutation, and generally do not allow for antigenic variation as a means to avoid T-cell immunity. Herpesviruses therefore, have devised a range of mechanisms to subvert adaptive immunity. Generalized T-cell immuno-evasion strategies shared by herpesviruses include latency, restriction of viral gene expression to immunoprivileged sites such as the CNS, interference with complement, cytokines, NK-cell function, and apoptosis.
Herpesvirus evasion of T-cell immunityhttp://www.ncbi.nlm.nih.gov/books/NBK47418/Relapse-Remitting MS: Varicella-Zoster Virus and cell mediated immunity
The acute nature of RR relapses suggests that the effects of the VZV virus may block the cell machinery leading to mitochondrial malnutrition that provide insufficient energy to maintain the charge of the ion pump. Eventually, the sitation will be dramatic and the immune system, initially evaded by VZV, will correct the cells that are in crisis. One possible mechanism is through intra-cellular viral control by interferon γ (IFNγ) by T cells (arrival of CD4+ T lymphocytes, CD8+ cytotoxic T cells produce IFNγ). IFN’s are a group of proteins known primarily for their role in inhibiting viral infections. As cells recover, remittance is seen of MS symptoms.
The high load of autoreactive T- and B-cells will pass the Central Nervous System (CNS) and cross-react with the transgenes/HERVs in the OPCs. Due to this cross-reaction, many OPCs will die which leads to a diminishing number of OPCs, of dendrocytes and a reduced myelination of neurons. During this cross-reaction, many mediators will be released by the infiltrating T-cells. This will increase angiogenesis and cause hyperproliferation of surrounding tissue cells in the CNS which in turn causes the pathological lesions (sclerotic plaques) typical for MS.
A well functioning intestine with sufficient production of IFN’s is essential. A distorted gut microbiota, gut leakage and compromised cell lining caused by a “Western” diet with high fat and polysacharide may interfere with the production of IFNγ, leak toxins such as epsilon toxin into the circulation and may skew us towards getting sick.
In particular VZV which is an “inflammatory virus” is suspect at this stage. DNA from VZV was found in the CSF from 100% of MS patients studied during relapse. In contrast VZV was not found in CSF from controls. Results from other herpes viruses tested were similar in MS patients and in controls.
The participation of varicella zoster virus in relapses of multiple sclerosishttp://www.ncbi.nlm.nih.gov/pubmed/24635924
Varicella Zoster Virus and Relapsing Remitting Multiple Sclerosishttp://www.hindawi.com/journals/msi/2011/214763/
Interestingly, the presence of large quantities of DNA from VZV in subarachnoid space is almost restricted to the periods of exacerbations. Steady diminution and eventual disappearance from clinical relapse to clinical remission constitute strong evidence to support the participation of VZV in the pathogenesis of RR MS.
Varicella-zoster virus in cerebrospinal fluid at relapses of multiple sclerosishttp://www.ncbi.nlm.nih.gov/pubmed/18306233
This view is further supported by epidemiological observations [Kang]. Epidemiological studies don’t lie and if well conducted they are always right. Kang et al analysed a database of 349,477 patients who had VZV as a risk factor for MS in a region of the world historically considered low risk for MS. In the analysis, the data was compared with a randomly selected control group of participants who did not have herpes zoster that was 3 times as large as the patient sample (n = 1,262,200). The results show that the herpes zoster group has a 3.96 times greater risk of developing MS than did the control group.
The study highlights the time elapsed from the event of shingles until the ocurrance of MS, as approximately 100 days. In addition, evidence suggests that up to 30% of relapses among MS patients are associated with an infectious process. A possible explanation is the reactivation of latent herpes viruses by other infectious agents, and a cross-recognition of common viral antigens with antigens found in the myeline sheath. The time lag could be explained by a series of procresses required by the immune systems of genetically susceptible individuals to reach a “threshold” and start the disease process. The threshold may also explain, in part, the observation that some patients have higher recurrence rates of MS around a certain month of the year.
Other epidemiological studies from geographical areas, where the incidence of MS has increased in recent decades, pointed out a high frequency of varicella and zoster in the clinical antecedents of MS patients while laboratory investigations have found large quantities of DNA from VZV in leucocytes and CSF of MS patients. Again, these were restricted to the ephemeral period of MS relapses, followed by a disappearance of the virus during remission.
The above observations and the peculiar features for VZV, mainly characterised by its neurotropism and long periods of latency followed by viral reactivation, support the idea on the participation of VZV in the etiology of RR MS.
Herpes Zoster and Multiple Sclerosishttp://jid.oxfordjournals.org/content/204/2/177.full
Varicella zoster virus contributes to relapse in patients with multiple sclerosishttp://www.nature.com/nrneurol/journal/ ... o0798.html
Varicella Zoster Virus and Relapsing Remitting Multiple Sclerosishttp://www.hindawi.com/journals/msi/2011/214763/
Varicella-zoster virus particles have been found in CSF of patients during relapses, but this particles are virtually absent during remissions.https://en.wikipedia.org/wiki/Pathophys ... _sclerosis
The endothelial inflammation and microbleedings and MS
Varicella zoster virus (VZV) infects >95 % of the world population. Typically, varicella (chickenpox) results from primary infection. The virus then becomes latent in ganglionic neurons along the entire neuraxis. In immunocompromised individuals, VZV reactivates and causes herpes zoster (shingles), pain, and rash in 1-2 dermatomes. Multiple case reports showed a link between stroke and zoster, and recent studies have emerged which reveal that VZV infection of the cerebral arteries directly causes pathological vascular remodeling and stroke (VZV vasculopathy). In the past few years, several large epidemiological studies in Taiwan, Denmark, and the U.K. demonstrated that zoster is a risk factor for stroke and that antiviral therapy may reduce this risk. Herein, the history, clinical features, and putative mechanisms of VZV vasculopathy, as well as recent epidemiological studies demonstrating that zoster increases the risk of stroke, are discussed.
Endothelial cells lining the vessel wall are connected by adherens, tight and gap junctions. These junctional complexes are related to those found at epithelial junctions but with notable changes in terms of specific molecules and organization. Endothelial junctional proteins play important roles in tissue integrity but also in vascular permeability, leukocyte extravasation and angiogenesis. In this review, we will focus on specific mechanisms of endothelial tight and adherens junctions.
The endothelium connects the vascular and immune systems. It allows for permeability in the blood brain barrier, the gut and all 60,000 miles of blood and lymph vessels. The endothelial tight junctions line the vascularity and intestines.
The relationship between herpes zoster and stroke, Maria Nagelhttp://www.ncbi.nlm.nih.gov/pubmed/25712420
7T MRI: New Vision of Microvascular Abnormalities in Multiple Sclerosishttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2579786/
Endothelial adherens and tight junctions in vascular homeostasis, inflammation and angiogenesishttp://www.sciencedirect.com/science/ar ... 360700346X
Toxins and MS: Genetic rearrangement of transgenic cells
In MS, we see many patients with a leaky gut [leaky gut, ceuliacie, engrainisation…]. There is possibly a role for epsilon toxin from the gut bacteria Clostridium Perfringens. Bad gut bacteria produce for instance the ε-toxin that leak into the circulation and apparently home in on [dendric] cells that are virus infected. These are typically the OPCs because they help divide the viral genes. Other toxic substances from fungi are also suspect. Frederic Gay in his article speculates about a 50 kDa particle.
Bacterial toxins and Multiple Sclerosis, Gay F, Journal of the neurological sciences 262:1-2 2007 Nov 15 pg 105-12http://www.unboundmedicine.com/medline/ ... Sclerosis_
The bacteria Bordetella pertussis and its secreted toxin have been extensively used within the last 50 years to vaccinate against whooping cough. In the study, the bacteria appeared to induce neuropathology in experimental autoimmune encephalomyelitis, the key animal model for human MS.
Researchers say the bacteria can behave as a neuropathogen causing MS. Evidence supporting the hypothesis was the MS epidemic in the Faroe Islands during and immediately after World War II. According to the article, authors who studied the outbreak noted that “MS is the rare late outcome of a specific but unknown infectious disease of adolescence and young adulthood.”
