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Aetiology and pathogenesis of Multiple sclerosis
 

Aetiology and pathogenesis of Multiple sclerosis

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    Aetiology and pathogenesis of Multiple sclerosis Aetiology and pathogenesis of Multiple sclerosis Document Transcript

    • Royal Pharmaceutical Society of Great Britain There are 1 or more photographs and/or images missing from this PDF file You can buy a black & white/greyscale photocopy of this article from the Society's library For details see http://www.pjonline.com/about/photocopy.html Back issues are available from the Pharmaceutical Press Tel +44 (0) 1491 829272 website http://www.pharmpress.com E-mail rpsgb@cabi.org
    • Special Feature Aetiology and pathogenesis of Multiple sclerosis By GRAHAM G. NIEPEL, CHB, MRCP, and CRIS S. CONSTANTINESCU, MD, PHD In the first part of our special feature, the authors outline the genetic and viral factors involved in the aetiology of multiple sclerosis. Also discussed is the use of an IMAGE REMOVED Coloured magnetic resonance image (MRI) scan of a vertical section animal model that provides through the brain of a patient with multiple sclerosis. The two cerebral hemispheres, containing the fluid-filled ventricles (white), occupy the top part of the brain. Below these is the cerebellum (yellow). Lesions an insight into the caused by MS appear red in the cerebral hemispheres (upper right and centre left of brain) and white in the cerebellum (lower centre) pathogenesis of the disease M ultiple sclerosis (MS) is an After several years, the majority (70 per inflammatory demyelinating cent) of these patients will develop sec- can begin in childhood and also above disease of the central nervous ondary progressive disease (SP-MS), the age of 60 years. Overall, MS occurs system (CNS).1 It was in the whereby they experience a progressive more frequently in women than in men, 1830s when Cruveilhier and Carswell first neurological deterioration. They may still and the ratio is approximately 2:1. This presented reports and provided illustra- suffer from superimposed relapses. A female predominance is less defined in tions of pathological specimens that later subcategory of RR-MS patients (between patients with PP-MS, which typically devel- proved to be consistent with MS. 15 and 20 per cent) have benign MS. ops at a later age.3 In 1868, Charcot produced his lectures These patients have rare and mild relaps- There is a variation in the worldwide on “Sclerose en plaques”, providing the es and a long course of disease, with distribution of MS, with the highest preva- first detailed clinico-pathological descrip- minimal or no disability. lence in northern and central Europe, tion of the new disease, now termed If patients have a steady neurological North America, Canada and south-east- multiple, or disseminated, sclerosis. decline from the outset, without relapses, ern Australia. Clusters, or so-called By consensus, there are four main clini- they are described as having primary pro- epidemics, occur. For example, in the cal categories of MS.2 The commonest is gressive MS (PP-MS). This comprises Faroe Islands between the 1940s and relapsing remitting MS (RR-MS), which approximately 15-20 per cent of sufferers. 70s, there was a significantly higher than affects 80-85 per cent of patients. These A fourth, rare category of patients is pro- expected incidence of new MS cases. patients develop disease relapses, often gressive relapsing MS (PR-MS), which is There are also racial differences, with a without a specific trigger but possibly considered a variant of PP-MS, with similar low prevalence in black Africans and associated with infections. Disease relaps- prognosis. In patients with PR-MS, there is Asians,and a higher frequency in Cau- es can last between 24 hours and several a gradual neurological decline from the casians, especially of northern European months, and patients may, or may not, beginning. It is similar to PP-MS, but has descent.1,3 completely recover. Patients are clinically superimposed, acute relapses. stable between relapses, although they AETIOLOGY can have residual symptoms and disabili- EPIDEMIOLOGY ty. T he prevalence of MS in the United Kingdom is approximately 120 per The cause of MS isSupport forbutenviron- uncertain, evidence of both genetic and mental influences. there is a genetic Dr Niepel is research registrar in neurology and 100,000, with an incidence of seven new component is significant. Twin studies have Dr Constantinescu is senior lecturer/honorary cases per 100,000 per year. shown an increased risk of 30 per cent in consultant in neurology at University Hospital, The usual age of onset is within the third monozygotic, and around 5 per cent in Queen’s Medical Centre, Nottingham and fourth decades, although the disease dizygotic, twins. First degree relatives have J A N U A R Y 2003 V O L . 10 H O S P I TA L P H A R M A C I S T 13
