Multiple Sclerosis- an Alternative HypothesisHeidi Lindborg, MLIS

June 17, 2009

I believe there is enough evidence in the literature to consider the possibility that Multiple Sclerosis is a variant of the Zombie disorders.

It is what I consider a "tertiary" interaction. In addition to the herpes virus and antigliadin, there is another vector involved in the mechanism of the pathology.In this case another pathogen is required to disable the cells which surround the motor neurons in the brain.

Multiple Sclerosis(MS) occurs when motor neurons in the brain are damaged. Motor neurons have a long axon body which terminates in a muscle fiber which it stimulates. The axon is covered by other cells (oligodendrocytes) which produce a fatty substance called myelin. Myelin acts as an "insulator" for the electrical "wire" that is the neuron. Myelinated neurons propagate signals roughly 150 times faster than unmyelinated neurons. The acute motor symptoms of MS are thought to be caused by the inefficient conduction of the nerve impulse due to loss of myelin.

Historically, MS has been considered to be strictly a dysfunction of the oligodendrocytes which produce the myelin coating on the motor neurons. The lesions in MS are mostly made of aggregates of myelin. According to the current immunological explanation the demyelination process is triggered by T cells. T cells gain entry into the brain via the blood-brain barrier (BBB) during an unrelated viral infection. These lymphocytes recognize myelin as foreign and attack it as if it were a viral protein. When the viral infection subsides, the BBB tightens up and the symptoms subside. 

I propose a slightly different mechanism to account for the damage seen in MS.Unlike Parkinson's disease which shows slow incremental accumulation of symptoms, Multiple sclerosis can be marked by definite periods of symptomatic activity and latency. Not only that but these periods aggregate into overlapping yet distinct patterns. As there are four basic patterns with two axes, this argues for at least two variables interacting to produce the presentation of symptoms. I believe separate pathologies of the neurons and their associated oligodendrocytes may account for this variability. The patterns result because the symptoms are caused not only the decreased transmission rate caused by demyelination, but also accumulating underlying damage to the motor neuron itself.

This is how I think it might work: A pathogen invades the oligodendrocytes shuts them down. They atrophy and

the myelin coating on the axon degenerates. While the axon is demyelinated herpes can infect the underlying neuron.1

At the same time, the herpes virus promotes neuronal internalization of antigliadin antibodies and causes an accumulation of alpha-synuclein.

In the meantime the viral activity in the oligodendrocytes activates an immune response which results in latency of that virus. The cells recover and remyelinate the axon.

The herpes-antigliadin interaction in the neuron is effectively curtailed by physical obstruction.

Symptoms subside until circumstances reactivate the latent viruses in the oligodendrocytes and the process begins again.

However, each time this happens the neuron accumulates more alpha-synuclein, making it less vigorous. Since myelin production by oligodendrocytes is stimulated in proportion to the activity of the underlying neuron2, the myelin sheath becomes weaker and the cells are more susceptible to further viral activation.

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Here are the studies I have found to support this hypothesis:

Although demyelination is a cardinal feature in multiple sclerosis, neuronal injury also occurs.3

Neuronal pathology occurs in part independently of myelin plaque formation and this might help explain the observed dissociation between markers of inflammatory demyelination and disease progression.4

During early exacerbations of chronic multiple sclerosis, selective demyelination was associated with almost complete preservation of oligodendrocytes in the majority of cases.5

Alpha synuclein accumulation has been found in the plaques and motor neurons in MS.