Epidemiologic evidence for multiple sclerosis as an infectionhttp://www.ncbi.nlm.nih.gov/pubmed/8269393
Clostridium perfringens Epsilon Toxin Causes Selective Death of Mature Oligodendrocytes and Central Nervous System Demyelinationhttp://mbio.asm.org/content/6/3/e02513-14
Why do ε-toxin home in on OPCs? In fact, they may home in on all cells but in OPCs the "fertile" ground is found to do the genetic rearrangement. Which then shows up as microbleedings and white matter lesions. The herpes virus including VZV infect in particular OPCs and bone marrow because these cells divide.
It is postulated that ε-toxin, but perhaps other bacterial cell molecules and transportable proteins as well e.g. from the naso pharynx and/or from the gut, trigger transgene herpes/VZV primed cells to activate intra-cellular events e.g. through sharing segments of DNA. This would lead to the release of pro-inflammatory lipid mediators, enzymatic activities and modified cell signaling events.
Also mycotoxins such as black mold (stachybotrys) may trigger MS. The environment of Scotland and Seattle are extremely similar in many ways: they are on almost the same latitude, they are both maritime climates with average temperatures between 40's-60's Fahrenheit with 100% humidity. Both places rarely get strong heat or clear strong sun or enough UV rays to dry out moldy houses, cars, etc and dry out or kill spores in the air, nor does either place get much of a hard freeze to arrest mold growth and dry out air. With the advent of air conditioning, places that are normally very dry and sunny like Kuwait, are seeing an explosion in MS.
In other words, 'synergetic effects' of virus and bacterial and myco-toxins working together that Buhner talks about in his book Healing Lyme disease coinfections cause havoc in the cell’s genetic arrangement, shedding cytokines and chemokines and leading to inflammation and microcellular bleedings.
Clostridium perfringens Epsilon Toxin Causes Selective Death of Mature Oligodendrocytes and Central Nervous System Demyelinationhttp://mbio.asm.org/content/6/3/e02513-14
Healing Lyme Disease Coinfections: Complementary and Holistic Treatments for Bartonella and Mycoplasmahttp://www.amazon.com/Healing-Lyme-Dise ... me+disease
The role of the gut on cell mediated immunity (epigenetic control):
Our “Western” diet causes an effect on IFNγ and IL17 production which in turn causes an effect on cell-mediated immunity with T-cell (IFNγ) mediation. During periods of low immunity, periodic reactivation from latent viral reservoirs results in viral subclinical shedding and the associated inflammation with continued neurological and developmental issues.
When a representative model of the human gut eco-system was established in mice, switching from low-fat, plant polysaccharide-rich diet to a high fat, high sugar “Western” diet shifted the structure of the microbiota of these “humanized” mice in a single day and changed the metabolic pathways in the micro biome and its gene expression.
The Effect of Diet on the Human Gut Microbiome: A Metagenomic Analysis in Humanized Gnotobiotic Micehttp://stm.sciencemag.org/content/1/6/6ra14
Interferon Gamma (IFN-g)http://www.bio.davidson.edu/courses/imm ... gamma.html
Germ free mice induced for EAE produced lower levels of proinflammatory cytokines, IFNγ and IL17 in both the intestine and the spinal cord and displayed reciprocal increase of CD4 T cells.http://www.pnas.org/content/108/Supplem ... nsion.html
Some microbe families from the gut microbiota however promote the inflammatory cascade in the CNS. The strongest here being the unculturable Clostridium family of which the Segmented Filamentous Bacteria is the most active and have a key role in the coordinated maturation of gut helper T cell responses.
The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responseshttp://www.ncbi.nlm.nih.gov/pubmed/19833089
This observation coincides with the recent finding on ε-toxin: Clostridium perfringens Epsilon Toxin Causes Selective Death of Mature Oligodendrocytes and Central Nervous System Demyelination. It would thus occur that cell mutation is incited by both a lack of IFN γ combined with a toxic microcellular environment.