    • be associated with axonal degeneration in associated with a higher risk of MS.10 IMAGE REMOVED conditions such as Alzheimer’s disease. Another possible association is with Coloured magnetic resonance imaging Axonal loss is an important pathological Chlamydia pneumoniae which, in one (MRI) scan of damage (pink, arrowed) to feature of MS and evidence exists for its study, was found to have a high prevalence the spinal cord due to multiple sclerosis contribution towards irreversible clinical (64 per cent) in the CSF of MS patients. This (MS). Healthy nerve tissue is yellow. The disability. Consequently, studies have also was, however, not corroborated by further damaged areas (plaques) are where the shown that the APOE-4 allele is associat- investigations.11 myelin covering of the nerves in the ed with a faster progression of disability in It is unlikely that a specific infectious spinal cord has been destroyed. MS sufferers.7 agent directly induces MS, and searches The fact that 70 per cent of monozygot- for such agents over the decades have a 2 to 3 per cent increased risk, which, ic twins are discordant for MS strongly been fruitless. More likely, it is the although small, is considerably higher than suggests that environmental factors also immunological consequences of an expo- in the general population. The risk decreas- play a significant role in the development sure to a potentially more common virus es as the closeness of the relative of the disease. Ever since Charcot’s initial that triggers the disease in prone people. decreases; children of a sufferer are at a detailed clinico-pathological description The mechanisms of this phenomenon may higher risk than nephews or nieces. Adopt- of MS as an entity, investigations for an be multiple, and may involve molecular ed relatives have the same risk of environmental cause have concentrated mimicry, bystander activation (activation developing MS as the general population.4 on transmissible agents. Support for this of self-reactive T cells, eg, myelin-reactive Devic’s syndrome, or neuromyelitis opti- comes in the form of the epidemics of the T cells, in an inflammatory environment ca, is a demyelinating disease in which disease described earlier. Some viruses created by an infection in close proximity only the optic nerves and spinal cord are are also known to cause diseases that to these T cells), or superantigen activa- clinically affected. Some neurologists feel have similar clinical features to MS. One tion.12 it is a variant of MS, and certain studies example is human T-cell lymphotrophic Environmental factors, other than infec- have shown that this disease can run virus (HTLV)-I, which can lead to a spastic tious agents, for which there is some through families. However, there is no evi- paraparesis and, sometimes, optic nerve evidence of an association with MS, dence to suggest further that the early involvement. Human immuno-deficiency include low sunlight exposure, toxins, diet clinical expression of MS is hereditary.5 virus can also, among other neurological factors and trauma. complications, cause a myelopathy. Despite the unknown aetiology, the GENETIC INVOLVEMENT One of the characteristics of MS is the working consensus is that environmental presence of oligoclonal IgG bands, in factors, possibly combined with chance, No of MS is gene toNevertheless, there mode specific and likely inheritance. has been identified have a polygenic around 90 per cent of patients, on cere- brospinal fluid (CSF) examination. These bands reflect the intrathecal (within the trigger an autoimmune reaction against CNS myelin in genetically susceptible indi- viduals. is one well documented association CNS) synthesis of antibodies. Although sen- between MS and the major histocompati- sitive for MS, and thus helpful in PATHOGENESIS bility complex (MHC), in particular, the supporting the diagnosis, oligoclonal human leukocyte antigen (HLA)-DR2. The MHC is a group of proteins which are expressed on the surface of cells and bands are not specific for the disease.1 One of the conditions in which they are also prevalent is subacute sclerosing panen- The pathogenesisevidenceFeatures butan large body of of MS is unclear, autoimmune mechanism. supports a that enable self and non-self cells to be distin- cephalitis (SSPE), a condition that is caused support this mechanism include the higher guished. The human MHC is named HLA by the measles virus as a late complication. frequency in females (known to be more (human leukocyte antigen). There are two The antigenic specificity of the antibody in affected by autoimmune disease), the pre- types of HLA protein — class I and class II oligoclonal bands is not known in MS. In dominantly relapsing-remitting nature of — and each one is coded for by three sep- SSPE, however, it is known to be a protein the disease, evidence of an association with arate genes. These genes are HLA-A, -B component of the measles virus. Raised HLA and oligoclonal IgG bands in the CSF, and -C for class I, and HLA-DP -DQ and - , CSF IgG production is also associated with and the benefit derived from some forms DR for class II. Each person has two copies other neurological inflammatory or infective of immunomodulation and immunosup- of each gene, one maternal and one disorders. pression. The effect of pregnancy on MS is paternal. There are multiple forms of each also a characteristic shared with other gene available within the population and VIRAL PATHOGENS known autoimmune diseases. In pregnant these are numbered, for example, HLA- patients with MS, the relapse rate is reduced B27. There is evidence for a high proportion of HLA-DR2 in MS sufferers and, in areas Viral pathogensvirus-6 (HHV-6).include investigated and con- sidered to be involved in MS human herpes Some during the second and third trimesters, but the rate increases for approximately three to six post-parturition.13 with a high frequency of HLA-DR2 in the studies have shown the presence of HHV-6 There are several key pathological fea- local population, there is, accordingly, a DNA (detected by polymerase chain reac- tures of MS, and these are inflammation high prevalence of MS. However, this tion) in the brain tissue or CSF of patients (predominantly caused by T cells, genotype is not associated with the clini- with MS. Subsequent investigations, on the macrophages, and some plasma cells), cal expression or course of the disease. other hand, have not supported these demyelination, axonal loss, and gliosis Polymorphisms in the gene for tumour results.8,9 (overgrowth of nervous tissue). Axonal loss necrosis factor, an important proinflam- Epstein-Barr virus (EBV) has also been leads to indurated areas called plaques. matory cytokine, are also associated with implicated in MS. Nearly 100 per cent of Plaques are the pathological hallmark susceptibility to MS.5,6 Tumour necrosis patients with MS have circulating antibod- of MS, but the pathogenic mechanism by factor is part of the MHC. ies against EBV, compared with which they develop is unknown. The exact Other genes have been investigated approximately 60 per cent in the general process varies from person to person that may be associated with the severity of population. In addition, a history of symp- because, although the pathological fea- MS. One example is the apolipoprotein E tomatic infectious mononucleosis (caused tures are consistent in different lesions (APOE)-4 allele, which has been shown to by EBV), especially at an older age, is within an individual, there is a significant 14 H O S P I TA L P H A R M A C I S T J A N U A R Y 2003 V O L . 10
    • degree of heterogeneity between lesions within different patients.14 Plaques are generally located around blood vessels and extend along the line the vessel takes. This is described as Daw- son’s fingers. Plaques have a propensity for certain areas, such as the optic nerves, periventricular white matter, cerebellum, brain stem and spinal cord. Plaques are characterised by loss of myelin or oligodendrocytes, or both. The myelin sheath is a lipid and protein cell membrane, derived from the oligodendro- cyte, that wraps several times around an axon. The myelin sheath is segmented along its course and the areas between the sections are called nodes of Ranvier. These allow for saltatory conduction of nerve action potentials, whereby the impulses jump from node to node. This is much Figure 1. Examples of monophasic, relapsing, and chronic/relapsing EAE. Scoring of clinical more rapid than conduction along an signs of EAE are on a scale of 0 (normal) to 5 (moribund or dead resulting from EAE) unmyelinated or demyelinated axon. The important protein constituents of myelin (EAE), is an autoimmune CNS demyeli- macrophages. Macrophages can strip that are potential targets of an autoimmune nating disease that has made a major myelin, destroy oligodendrocytes, and can attack include myelin basic protein (MBP), contribution to the understanding of the produce further proinflammatory cytokines, proteolipid protein (PLP), myelin-oligoden- pathogenesis of MS. EAE can be induced such as TNF and IL-12. TNF may be direct- drocyte glycoprotein (MOG) and in a variety of species, including mice, ly cytotoxic to oligodendrocytes. myelin-associated glycoprotein (MAG). guinea pigs and primates. It is a good EAE is, therefore, largely a TH1 lympho- In the acute or active plaque, there is an model of MS and of organ specific cyte mediated disorder. Similarly, inflammatory infiltrate consisting predom- autoimmune disease in general. myelin-reactive T cells in the blood of an inantly of T lymphocytes and Monophasic, relapsing and chronic pro- MS patient are predominantly TH1 lympho- macrophages, as well as some B lympho- gressive forms of EAE have been cytes.15 However, the TH1/ TH2 ratio may cytes. Chronic, inactive plaques are developed (see Figure 1). The monopha- not be so clear-cut. In some circum- largely