Elsevier

Journal of Neuroimmunology

Volume 113, Issue 2, 15 February 2001, Pages 171-184
Journal of Neuroimmunology

Review article
Multiple sclerosis: Genomic rewards

https://doi.org/10.1016/S0165-5728(00)00444-6Get rights and content

Abstract

A large body of immunologic, epidemiologic, and genetic data indicate that tissue inury in multiple sclerosis (MS) results from an abnormal immune response to one or more myelin antigens that develops in genetically susceptible individuals after exposure to an as-yet undefined causal agent. The genetic component of MS etiology is believed to result from the action of several genes of moderate effect. The incomplete penetrance of MS susceptibility alleles probably reflects interactions with other genes, post transcriptional regulatory mechanisms, and significant nutritional and environmental influences. Equally significant, it is also likely that genetic heterogeneity exists, meaning that specific genes influence susceptibility and pathogenesis in some affects but not in others. Results in multiplex MS families confirm the genetic importance of the MHC region in conferring susceptibility of MS. Susceptibility may be mediated by the class II genes themselves (DR, DQ or both), related to the known function of these molecules in the normal immune response, e.g. antigen binding and presentation and T cell repertoire determination. The possibility that other genes in the MHC or the telomeric region of the MHC are responsible for the observed genetic effect cannot be excluded. The data also indicate that although the MHC region plays a significant role in MS susceptibility, much of the genetic effect in MS remains to be explained. Some loci may be involved in the initial pathogenic events, while others could influence the development and progression of the disease. The past few years have seen real progress in the development of laboratory and analytical approaches to study non-Mendelian complex genetic disorders and in defining the pathological basis of demyelination, setting the stage for the final characterization of the genes involved in MS susceptibility and pathogenesis. Their identification and characterization is likely to define the basic etiology of the disease, improve risk assessment and influence therapeutics.

Section snippets

Introduction: multiple sclerosis as a genetic disease

Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system (CNS) characterized by myelin loss, gliosis, varying degrees of axonal pathology, and progressive neurological dysfunction (Hauser and Goodkin, 2001). A large body of data indicates that tissue injury in MS results from an abnormal immune response to one or several myelin antigens occurring in genetically susceptible individuals after exposure to an as yet undefined environmental factor or factors. A genetic

An interplay of genes and environmental factors

Migration studies have been widely used to illustrate potential environmental influences on MS (Kurtzke, 1983, Martyn and Gale, 1997). Children born to parents who have migrated from a high-risk area to a low-risk area for MS appear to have a lower lifetime risk than their parents. Conversely, migration of parents from a low-risk area to a high-risk area may confer a higher risk for MS in the children. Although the interpretation of migration studies has been difficult, in part because the

Population versus family-based studies

The genetic analysis of MS has traditionally focused on population-based association studies of candidate polymorphic genes, in which the frequencies of marker alleles in groups of patients and healthy controls are compared, and the difference is subjected to statistical analysis. The association is often expressed as the relative risk that an individual will develop the disorder if he/she carries the particular allele or marker, compared to an individual who does not carry the allele or

The MHC and multiple sclerosis

The MHC chromosomal region is the strongest and most consistent effect identified in MS, and must be discussed in detail. MHC class I and class II molecules are polymorphic cell surface glycoproteins whose primary role in an immune response is to display and present short antigenic peptide fragments to antigen-specific CD4+ and CD8+ T cells, which can then become activated by a second stimulatory signal and initiate an immune response. In addition, MHC molecules present on stromal cells on the

Susceptibility genes versus modifiers

As summarized above, the MHC locus has consistently demonstrated both association and linkage with MS in case–control and family studies, however the role of a gene within this region in determining clinical features or subtypes of MS is unclear. HLA-DR2 has been reported to be associated with lower age at onset, gender, severe, relapsing-remitting, and mild MS courses, or to have no influence (Celius et al., 2000, Kira et al., 1996, Masterman et al., 2000, McDonnell et al., 1999, Olerup et

Gene expression studies

During the process of lesion formation, lymphocyte activation and recruitment, extravasation, and effector functions involve several cellular phenotypic changes triggered by specific gene expression pathways. Cytokines, adhesion molecules, growth factors, and other molecules, such as free radicals, proteases and vasoactive amines, induce and regulate numerous critical cell functions. The comprehensive analysis of these cellular transcriptional programs, the transcriptome, both in the CNS and

Genetic heterogeneity in MS

Studies with multiplex families confirmed the genetic linkage to the MHC region and the specific association with the HLA-DRB1*1501 allele (MS Genetics Group, 1998). