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Special Article

Multiple sclerosis: looking beyond autoimmunity

Abhijit Chaudhuri PhD FRCP  ¹   Peter O Behan DSc FRCP  ²

¹ Department of Neurology, Essex Centre for Regional Neurosciences, Romford RM7 0BE
² University of Glasgow, Scotland, UK

Correspondence to: Dr A Chaudhuri E-mail: abhijitchaudhuri{at}btinternet.com

	INTRODUCTION

TOP INTRODUCTION HISTORICAL PERSPECTIVE DISSOCIATION OF MS FROM... BEYOND AUTOIMMUNITY IN MS CONCLUSIONS REFERENCES

 

'My dictionary gives the Latin root for falsity as fallere, which is the same root for the word failure.'—Lewis Thomas¹

The chronic incurable disorder multiple sclerosis (MS) is characterized by neurodegeneration, multifocal demyelination and astroglial proliferation (gliosis).² The prevalence of MS is influenced by geography and genetics. In the Western world it is a leading cause of neurological disability in the young. The cause and exact pathogenesis are still unknown. Some see MS as a T-cell-driven autoimmune inflammatory disease, targeting the myelin sheaths in the central nervous system,³ but there is no proof. Unlike autoimmune conditions such as rheumatoid arthritis, systemic lupus erythematosus or myasthenia gravis, MS has no specific immunological marker.^2,4

An animal model that has been used in MS research is experimental allergic encephalomyelitis (EAE), in which demyelination is induced by sensitization against myelin basic protein. Clinically and pathologically, however, EAE resembles acute disseminated encephalomyelitis (ADEM) rather than MS.² Nonetheless, the EAE model has been used to drive the autoimmune theory and to develop treatments. An inflammatory hypothesis of demyelination also fails to explain various salient features of the disease (Box 1).^5-7 Here, we explain our view that research and treatment strategy in MS need to change direction.

	HISTORICAL PERSPECTIVE

TOP INTRODUCTION HISTORICAL PERSPECTIVE DISSOCIATION OF MS FROM... BEYOND AUTOIMMUNITY IN MS CONCLUSIONS REFERENCES

 
It was during the 1940s and 1950s that researchers became interested in experimentally induced demyelination. Hyperacute and acute demyelination (ADEM) in man came to be recognized as a complication of immunization with brain derived tissue (e.g. post-rabies-vaccine encephalomyelitis) and a similar 'allergic' basis of demyelination in MS was postulated. Adams made a detailed histological comparison of ADEM and MS in terms of morphological criteria for demyelinative disease—namely, destruction of myelin sheaths of nerve fibres; relative sparing of all other elements of nervous tissue (i.e. nerve cells, axis cylinders and supporting structures); and distribution of lesions, often perivenous, in multiple locations throughout the brain and spinal cord or to single foci spreading from one or more centres.⁸ From Table 1, summarizing his observations, it is apparent that there are similarities but also important differences. Adams regarded the syndrome of acute bilateral optic neuritis and transverse myelitis (neuromyelitis optica, Devic's disease) as a regional variant of ADEM; the clinical syndrome of myelitis was judged merely a matter of localization within the spinal cord, where the tight confines of the pia and the oedema of very rapidly evolving lesions of ADEM led to infarction-necrosis (a condition seldom seen in the brain).

View this table: [in this window] [in a new window]   Table 1. Comparative pathology of the demyelinative lesions in acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS)

 

Subsequently, one of us (POB) showed that both EAE and ADEM are T-cell-dependent, organ-specific, autoimmune diseases of the central nervous system.^9,10 This has not been found true for MS, despite three decades of intensive research. Indirect evidence cited in support of an autoimmune pathogenesis for MS has likewise been found wanting (Table 2).

