Ana sayfa | MS’in Derinliği  | MS Slide Resource

Several lines of evidence indicate that environmental factors are not the sole influence on who gets MS and who does not. Clearly, genetic factors are involved also.^4,5

Familial MS

As early as the nineteenth century, reports were made of MS occurrence in more than one member of the same family.²⁶ By 1950, 85 such multiplex families had been identified, and pedigree analyses had prompted investigators to begin formulating theories about the nature of MS susceptibility.²⁶

It was apparent from the pedigrees that MS did not fit the classic Mendelian pattern of inheritance. The majority view was that the aetiology of MS owed more to nurture than to nature.^14,26 Although this remains a matter for debate in the 1990s, it is accepted that MS does occur more frequently in the relatives of affected patients than in the population in general.²⁶

When MS is familial, it most often involves only two affected individuals; usually these are siblings.²⁷ When counselling MS patients and their relatives about the chances of a second family member developing the disease, the best way of describing the risk is to assess the recurrence rate in particular categories of relatives. This was the approach used in a large, population-based survey in British Columbia.²⁷ Overall, siblings had the highest age-adjusted recurrence risk (4%), followed by parents (3%), children (2.5%), uncles, aunts and cousins (2%), and nephews and nieces (1.5%). However, the risks differed slightly depending on the gender of the affected individual and of the relative, and there may have been a major ascertainment factor affecting the recurrence risk in cousins.²⁶

A recurrence risk of less than 10% for every category of relative virtually excludes the possibility that a single gene responsible for MS susceptibility.²⁷ The consistently higher recurrence risk observed in siblings compared with other relatives suggested to one observer that some or all of the genes responsible for MS susceptibility have a recessive mode of inheritance.²⁷

Despite this, it is still possible that shared environment could account for the slight increase in cases among siblings.²⁶

Twin studies

Twin studies are the classic method of investigating the relative importance of environmental and genetic factors in multifactorial diseases, including MS.¹⁴ Such studies allow comparison of concordance (the frequency with which the disease affects both) in monozygotic (MZ) twins, who are genetically identical, with that for dizygotic (DZ) twins. DZ twins are no more genetically alike than any other non-twin siblings (although they probably share a more similar environment than non-twin siblings).¹⁴ Hence, comparison of concordance:

• between MZ and DZ pairs measures the influence of genetic factors

• between DZ pairs and non-twin siblings measures the influence of non-genetic factors.¹⁴

Although the concept of twin studies is simple, they are difficult to do and to interpret. Ascertainment presents a major problem. To obtain a sufficiently large number of twin pairs for study, most investigators have relied on public appeal for volunteers. This method of recruitment tends to result in an over-representation of females, and of MZ, concordant pairs.¹⁴

Several twin studies have managed to minimize ascertainment bias by identifying suitable twin pairs from large populations either of MS patients or of twins.^28-32 Thus, they approximate to population-based studies.²⁷

When combined, the results of these studies show a concordance rate of about 27% for MZ twins.¹⁴ This contrasts sharply with the rate of 3.5% obtained for like-sexed, DZ twins - a rate similar to that found for non-twin siblings (not corrected for sex).¹⁴

Perhaps suprisingly, a sibling concordance rate slightly higher than the DZ twin rate was found in a study that gave more attention to siblings.^33,34 An increased risk for concordance does seem to exist between like-sexed siblings, with concordance rates of approximately 4% and 6% for male-male and female-female pairs, respectively.³³

These twin studies allow several tentative conclusions to be made:^14,35

• There is a substantial genetic component to MS susceptibility.

• At least two, and almost certainly several, genes influence MS susceptibility.

• Since most MZ pairs are discordant (even after age correction and MRI scans), there is probably a substantial environmental/ chance component to MS susceptibility.

Therefore, it is possible that although genetic factors increase susceptibility to MS their effect is only apparent in the appropriate environmental conditions.²⁹

Susceptibility loci

Animal models of autoimmunity

Research into animal models of autoimmunity have influenced the thinking of investigators seeking susceptibility genes for known or suspected autoimmune disorders of humans.¹⁴ However, there is no spontaneous experimental animal model for MS, and induction of experimental allergic encephalo-myelitis (EAE - the primary animal model for MS), may not be a faithful model of the processes involved in MS initiation.¹⁴ Therefore, despite the resemblance of pathology and immunological alterations seen between the chronic forms of EAE and MS, its relevance to MS aetiology remains uncertain.

