P.O. Behan, Professor Emeritus of Clinical Neurology and A. Chaudhuri, Senior Lecturer in Clinical Neurosciences, Department of Neurology, Institute of Neurological Sciences, Glasgow University, Scotland; B.O. Roep, Associate Professor in the Immunology of Diabetes, Department of Immunohaematology and Blood Bank, Leiden University Medical Center, Leiden, The Netherlands.
The fact that an opinion has been widely held is no
evidence whatever that it is not utterly absurd; indeed
in view of the silliness of the majority of mankind, a
widespread belief is more likely to be foolish than
sensible. Bertrand Russell*
SUMMARY
Multiple sclerosis (MS) is a chronic disease of unknown aetiology that affects the human central nervous system (CNS). Its pathology is characterised by areas of myelin loss in a periventricular and perivenular distribution in association with conspicuous astrocytic proliferation and a variable degree of neuronal and axonal damage. Only a proportion of lesions are clinically eloquent. The principal determinant of long-term MS disability is neuronal degeneration and this may be extremely variable. The presence of mild scant lymphocytic infiltrates in the demyelinating lesions has been generally interpreted as the evidence of an inflammatory autoimmune process. Because specific T-cell mediated autoimmunity can be reproduced in animals after myelin protein sensitisation (Experimental Allergic Encephalomyelitis (EAE)) it has been assumed (but never proven) that a similar T-cell driven immune mechanism is responsible for demyelination in MS. In this review the literature for evidence of autoimmunity in the disorder is analysed critically. In contrast to the accepted theory, the human counterpart of the experimental autoimmune demyelinating disease, EAE is not MS but a different demyelinating disorder, i.e. acute disseminated encephalomyelitis (ADEM) and acute haemorrhagic leukoencephalitis (AHLE). Extrapolation of EAE research to MS has been guided largely by faith and a bland acceptance rather than sound scientific rationale. No specific or sensitive immunological test exists that is diagnostic of MS despite the extensive application of modern technology. Critical analysis of the epidemiological data shows no association with any specific autoimmune diseases. Geographic factors and age at development suggest an early onset possibly dependant on environmental influences. Certain neurological diseases are, however, found in association with MS, namely hypertrophic peripheral neuropathy, neurofibromatosis-I, cerebral glioma, glioblastoma multiforme and certain familial forms of narcolepsy. These share a common genetic influence mainly from genes on chromosome 17 affecting cellproliferation. Immunosuppression has failed to have anyconsistent effect on prognosis or disease progression. The available data on MS immunotherapy are conflicting, at times contradictory and are based on findings in animals with EAE. They show predominantly a 30% effect in relapsing/remitting MS that suggests a powerful placebo effect. Our studies allow us to offer an alternative hypothesis of pathogenesis. We suggest that MS is a neurodegenerative and metabolic disorder with a strong polygenic influence, the predominant genes being on chromosome 17, and in conjunction with environmental factors and endogenous sex hormones. The principal cellular abnormality appears to occur in the astrocyte and this gives rise to disruption of the blood-brain barrier with secondary metabolic changes in the myelin. The process is generalised throughout the CNS, the plaques being focal areas of increased tissue damage. Our data would argue that primary progressive MS is the prototype disease and that what is needed in future research is a new approach based on the firm established facts that now exist. ………………………………………………..
Read & learn more, full paper: http://www.rcpe.ac.uk/journal/issue/journal_32_4/3_pathogenesis_of_MS.pdf