View this table: [in this window] [in a new window]   Table 2. Autoimmunity and multiple sclerosis (MS)

 

	DISSOCIATION OF MS FROM EAE AND ADEM

TOP INTRODUCTION HISTORICAL PERSPECTIVE DISSOCIATION OF MS FROM... BEYOND AUTOIMMUNITY IN MS CONCLUSIONS REFERENCES

 
The clinical, radiological, and histological differences between EAE and MS, we believe, argue against a common pathogenesis. EAE is typically a monophasic disorder, and even subacute or chronic relapsing models of EAE represent recurrent challenges to some encephalitogenic antigen, a phenomenon that has not been shown to apply in MS. The progressive and global brain and spinal cord atrophy that characterizes the human disease from its earliest stages⁷ has not been reproduced in animals with EAE. EAE and ADEM also differ from MS in that the uninvolved white matter is normal.¹¹

Box 1 Important facts about MS that cannot be explained by the concept of myelin-specific autoimmunity Age effect of migration Geographic variation (higher prevalence in most northern latitudes) Maternal contribution to disease risk (Ref. 5) Early and extensive grey matter involvement (estimated number of deep grey matter lesions per gram wet weight is higher than in any other brain structure [Ref. 6]) Progressive brain and spinal cord atrophy, beginning at the stage of clinically isolated demyelinating syndromes (Ref. 7) Selective anatomical localization, symmetry and sharp margins of plaques Absence of specific immunological marker Effect of stress General failure of immunotherapies that are highly successful in other organ-specific autoimmune diseases and transplant rejection Associations with Charcot-Marie-Tooth disease and neurofibromatosis-1 (Ref. 2)

 

One of the characteristic histological features of EAE is destruction of cerebral endothelial cells by an immunological mechanism, and this is seen in human cases of ADEM after immunization (post-rabies vaccine encephalomyelitis) or endotoxic shock,¹² but not in MS. Even from the early days it was acknowledged that chronic relapsing MS had pathological features that were absent in acute or subacute EAE, such as the large sizes and confluence of individual demyelinating lesions ('plaques'), the shadow plaques and the appearance of fresh lesions at the borders of the older ones 'as though the pathological process had spread in a succession of waves from a more central focus'.⁸ Furthermore, there are inherent pitfalls in the assumption of a common pathogenesis based on morphological similarities alone, when the range of histological responses to injury is so limited within the nervous system. For example, ischaemic brain tissue will look much the same in cerebral infarcts due to systemic lupus, cardioembolic stroke or thrombotic stroke, though the pathogenesis and treatment will differ. Morphological issues apart, an important reason for questioning the extrapolation of EAE to MS pathogenesis is the failure to identify an encephalitogenic marker specific for MS. In Devic's disease (a variant of ADEM), Lennon et al. have now found an antibody that localizes with laminin at the blood-brain barrier.¹³ We would recommend immunosuppression in Devic's disease but not in MS.

	BEYOND AUTOIMMUNITY IN MS

TOP INTRODUCTION HISTORICAL PERSPECTIVE DISSOCIATION OF MS FROM... BEYOND AUTOIMMUNITY IN MS CONCLUSIONS REFERENCES

 
The definition of MS as a T-cell-specific autoimmune demyelinative disease is in our view too narrow. First, nearly 60 years of EAE-based research yielded not a single MS-halting therapy. This in itself should be an important reason to consider a shift in research direction. Although the existing disease-modifying therapies reduce relapse rates in some patients by up to one-third there is little evidence that the common features of fatigue, pain, depression and cognitive decline are positively influenced.¹⁴ There is also a concern, theoretical at present, that early benefit of reduced relapse rates may later be offset by accelerated brain atrophy.¹⁵

Second, neurodegeneration is now regarded as an important component in MS. It is neurodegeneration rather than demyelination that contributes to long-term disability. Several pathological and MRI studies indicate that grey matter involvement is early and extensive. Axonal transection may be degenerative, inflammatory or both, but brain and spinal cord atrophy is considered to be the direct result of neurodegeneration. If we accept axonal degeneration and neuronal loss to be essential features, then MS no longer fulfils the original criteria of a primary demyelinative disease and comparison with EAE becomes even less apposite. Longitudinal studies of brain volume in MS teach us that the rate of brain atrophy is independent of the disease subtype;¹⁶ in other words, whether the disease is classed as relapsing-remitting or progressive, the loss of brain volume is the same and is due to neurodegeneration. While the concept of clinical and pathogenic heterogeneity¹⁷ has been proposed to identify an inflammatory subgroup in necropsy studies, it is clear that all patients, whatever their clinical phenotype, require neuroprotection.