Clostridium perfringens Epsilon Toxin Causes Selective Death of Mature Oligodendrocytes and Central Nervous System Demyelinationhttp://mbio.asm.org/content/6/3/e02513-14Impaired transport from Golgi apparatus results in evasion of T-cell immunity
Abendroth et al (2001) sought to examine the effects of varicella-zoster virus (VZV) infection on the expression of major histocompatibility complex class I (MHC I) molecules by human fibroblasts and T lymphocytes. They found that VZV downregulates MHC I expression by impairing the transport of MHC I molecules from the Golgi compartment to the cell surface. This effect may enable the virus to evade CD8+ T-cell immune recognition during VZV pathogenesis, including the critical phase of T-lymphocyte-associated viremia.
Varicella-zoster virus retains major histocompatibility complex class I proteins in the Golgi compartment of infected cellshttp://www.ncbi.nlm.nih.gov/pubmed/11312359
High anti-golgi autoantibody levels: an early sign of autoimmune disease?http://www.ncbi.nlm.nih.gov/pubmed/10468179
Antibodies from patients with autoimmune disease react with a cytoplasmic antigen in the Golgi apparatushttp://www.ncbi.nlm.nih.gov/pubmed/6373921
The Golgi complex is an organelle involved in terminal processing, sorting and transporting of proteins to their final destinations.
Anti golgi antibodies and cryoglobulinshttp://medind.nic.in/iac/t12/i1/iact12i1p16.pdf
Cell surface expression of class I molecules is reduced upon VZV infection, an effect that has been observed in both human T-cells in the SCID-hu thymus/liver mouse model and in skin biopsy specimens. Microscopic and biochemical experiments demonstrate the accumulation of class I MHC molecules in the Golgi compartment in VZV-infected cells.
The ORF66 gene-product is expressed during the early period of virus infection and serves to retain class I molecules in the Golgi complex. Cellular transfectants that express ORF66 demonstrate reduced cell surface expression of class I MHC. The molecular mechanism by which VZV halts class I in the Golgi has yet to be fully elucidated. The UL49.5 gene-product of several varicelloviruses including bovine herpesvirus I, pseudorabies virus, and equine herpesvirus 1, though not of varicella zoster, blocks the TAP peptide transporter through conformational arrest and subsequent proteasomal degradation.
Dendritic cells (DCs) are professional antigen-presenting cells that play a crucial role in stimulation of adaptive T-cell responses. Multiple members of the human herpesvirus family decrease the capacity of DC to stimulate T-cells.
Infection of DCs by other herpes viruses can even facilitate VZV dissemination and support infection of T-cells themselves. VZV-infected T-lymphocytes play an important role in supporting persistent viremia.
VZV also interferes with Jak/STAT signaling, apparently by the inhibition of Jak/STAT2 protein synthesis.
Herpesvirus evasion of T-cell immunityhttp://www.ncbi.nlm.nih.gov/books/NBK47418/Progressive MS: Epstein-Barr Virus and deficient humoral immunity
Many observations implicate Epstein–Barr virus (EBV) in the pathogenesis of MS, namely universal EBV seropositivity, high anti-EBV antibody levels, alterations in EBV-specific CD8+ T-cell immunity, increased spontaneous EBV-induced transformation of peripheral blood B cells, increased shedding of EBV from saliva and accumulation of EBV-infected B cells and plasma cells in the brain.
Several mechanisms have been postulated to explain the role of EBV in the development of MS including cross-reactivity between EBV and CNS antigens, bystander damage to the CNS by EBV-specific CD8+ T cells, activation of innate immunity by EBV-encoded small RNA molecules in the CNS, expression of αB-crystallin in EBV-infected B cells leading to a CD4+ T-cell response against oligodendrocyte-derived αB-crystallin and EBV infection of autoreactive B cells, which produce pathogenic autoantibodies and provide costimulatory survival signals to autoreactive T cells in the CNS.