Animal models show clearly that susceptibility to autoimmune diseases involves a number of interacting genes (i.e. susceptibility is a polygenic trait).¹⁴ These genes appear to interact at different stages in the initiation of the autoimmune process.¹⁴ The non-obese diabetic mouse (NOD) model of autoimmune disease provides an example of such interaction between genes and the early life microenvironment.¹⁴

When colonies of these genetically homogeneous mice are sent to different areas of the world they display a marked variability in the level of phenotypic expression (penetrance) of diabetes.¹⁴ Diet, cage cleanliness, and viral contamination of breeding colonies strongly influence the degree of disease penetrance. A germ-free environment in early life results in full penetrance of diabetes.¹⁴

Susceptibility to diabetes in the NOD mouse appears to be polygenic, involving a minimum of 9 gene I. At least one of these loci lies within the major histocompatibility complex (MHC) on chromosome 17.³⁶ The susceptibility loci seem to have strong epistatic effects, that is they can suppress or enhance the phenotypic expression of other genes.³⁶ Although these observations are interesting, it is not yet known whether they are relevant to the epidemiology of MS.

MS susceptibility loci

There is strong, but circumstantial, evidence that MS is an autoimmune disease.³⁷ This, together with data from animal models suggesting that genetic loci that influence immune system regulation are important in disease susceptibility, has led to increased interest in the corresponding loci in humans.¹⁴ Attention has focused on the genes that code for components of the trimolecular complex (MHC Class II product, T-cell receptor, and antigen), which activates the T-cells.¹⁴

Major histocompatibility complex

The MHC is the best studied of the human susceptibility loci. This complex of genes produces two types of self-recognition antigens, human leucocyte antigens (HLAs) Class I and Class II. Class I molecules (HLA A, B, and C) are expressed on the surface of all somatic cells. Class II molecules (HLA DP, DQ, and DR) are expressed by macrophages, antigen-presenting cells and B-cells.

The MHC Class II genes are highly variable both in structure and at the level of DNA sequence. Each individual possesses a set of gene variants (alleles) that express a particular range of HLAs - their HLA haplotype. Specific HLA antigens may be associated with particular disease susceptibilities, e.g. insulin-dependent diabetes mellitus.^38,39

In north European populations MS has been linked with the Class I HLAs A3 and B7, and Class II HLAs D2, DQW1, DQA1, and DQB1.¹⁴ The strongest association is with the Class II HLAs.¹⁴ Particular MHC Class II alleles (especially DR2) are considered to be risk factors for MS, and not simply genetic markers for the population of origin.⁴⁰

However, this relationship is not universal and MS is linked to alleles other than DR2 in some populations (e.g. Jordanian Arabs and Japanese).²⁶ This suggests that there is some heterogeneity in the contribution of MHC Class II polymorphisms to MS susceptibility.¹⁴

Although Class II MHC alleles increase the risk for MS, no specific allele (or sequence common to several alleles) has yet been identified that is necessary for the development of MS. Overall, the contribution of the MHC to MS risk is probably minor.¹⁴

T-cell receptor genes

The highly polymorphic genes that code for the alpha and beta chains of the T-cell receptor (TCR) are candidates for involvement in MS susceptibility also. Disparate results have been obtained from studies to investigate possible links between alpha chain and beta chain polymorphisms and MS.^39,41,42

Other candidate genes

Genes for immunoglobulin constant/variable region (Gm allotypes), myelin basic protein (MBP), tumour necrosis factor-alpha (TNF-alpha) and the BcG locus have all been considered in the search for candidate loci for MS susceptibility.¹⁴

The frequency of the Gm allotype alleles is highly ethnic-specific. Hence, in studies it is important to match cases and controls for racial and ethnic background - one of the major problems in identifying population associations with human disease.¹⁴ Although an association seems to be certain between the immunoglobulin variable region VH2-5 polymorphism, data on haplotype sharing in MS-affected sibling pairs may indicate that this locus is of minor importance in MS susceptibility.¹⁴