1 Herpes simplex virus in the vestibular ganglion and the geniculate ganglion-role of loose myelin.Wakisaka H, Kobayashi N, Mominoki K, Saito S, Honda N, Hato N, Gyo K, Matsuda S.J Neurocytol. 2001 Aug;30(8):685-93.2 Axonal signals in central nervous system myelination, demyelination and remyelination.Coman I, Barbin G, Charles P, Zalc B, Lubetzki C.J Neurol Sci. 2005 Jun 15;233(1-2):67-71. Review.3 Grey matter pathology in multiple sclerosis.Bö L, Geurts JJ, Mörk SJ, van der Valk P.Acta Neurol Scand Suppl. 2006;183:48-50. Review.4 Gray matter involvement in multiple sclerosis. Pirko I, Lucchinetti CF, Sriram S, Bakshi R.Neurology. 2007 Feb 27;68(9):634-42. Review. 5 Patterns of oligodendroglia pathology in multiple sclerosis.Ozawa K, Suchanek G, Breitschopf H, Brück W, Budka H, Jellinger K, Lassmann H.Brain. 1994 Dec;117 ( Pt 6):1311-22.

 Alpha-synuclein immunoreactivity was found in the cytoplasm of neurons, activated microglia, and oligodendrocytes within and surrounding the MS lesions. This alpha-synuclein immunoreactivity was preferentially expressed in lesions of the brainstem.6

In addition, increased alpha-synuclein expression was detected in neurons and glia in and close to MS lesions. Although the increased expression of alpha-synuclein was detected as a granular cytoplasmic labeling rather than inclusion bodies, this result does suggest that neuronal cell death in immune-mediated demyelinating disease may share some common features with other neurodegenerative conditions.7

(I suspect the alpha-synuclein aggregates as granules instead of Lewy Bodies due to a lack of the requisite aggresomal proteins.)

MS has been associated with high levels of herpes virus antibodies.  DNA from HSV3 was found in 95% of MS patients during relapse and in 17%

during remission; all controls were negative.8 9

IgG antibodies: A study has shown that nonspecific IgG antibodies can be taken up in a dose

dependent fashion by motor neurons of the brain which have axons projecting to the periphery through a process of internalization (endocytosis) and  cell to cell transmission (retrograde axonal transport). 10 11 12

Highly significant increases compared with controls were found for IgA and IgG antibodies against gliadin and gluten.13

MS is associated with celiac related HLA genes. HLA-DQB1 *0201 and *0302 alleles have been correlated with multiple

sclerosis.14

There is a strong association between MS and the DQB1*0602 gene, which is also associated strongly with narcolepsy.15

8 Varicella-zoster virus at relapses of multiple sclerosis.Sotelo J, Ordoñez G, Pineda B.J Neurol. 2007 Apr;254(4):493-500. Epub 2007 Mar 31.9 Varicella-zoster virus in cerebrospinal fluid at relapses of multiple sclerosis.Sotelo J, Martínez-Palomo A, Ordoñez G, Pineda B.Ann Neurol. 2008 Mar;63(3):303-11.10 Immunoglobulin Fc gamma receptor promotes immunoglobulin uptake, immunoglobulin-mediated calcium increase, and neurotransmitter release in motor neurons.Mohamed HA, Mosier DR, Zou LL, Siklós L, Alexianu ME, Engelhardt JI, Beers DR, Le WD, Appel SH.J Neurosci Res. 2002 Jul 1;69(1):110-6.11 Intraneuronal IgG in the central nervous system: uptake by retrograde axonal transport.Fabian RH, Petroff G.Neurology. 1987 Nov;37(11):1780-4.12 Uptake of plasma IgG by CNS motoneurons: comparison of antineuronal and normal IgG.Fabian RH.Neurology. 1988 Nov;38(11):1775-80.

HLA-DRB1*1501, -DQB1*0301, -DQB1*0302, -DQB1*0602, and -DQB1*0603 alleles are associated with more severe disease outcome in patients with multiple sclerosis. 16

In addition, individuals carrying two sets of risk genes have a highly increased risk of MS compared with individuals who carry none. 17

Symptoms which indicate orexin system dysfunction are common: Depression and anxiety are significant problems. 18 19 20

Pain syndromes can be common in MS patients. 21

Sleep disorders such as insomnia, sleep movement and breathing disorders, and narcolepsy are pervasive in patients with multiple sclerosis.22

Several herpes viruses can infect the oligodendrocytes, which complicates the matter even further.