hypocellular. Disruption of the sic form is a closer human counterpart of stances, a shift to TH2 has been found to blood-brain barrier also occurs in the acute disseminated encephalomyelitis worsen the disease and EAE-like CNS acute phase and may be the first evident than of MS itself. inflammation can be mediated by TH2 lym- feature to develop on magnetic reso- MS is induced by active immunisation phocytes.16 nance imaging (MRI). In the MRI sequence with myelin proteins, such as PLP MBP or , In MS, currently available immuno- called T1-weighted, disruption of the MOG, or their encephalitogenic peptide modulatory treatments (interferon beta or blood-brain barrier can be seen as an fragments, in the presence of adjuvants. glatiramer acetate) act, in part, by sup- increase in the MRI signal intensity Alternatively, it is induced by passive pressing T H1 lymphocytes while (enhancement) after administration of the (adoptive) transfer of T lymphocytes from increasing T 2 lymphocytes. H paramagnetic contrast agent, gadolinium. immunised animals that are specific and CD8 positive TC cells have also been In the MRI sequence called T2-weighted, auto-reactive for various neuroantigens. implicated in EAE and MS. TC lympho- the presence of hyperintense, ovoid or The adoptive transfer model suggests that cytes specific for myelin and MBP have round lesions on the images is a radiologi- EAE is T cell mediated, and that T cells induced EAE.17 These cells have also cal hallmark and an important feature for are clearly important in MS.15 Highly been found in significant numbers in MS the diagnosis of MS. These lesions occur in active T cells that recognise myelin anti- lesions. They can lead to pathology in the white matter, with predominantly gen have been found in the blood and various ways. They can cause apoptosis periventricular localisation, and also in the CSF of patients with MS, and this corre- (programmed cell death) by expressing corpus callosum, brain stem, cerebellum lates with disease activity.1 Fas ligand and binding to Fas antigen on and spinal cord. There are two subsets of T lymphocytes, oligodendrocytes. TC cells can also Axonal loss is an increasingly recognised categorised according to which surface release enzymes, such as perforin and feature of MS plaques although, tradition- proteins they express and which class of granzymes, which can destroy targeted ally, it was believed that MS is a MHC protein they recognise. Helper T cells. demyelinating disorder with relative preser- lymphocytes (TH cells) are CD4 positive B lymphocytes are also suspected of vation of axons. On MRI, low signal areas and recognise MHC class II protein. Cyto- having a role. Once activated, B cells pro- on T1-weighted imaging, as well as cere- toxic T lymphocytes (TC cells) are CD8 duce antibodies or immunoglobulins. It bral atrophy, are considered to be evidence positive and recognise MHC class I pro- was previously mentioned that CSF exami- of axonal degeneration, which correlates tein. There are also two sub-types of TH nation commonly demonstrated raised with irreversible clinical disability. Gliosis cells. These are termed TH1 and TH2 cells IgG synthesis in MS. Auto-antibodies to and scarring can be a feature, particularly and differ in the cytokines they secrete MOG, MBP and other myelin proteins, , of chronic plaques. and, therefore, the functions they perform. have also been found in the serum or CSF For the greatest part, TH1 cells mediate of patients with MS. In the animal model, it ANIMAL MODEL EAE. The cytokines they release include has been recognised that administration interferon-gamma (IFN-g), tumour necrosis of anti-MOG antibodies can exacerbate The animal model, experimental aller- gic (autoimmune) encephalomyelitis factor beta (TNF-b) and interleukin-2 (IL-2). IFN-g and TNF-b both activate EAE.18,19 These processes could all lead to J A N U A R Y 2003 V O L . 10 H O S P I TA L P H A R M A C I S T 15
    • demyelination. Denuded axons could be Jendroska K, Oettle H, Siegert W. A prone to axonal degeneration by the CONCLUSION potential role for human herpes virus absence of trophic support, and are at type 6 in nervous system disease. J increased vulnerability to an immune attack. Another contributing mechanism of axonal loss is destruction via toxic The aetiology and pathogenesis ofa MS is unknown, but probably involves com- bination of genetic and environmental Neuroimmunol 1994; 49:213-4. 10. Bray PF, Bloomer LC, Salmon VC, Bagley MH, Larsen PD. Epstein-Barr mediators, such as free radical nitric factors and, possibly, chance. This combi- virus infection and antibody synthesis in oxide, released by the inflammatory nation triggers an immune process leading patients with multiple sclerosis. Arch process. to inflammation, demyelination and axonal Neurol 1983;40:406-8. In the inflammatory process, T cells in loss. The mechanism by which this occurs 11. 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