The rapidly accumulating evidence for a pathogenic role of EBV in MS provides ground for optimism that it might be possible to prevent and cure MS by effectively controlling EBV infection through vaccination, antiviral drugs or treatment with EBV-specific cytotoxic CD8+ T cells. Adoptive immunotherapy with in vitro-expanded autologous EBV-specific CD8+ T cells directed against viral latent proteins was recently used to treat a patient with secondary progressive MS. Following the therapy, there was clinicall improvement, decreased disease activity on magnetic resonance imaging and reduced intrathecal immunoglobulin production.
Epstein–Barr virus and multiple sclerosis: potential opportunities for immunotherapyhttp://www.nature.com/cti/journal/v3/n1 ... 1425a.html
The B-cell mechanism that occurs as of mid-age but that is probably underway much longer is a different mechanism all together than the VZV mechanism underling RR MS. EBV infected B-cells cause immune subversion and disease progression. With the virtual non-existence of MS in EBV seronegative people (still 5 - 10 % of population), epidemiological analysis would seem to confirm the very strong relationship of EBV with MS.
Universal EBV seropositivity, high EBV antibody levels and alterations in EBV-specific CD8+ T-cell immunity are commonly observed and likely to be an important contributing factor to MS rather than the result of MS.
The EBV virus has spread so far that increasingly B-cells get infected with a lack of sufficient T-cell control function to contain an unbridled B-cell replication. In fact, HERV may help T-cells to stimulate B-cell growth factors via a viral superantigen in order to stimulate growth of its host cell, the B-cell. EBV is the beneficiary; otherwise EBV infected cells might develop into cancers and that would be the end of story.
Disruption of the highly evolved balance (after many millions of years of co-evolution) between the EBV lytic and latent life cycles and host immune control results in a range of EBV-associated diseases involving B-cells, epithelial cells, T-cells, natural killer (NK) cells and muscle cells.
Here a weak [epigenetic] control may activate HERV virus and contribute to a spreading of the disease in meningal follicles. Staphylococcal immune complexes and myelinolytic toxin in early acute MS lesions connects the matter to EBV proliferation from the pharyngeal cells.
Viruses as an endothelial disrupters
The association between EBV infection and CCSVI has not yet been explored; however, it could be hypothesized that venous stasis in the superior saggital sinus due to extracranial outflow impairment could affect the drainage of bridging veins that pass through the subarachnoid space (near the meninges and EBV-infected B-cell follicles) and contribute to EBV activation. The venous stasis hypothesis in the SSS may contribute to understanding why so many different viruses and bacteria have been linked to increased MS susceptibility risk over the last 50 years.http://ccsviinms.blogspot.be/2011/08/bn ... d-ebv.html
MS and B cell depletion:
A new study has uncovered a type of B cell that may fuel inflammation in patients with multiple sclerosis. The findings help explain the long-standing question of why an experimental therapy that removes these immune cells from the body is effective against the disease. Selectively eliminating the pool of rogue B cells, while sparing healthy B cells, may offer a more targeted approach for treating multiple sclerosis and potentially other autoimmune disorders. Some [B cells] may be bad in MS and some may actually be beneficial. The subset of pro-inflammatory B cells may also serve as a potential marker of disease relapse and patients' response to treatment.
Multiple sclerosis is traditionally viewed as a T cell-driven disease. In this autoimmune disorder, the immune system, primarily T cells as well as immune cells called myeloid cells, are thought to destroy myelin, a fatty substance that insulates and protects nerve fibres. [This is RR]
B cell depletion therapy, which removes B cells from the blood, can keep relapses at bay in multiple sclerosis patients. The success of this treatment in clinical trials has put the spotlight on B cells as key players in the disease. B cells are best known for their ability to make antibodies, and abnormal antibodies are common in multiple sclerosis patients.
However, the B cell depletion treatment has little effect on the abnormal antibodies found in these patients. This "striking and surprising observation" led Bar-Or and colleagues to suspect functions for B cells beyond antibody production, he said. B cells fulfil other important roles, including secretion of cytokines, small signalling proteins that can either quench or promote inflammation.
Analysing B cells in blood samples from multiple sclerosis patients and healthy individuals, and studying patients' immune responses before and after B cell depletion therapy, Bar-Or's team identified a subpopulation of B cells that releases a powerful pro-inflammatory cytokine called GM-CSF, which is known to drive inflammation in the brain.