The major protein component of myelin, myelin basic protein, is used to initiate experimental allergic encephalomyelitis in experimental animals. This provides the rationale for its investigation as a factor in MS pathogenesis, and consideration as a candidate locus for MS susceptibility.¹⁴ However, initial reports linking MS to the MBP gene have not been confirmed.¹⁴

Evidence that TNF-alpha is involved in the pathogenesis of the MS lesion is plentiful.¹⁴ Encouraging early data make this highly polymorphic locus a candidate for MS susceptibility at the germline level. It may be involved also in influencing the severity and progression of MS.¹⁴

The BcG locus determines susceptibility to a wide variety of pathogens, including intracellular mycobacteria.¹⁴ The gene directly regulates T-cell independent macrophage activation, and indirectly regulates the magnitude and quality of specific immune responses to mycobacteria antigens.¹⁴ Recent findings in the NOD mouse suggest that the BcG locus may be a major susceptibility gene that influences the severity of diabetes in this autoimmune disease model.¹⁴

Despite numerous epidemiological and immunological studies, and the multitude of theories that have been formulated, the aetiology of MS remains an enigma. That is not to say that no progress has been made towards understanding the causes of the disease, but the breakthrough that will draw together all the known facts is yet to come.

What do epidemiological studies suggest?

The picture of MS aetiology emerging from epidemiological studies suggests a complex, multifactorial interaction between genetic predisposition, host susceptibility, and as yet undefined environmental influences. There is plentiful evidence to support the involvement of these components, and nothing to indicate that they are mutually exclusive.

What is the evidence?

Evidence for the involvement of genetic factors:

• differences in susceptibility between races,

• existence of resistant groups - even when resident in an otherwise high-risk area,

• concordance rates for MZ compared with DZ twin pairs,

• proposed haplotype associations/susceptibility genes.

Evidence for the involvement of environmental factors:

• geographic gradients of susceptibility,

• changes in prevalence in migrant populations,

• effect of age at migration on MS risk,

• epidemics and clusters of cases,

• less than complete concordance between MZ twin pairs,

• similar concordance for DZ twins and sibling pairs.

In addition, some of these data have implications for the likely nature of the environmental factor(s) that affect MS. For example, the similarity of the concordance rates observed for DZ twins and non-twin siblings suggests that the environmental factors are likely to be global in effect, such as climate, diet or a commonly-encountered infectious agent.⁴ This is supported by the tendency for affected sibling pairs to be randomly ordered in birth sequence, and to have the same age at disease onset, rather than to experience disease onset in the same calendar year.⁴

Is there any subsidiary evidence?

Many anecdotal reports have suggested that precipitating factors or environmental triggers may initiate MS onset, or relapse, or cause the disease to worsen. However, none of these factors, which include trauma, stress and pregnancy, are universal precipitating factors and some studies have failed to support any such relationship.^4,43,44

The situation is more clear regarding viral infections, which may precede MS onset, and have an association with the timing of relapse. Nevertheless, most relapses have no known precipitant.

Is MS an autoimmune disease?

Despite the circumstantial nature of much of the evidence, an immunopathogenic basis for MS is very likely.⁴ The characteristics of the disease that support this hypothesis are its:

• predominantly relapsing/ remitting course,

• female predilection,

• similarity in twin study concordance rates to those seen in systemic lupus erythematosus and juvenile-onset diabetes,

• possible HLA associations,

• resemblance to the animal model EAE, and

• the finding of immunologically active cells in the brain, spinal cord, and spinal fluid of MS patients.³⁷

Although at this stage it is possible to make only a tentative conclusion regarding the aetiology of MS, evidence is accumulating, and the areas that need closer examination can be defined more accurately than ever before. Therefore, as methodology improves, it becomes more and more likely that a definitive answer, albeit a complex one, will soon be achieved.

Bu sayfadaki bilginin en son güncellendiği/doğrulandığı tarih:

11/09/2001

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