Epstein Barr virus (HHV4) is highly associated with relapsing-remitting MS. 23

EBV specific T cells from patients with multiple sclerosis cross react with myelin antigens. 24

Cytomegalovirus (HHV5) is associated with multiple sclerosis.25

Recent reports show that HHV-6 is expressed to an unusual degree in the oligodendrocytes of multiple sclerosis patients, and these studies suggest an association of HHV6 with the etiology or pathogenesis of multiple sclerosis 26

In addition there are a number of other viruses and bacteria known to cause demyelination. 27

Possible Scenarios-

Relapsing/Remitting MS-In this form or stage of MS there are attacks, during which new symptoms appear and/or existing ones become more severe. They can last for varying periods (days or months) and are followed by partial or total recovery and remission. There may be months or years between attacks. However, the disease process is ongoing and damage continues, microscopic lesions and axonal loss silently proceed.

I believe this pattern indicates two separate pathologies as I described above. One pathogen which shuts down the oligodendrocytes and the HHV3/Antigliadin combo which affects the neuron. The subsequent remyelination of the neuron eventually protects it from antibody infiltration, allows it to release the neurotransmitter, and clears out some of the accumulated alpha-synuclein.

Secondary/Progressive MS - In individuals who initially had Relapsing MS , the disease pattern changes, evolving into the Progressive stage. Recovery from attacks become less and less complete, deficits increase and disability grows.

I believe at this stage the neuron has accumulated enough alpha-synuclein to affect its activity level. Since myelin production by oligodendrocytes is stimulated in proportion to the strength of the underlying neuron, the myelin sheath becomes weaker and the cells are more susceptible to further viral activation and antibody infiltration resulting in the accelerating damage.

6 Jian-Qiang Lu, Yan Fan, Alim P Mitha, Wee V YongInvolvement of Alpha-Synuclein in Neurodegeneration in Multiple Sclerosis?FASEB. 2008 22:173.12 Meeting Abstract7 Upregulation of alpha-synuclein in neurons and glia in inflammatory demyelinating disease.Papadopoulos D, Ewans L, Pham-Dinh D, Knott J, Reynolds R.Mol Cell Neurosci. 2006 Apr;31(4):597-612. 13 IgA antibodies against gliadin and gluten in multiple sclerosis.Reichelt KL, Jensen D.Acta Neurol Scand. 2004 Oct;110(4):239-41.14 HLA-DQB1 genotype in Sardinian multiple sclerosis: evidence for a key role of DQB1 *0201 and *0302 alleles.Marrosu MG, Muntoni F, Murru MR, Costa G, Pischedda MP, Pirastu M, Sotgiu S, Rosati G, Cianchetti C.Neurology. 1992 Apr;42(4):883-6.15 Association of HLA-DR and -DQ genes with narcolepsy in Koreans: comparison with two control groups, randomly selected subjects and DRB1*1501-DQB1*0602--positive subjects.Roh EY, Park MH, Park H, Park DH, Choi JB, Kim SJ, Jeong DU.Hum Immunol. 2006 Sep;67(9):749-55. Epub 2006 Jun 30.16 HLA-DRB1*1501, -DQB1*0301, -DQB1*0302, -DQB1*0602, and -DQB1*0603 alleles are associated with more severe disease outcome on MRI in patients with multiple sclerosis.Zivadinov R, Uxa L, Bratina A, Bosco A, Srinivasaraghavan B, Minagar A, Ukmar M, Benedetto S.Int Rev Neurobiol. 2007;79:521-35.17 Inheritance mode of multiple sclerosis: the effect of HLA class II alleles is stronger than additive.Boon M, Nolte IM, De Keyser J, Buys CH, te Meerman GJ.Hum Genet. 2004 Sep;115(4):280-4.18 Multiple sclerosis beyond EDSS: depression and fatigue.Ziemssen T.J Neurol Sci. 2009 Feb 1;277 Suppl 1:S37-41.19 The burden of mental comorbidity in multiple sclerosis: frequent, underdiagnosed, and undertreated.Marrie RA, Horwitz R, Cutter G, Tyry T, Campagnolo D, Vollmer T.Mult Scler. 2009 Mar;15(3):385-92. 20 Social anxiety in a multiple sclerosis clinic population.Poder K, Ghatavi K, Fisk JD, Campbell TL, Kisely S, Sarty I, Stadnyk K, Bhan V.Mult Scler. 2009 Mar;15(3):393-8. 21 Central pain in multiple sclerosis - Sensory abnormalities.Osterberg A, Boivie J.Eur J Pain. 2009 Apr 7. 22  Sleep disorders in multiple sclerosis.Fleming WE, Pollak CP.Semin Neurol. 2005 Mar;25(1):64-8. Review.23 An altered immune response to Epstein-Barr virus in multiple sclerosis: a prospective study.Sundström P, Juto P, Wadell G, Hallmans G, Svenningsson A, Nyström L, Dillner J, Forsgren L.Neurology. 2004 Jun 22;62(12):2277-82.24 EBNA1-specific T cells from patients with multiple sclerosis cross react with myelin antigens and co-produce IFN-{gamma} and IL-2.