Compared to healthy individuals, untreated multiple sclerosis patients had abnormally abundant and more readily activated GM-CSF-producing B cells. These B cells stimulated myeloid cells in a dish to secrete pro-inflammatory cytokines, which in turn can activate pro-inflammatory T cells.
After undergoing B cell depletion therapy, multiple sclerosis patients experienced fewer flare-ups of their symptoms and showed reduced inflammation in their blood. The results suggest that by partially eliminating the rogue B cell pool, the therapy may have blunted inflammation triggered by myeloid cells and T cells. These benefits persisted for months after treatment and even as patients formed new B cells.
While B cell depletion therapy has proven highly effective in advanced clinical trials, its long-term safety remains to be seen. The therapy "may be taking some of the good with the bad, so by getting a better sense of who the bad guys are, we can hopefully develop treatments that are as effective and potentially even safer," said Bar-Or.
Rogue B Cells May Drive Inflammation in Multiple Sclerosis, American association for the advancement of science, 27/10/15http://www.aaas.org/news/rogue-b-cells- ... clerosis-0Oxidative stress leads to mitochondrial failure and disease progression
EBV infected B cells cause a huge oxidative stress on the mitochondrial membranes with insufficient protective cellular feeding and antioxidant mechanisms (such as astrocytes). As a consequence, mitochondria will fail one by one up to the point where the ion pump cannot maintain the equilibrium of charging to perform normal motor operation. This occurs first because the ion pump needs most energy, in fact more than the muscle cells. At this point, cells may not have died but have become ‘electrically’ dormant. The neurological path is weakened.
Characterization of the superoxide-generating system in human peripheral lymphocytes and lymphoid cell lineshttp://www.ncbi.nlm.nih.gov/pubmed/7592536
Peroxynitrite: biochemistry, pathophysiology and development of therapeutics, Csaba Szabóhttp://www.enzim.hu/~lbarna/articles/17667957.pdf
Oxidative stress has been strongly implicated in both the inflammatory and neurodegenerative pathological mechanisms in MS. In response to oxidative stress, cells increase and activate their cellular antioxidant mechanisms. Glutathione (GSH) is the major antioxidant in the brain, and as such plays a pivotal role in the detoxification of reactive oxidants. Previous research has shown that GSH homeostasis is altered in MS.
Glutathione in multiple sclerosis: more than just an antioxidant?http://www.ncbi.nlm.nih.gov/pubmed/24842957
Oxidative stress is often seen in papers about SNP, epigenetics and the gut microbiome. There, it is often argued that oxidative stress follows when it has all gone wrong. But it might be different where oxidative stress contributes to the cause, where oxidative stress puts in motion a vicious cycle. This would also explains why the massive use of antioxidants may start to make a difference, after some period of time. [Terry Wahls had her metabolism flooded with supplements for quite a while before she started the diet and recovered from MS.]
If identical twins get separated at young age but before adolescence, the person that moves further South has less risk to develop MS at a later date. That person will have more sun exposure and therefore a higher vitamin D level in the circulation during adolescence when the body goes through a main phase of cellular growth. When the cells are formed, they take vitamin D directly from the circulation where the vitamin D level determines the number of mitochondria per cell (1500-3000; the heart up to 5000, Sinatra). And when the cells have more mitochondria, they will be more resilient. And one is better protected against MS or rheuma arthritis.