Third, the most neglected aspect of MS research is prevention, and we believe that this again is explained by the erroneous assumption of autoimmunity. Several potentially modifiable environmental factors are associated with the risk of developing MS. One is infectious mononucleosis due to Epstein-Barr virus (EBV), which emerged in a large case-control study of MS and virus infection among US women (Nurses' Health Study I and II) as the single most important risk factor.¹⁸ Currently, the search for an effective EBV vaccine is focused on prevention of lymphoproliferative disorders and nasopharyngeal carcinoma in susceptible populations,¹⁹ but such a vaccine has huge potential for reducing the risk of several other debilitating clinical syndromes including MS. Smoking is another modifiable risk factor;²⁰ in female nurses there was a clear dose-response relation between cigarette consumption and MS, and in a general population the risk of MS was higher in smokers than in never-smokers.²¹ Clearly, smoking needs to be especially discouraged, from the time of diagnosis, in a patient with MS.

Finally, of all the environmental risk factors associated with MS, vitamin D seems the most easily modified.²² In a longitudinal follow-up study of over 90 000 women, those taking vitamin D supplements had a 40% lower incidence of MS than those who did not.²³ MS is rare in the tropics and a direct relation between sunlight exposure and MS has been confirmed in epidemiological studies since 1960.²⁴ Therefore an argument can be made for vitamin D supplementation to reduce the risk of MS in areas of high disease prevalence in the northern latitudes where solar exposure is inadequate for vitamin D synthesis throughout the year.²²

	CONCLUSIONS

TOP INTRODUCTION HISTORICAL PERSPECTIVE DISSOCIATION OF MS FROM... BEYOND AUTOIMMUNITY IN MS CONCLUSIONS REFERENCES

 
After six decades of autoimmune and EAE-based research, the time has come for a change in direction. For basic scientists, the challenge is to develop a new animal model of MS that replicates both demyelination and neurodegeneration. Solvent-induced demyelination might be such a model, in view of the association between solvent exposure and MS risk.^25,26 For clinicians the task is to evaluate existing neuroprotective treatments. Possible candidate agents for randomized trials in early MS are antioxidants such as coenzyme Q₁₀,²⁷ omega-3-essential fatty acids,²⁸ minocyclin,²⁹ and cannabinoids,³⁰ alone or in combination.

	REFERENCES

TOP INTRODUCTION HISTORICAL PERSPECTIVE DISSOCIATION OF MS FROM... BEYOND AUTOIMMUNITY IN MS CONCLUSIONS REFERENCES

 

1. Thomas L. Falsity and failure. In: Late Night Thoughts on Listening to Mahler's Ninth Symphony. New York: Penguin Books, 1995: 113

2. Behan PO, Chaudhuri A, Roep BO. The pathogenesis of multiple sclerosis revisited. J R Coll Physicians Edinb2002; 32:244 -65

3. Weiner HL. Multiple sclerosis is an inflammatory, T-cell mediated autoimmune disease. Arch Neurol2004; 61:1613 -15[Free Full Text]

4. Chaudhuri A, Behan PO. Multiple sclerosis is not an autoimmune disease. Arch Neurol2004; 61:1610 -12[Free Full Text]

5. Ebers GC, Sandovnick AD, Dyment DA, Yee JML, Willer CJ, Risch N. Parent-of-origin effect in multiple sclerosis: observations in half-siblings. Lancet2004; 363:1773 -4[Medline]

6. Lumsden C. The neuropathology of multiple sclerosis. In: Bruyn GW, Vinken P, eds. Handbook of Clinical Neurology. Amsterdam: Elsevier, 1970:217 -309

7. Dalton CM, Chard CT, Davies GR, et al. Early development of multiple sclerosis is associated with progressive grey matter atrophy in patients presenting with clinically isolated syndromes. Brain2004; 127:1101 -7[Abstract/Free Full Text]

8. Adams RD. A comparison of the morphology of the human demyelinative diseases and experimental 'allergic' encephalomyelitis. In: Kies MW, Alvord EC Jr, eds. "Allergic" Encephalomyelitis. Washington: Charles C Thomas,1959 : 183-209