Primary/Progressive MS - This form of MS is characterized by a slow steady onset, usually beginning with problems walking, steadily worsening disability, but with a total lack of distinct inflammatory attacks. Fewer and smaller cerebral lesions, yet increased spinal cord damage and axonal loss are typical of this form of MS.

This linear progression argues for more distinctly neuronal process. That somehow the viruses and antibodies infiltrate the motor neurons without periods of demyelination.

Progressive/Relapsing MS - This subtype of Progressive MS includes periods of acute exacerbations that look like Relapsing MS, but lost functions never return.

This could be due to a more vigorous strain of neuronal virus. One that more completely shuts down the lysosomal recycling system and does not allow clearance of alpha-synuclein. These cells may die rapidly.

Discussion

This model predicts that treating the herpes/antigliadin pathology will curtail degeneration of the neuron and thereby the progressive nature of the disorder. It does not predict any improvement of the acute episodes, however. It may be that the oligodendrocytes are also affected by a herpes virus, and that antiviral treatment will attenuate all activity, but it’s more likely that several different pathogens are capable of demyelinating the neuron.

This model may at least offer a strategy by which to ascertain the patient’s additional pathogen. If antiviral and gluten diet therapy are effective, assays for known demyelinating agents can be collected during episodes and appropriate treatments can be attempted.

It is also possible that the model could provide a starting algorithm to analyze existing genetic data for various combinations and clusters of suspect alleles. By removing the

Lünemann JD, Jelcic I, Roberts S, Lutterotti A, Tackenberg B, Martin R, Münz C.J Exp Med. 2008 Jul 28. 25 Positivity of cytomegalovirus antibodies predicts a better clinical and radiological outcome in multiple sclerosis patients.Zivadinov R, Nasuelli D, Tommasi MA, Serafin M, Bratina A, Ukmar M, Pirko I, Johnson AJ, Furlan C, Pozzi-Mucelli RS, Monti-Bragadin L, Grop A, Zambon M, Antonello RM, Cazzato G, Zorzon M.Neurol Res. 2006 Apr;28(3):262-9.26 Plaque-associated expression of human herpesvirus 6 in multiple sclerosis.Challoner PB, Smith KT, Parker JD, MacLeod DL, Coulter SN, Rose TM, Schultz ER, Bennett JL, Garber RL, Chang M, et al.Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7440-4.27 Multiple Sclerosis: Immunology, Pathology, and PathophysiologyRobert M. Herndon, Demos Medical Publishing, LLC, 2003 p.113

DQB1 and DR alleles from analysis, one could concentrate on genes known to be associated with the suspected oligidendrocyte vectors.

(C’mon, you Bioinformatic analytical statisticians- this might unlock the whole thing- get your geek freak on!)