Mitochondria May Play a Role in MS Development and Progressionhttp://multiplesclerosisnewstoday.com/2 ... ogression/
Besides a cross-reaction with transgenic OPCs (cause collateral damage on myelin and endothelial inflmmation), the autoreactive B-cells have substantial super-oxygen generating capability (the mechanism to prevent recurrent infections). The superoxide reacts with the nitric oxide (NO) in the cell membranes and produces excess peroxynitrite which is by far the worst free radical. Peroxynitrite is the cyclic culprit of immune system apoptosis and responsible for the damage in MS. [Scaby]
Peroxynitrite-induced membrane lipid peroxidation: the cytotoxic potential of superoxide and nitric oxidehttp://www.ncbi.nlm.nih.gov/m/pubmed/1654835
Results indicate that the oligodendrocyte loss and demyelination observed in MS and spinal cord injury may be due to the toxic effects of Peroxynitrite on oligodendrocytes.http://www.sciencedirect.com/science/ar
Peroxynitrite, generated by the reaction of nitric oxide (NO) with superoxide at sites of inflammation, is a strong oxidant capable of damaging tissues and cells. Detection of nitrotyrosine (NT) at inflammatory sites serves as a biochemical marker for peroxynitrite-mediated damage. In this study, NT was detected immunohistochemically within autopsied CNS tissues from six of nine multiple sclerosis (MS) patients, and in most of the MS sections displaying inflammation. Nitrite and nitrate, the stable oxidation products of NO and peroxynitrite, respectively, were measured in cerebrospinal fluid samples obtained from MS patients and controls. Levels of nitrate were elevated significantly during clinical relapses of MS. These data suggest that peroxynitrite formation is a major consequence of NO produced in MS-affected CNS and implicate a role for this powerful oxidant in the pathogenesis of MS.
Peroxynitrite is highly destructive causing Apoptosis, Programmed Cell Death, Oxidative stress, ROS,
RNS, DNA oxidation and nitration, Lipid oxidation, peroxidation and nitration, Protein oxidation.
DNA strand alterations and breakdown, Mitochondrial dysfunction.
Reduced cortical microvascular oxygenation in multiple sclerosis: a blinded, case-controlled study using a novel quantitative near-infrared spectroscopy methodhttp://www.nature.com/articles/srep16477
Although the peroxynitrite may inhibit viral replication, it disables glyceraldehyde 3 phosphate which impacts the sodium/potassium pump and cell viability. Over time the vitality of the cell declines as ATP levels decline and the loss of some AMP leads to a fall in Adenosine (endogenous inhibitor of arachidonic acid) and a loss of purine from Adenosine loss.
Ultimately energy levels decline and uric acid levels fall. The loss of Adenosine and cellular IFNγ will lower the ability to control inflammation and indeed the suppression of the transfer of EBV from latently infected cells to other cells. And the endothelium inflammates leading to an endothelial dysfunction.
As regards the anti-inflammatory properties of Adonesine (the A in ATP), Adenosine is a purine. The last step in the metabolism of purines is Uric acid. As Uric acid is low in MS, it is likely the recycling is faulty. Probably cells convert 2 ADP into 1 ATP and 1 AMP. The AMP washes out of the cell and the ATP is spent to become ADP and then combines with another ADP to become ATP and AMP again but the purine gets gradually lost to the cell until it is unviable. Uric acid also is a scavenger of peroxynitrite so the cycle worsens over time.
The huge oxidative stress jams mitochondria of the cells, causes effects on the mitochondrial electron transport chain and ion pump inactivation, inhibits ADP to ATP conversion and depletes energy in the form of ATP resulting in a mitochondrial energy failure.
As the ion pumps already run on their edge where a number of mitochondria in the cell have failed, the equilibrium can not be easily maintained. When cell gates close with increasing temperature (either from the outside or fever induced; cooler weather or high air pressure have the reverse effect), the conduction of the nerve path runs down. Here the ion pumps are the most important energy consumers that require the biggest amount of cellular energy.
Metabolic Cardiology, Steven Sinatrahttp://www.amazon.com/Sinatra-Solution- ... en+sinatra
Energy transduction: uses of ATPhttp://biochem-vivek.tripod.com/id55.html
Cellular respirationhttps://sites.google.com/site/accessrev ... espiration
As the number of active gates/mitochondria per cell decreases, we see an increasingly big temperature effect in patients with MS and a loss of muscle strength and sensitivity in the periphery. As cells shrink in size because gates/mitochondria successively fail, it causes whole brain atrophy.
Hence, the typical fatigue, weakening of muscles and whole-brain atrophy observed in MS patients is partly caused by the EBV infected B cells but with a completely different underlying mechanism than the demyelinating plaques in the brains. And the typical MS motor dysfunction will be caused by a combination of factors.