9. Behan PO, Geshwind N, Lamarche JB, et al. Delayed hypersensitivity to encephalitogenic protein in disseminated encephalitis. Lancet1968; ii:1009 -12

10. Behan PO, Kies MW, Lisak RP, et al. Immunologic mechanisms in experimental encephalomyelitis in non-human primates. Arch Neurol 1973;29:4 -9[Abstract/Free Full Text]

11. Ingelse M, Salvi F, Iannucci G, et al. Magnetization transfer and diffusion tensor MR imaging of acute disseminated encephalomyelitis. Am J Neuroradiol2002; 23:267 -72[Abstract/Free Full Text]

12. Graham DI, Behan PO, More IAR. Brain damage complicating septic shock. Acute haemorrhagic leukoencephalitis as a complication of generalised Shwartzman reaction. J Neurol Neurosurgery Psychiatry1979; 42:19 -28[Abstract/Free Full Text]

13. Lennon VA, Wingerchuck DM, Kryzer TJ, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet2004; 364:2106 -12[Medline]

14. Chaudhuri A, Behan PO. Treatment of multiple sclerosis beyond the NICE guideline. Quart J Med2005; 98:373 -8

15. Chaudhuri A. Beta interferon, progressive multiple sclerosis and brain atrophy. Lancet Neurol2005; 4:208 -9[Medline]

16. Kalkers NF, Ameziane N, Boost JCJ, Minnebo A, Polman CH, Barkhof F. Longitudinal brain volume measurement in multiple sclerosis. Rate of brain atrophy is independent of the disease subtype. Arch Neurol 2002;59:1572 -6[Abstract/Free Full Text]

17. Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H. Heterogeneity of multiple sclerosis lesions: implications for pathogenesis of demyelination. Ann Neurol2000; 47:707 -17[Medline]

18. Hernan MA, Zhang SM, Lipworth L, Olek MJ, Ascherio A. Multiple sclerosis and age at infection with common viruses. Epidemiology2001; 12:301 -6[Medline]

19. Macsween KF, Crawford DH. Epstein-Barr virus—recent advances. Lancet Infect Dis2003; 3:131 -40[Medline]

20. Hernan MA, Olek MJ, Ascherio A. Cigarette smoking and incidence of multiple sclerosis. Am J Epidemiol2001; 154:69 -74[Abstract/Free Full Text]

21. Riise T, Nortvedt M, Ascherio A. Smoking is a risk factor for multiple sclerosis. Neurology2003; 61:1122 -4[Abstract/Free Full Text]

22. Chaudhuri A. Why we should offer routine supplementation of vitamin D in pregnancy and childhood to prevent multiple sclerosis. Med Hypotheses 2005;64:608 -18[Medline]

23. Munger KL, Zhang SM, O'Reilly E, et al. Vitamin D intake and incidence of multiple sclerosis. Neurology2004; 13:62:60 -5

24. Acheson ED, Bachrach CA, Wright FM. Some comments on the relationship of the distribution of multiple sclerosis to latitude, solar radiation and other variables. Acta Psychiatry Scand1960; 147(suppl):132 -47

25. Landtblom A-M, Flodin U, Soderfeldt B, Wolfson C, Axelson O. Organic solvents and multiple sclerosis: a synthesis of the current evidence. Epidemiology1996; 7:429 -33[Medline]

26. Riise T, Moen BE, Kryvik KR. Organic solvents and the risk of multiple sclerosis. Epidemiology2002; 13:718 -20[Medline]

27. Shultz CW. Coenzyme Q10 in neurodegenerative diseases. Curr Med Chem2003; 19:1917 -21

28. Calon F, Lim GP, Yang F, et al. Docosahexanoic acid protects from dendritic pathology in an Alzheimer's disease mouse model. Neuron2004; 43:633 -34[Medline]

29. Chen M, Ona VO, Li M, et al. Minocycline inhibits caspase-3 expression and delays mortality in a transgenic mouse model of Huntington's disease. Nature Med2000; 6:797 -801[Medline]

30. Baker D, Pryce G, Giovannoni G, et al. The therapeutic potential of cannabis. Lancet Neurol2003; 2:291 -8[Medline]

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