If the health of the mitochondria runs down, the heat effect - a natural protective mechanism of the cells that closes the gates or slows down the cells - will become more pronounced. If it gets colder, the mitochondria will work faster. And the pump charges better, and even progression may slow down.
Strictly speaking, it is not the ion channels themselves that are impaired. It is the supply of energy to the ion channels that declines. T he availability of energy to the ion channel, which is ATP dependent, and thus the formation of ATP in the mitochondria. That in turn is dependent on fats and nucleic acids from the glycolysis side and the functioning of the electron transport chain on the other. Then it depends on the permeability of the membrane for ADP and ATP which is carnitine dependent. The carnitine would need a fatty acyl CoA enzyme (also ATP dependent) to become acetyl-L-carnitine.
(Short term) stressors initiate cases of multisystem illnesses by stimulating nitric oxide synthase (NOS) activity and consequently produce increased levels of NO and its oxidant product peroxynitrite. The immune system will be triggered by the biochemical cycle mechanism with NF-кB a first responder to the harmful cellular stimuli. The increased NF-кB activity will lead to increased iNOS activity by stimulating through the inflammatory cytokines the activity of the iNOS gene itself.
NO synthase is influenced by sex hormones, is higher in women which explains the gender bias in autoimmunity. Further, the study below supports the hypothesis of a direct involvement of HERV-W/MSRV in MS pathogenesis, identifying a genetic marker on chromosome X that could be one of the causes underlying the gender differences in MS. The gender bias may therefore be a combination of hormonal and genetic factors.
HERV-W polymorphism in chromosome X is associated with multiple sclerosis risk and with differential expression of MSRVhttp://www.retrovirology.com/content/11/1/2
In the chain of events leading to MS, at some point the HPA axis may also get affected with consequences for cortisol production and with that gut functioning resulting in yet another vicious cycle.http://www.amazon.com/Explaining-Unexpl ... artin+pall
Nitric Oxide and health:
NO is one molecule of nitrogen and one of oxygen. It is a gas and when formed naturally in the body is a signalling agent. It is critical for good health and is responsible for vasodilation and is integral to prevention of hypertension, limiting arterial plaques, modulating cholesterol, controlling bacterial infection, bone density and managing inflammation. It is in every cell, tissue and organ in your body.
Nitric oxide diffuses out of the endothelium into the smooth muscle of the artery.
The production of NO is triggered three enzymes known as Nitric Oxide synthases. They are either constitutive such as endothelial (eNOS) and neuronal (nNOS) or inducible (iNOS). The various forms of NOS oxidize L-arginine to produce NO.
The Truth About L-Arginine https://www.youtube.com/watch?v=IPd2NB9mjaM
Peroxynitrite is the product formed by the interaction of NO and Superoxide. Normal oxygen gas in the body is O2 which is two molecules of oxygen. Superoxide is two molecules of oxygen with an extra electron. It has a negative charge and is what we call a free radical.
Combining NO and superoxide creates another free radical called peroxynitrite. This is a particularly troublesome product as it can disable the enzyme Glyceraldehyde-3-phosphate dehydrogenase. This is an acidic protein that acts as the major link between carbohydrate metabolism and lipid metabolism and is key in the breakdown of sugars when converting glucose to pryruvate. The energy released in that process forms ATP and that is required to drive the citric acid cycle.
A lack of ATP will prevent the correct exchange of sodium and potassium through the cell resulting in cells that are sodium clogged. That overload of sodium will also trigger the release of calcium into the cell from the sarcoplasmic reticulum signalling muscles to contract. The protein strands in the contracted muscles require ATP to signal them to release. As it is in short supply our muscles stay tight. If this process arises during a major inflammatory attack then it may be associated with a reperfusion injury which will result in some cells becoming denatured and some ion channels may be jammed open or shut.
The 1998 Nobel prize was awarded to three US researchers only six years after they published for their work on the role of Nitric Oxide. The gas was named the molecule of the century. NO is a major messenger in talk between cells.
Louis Ignarro “Nitric Oxide: Biology and Pathobiology” http://www.amazon.com/Nitric-Oxide-Seco ... thobiology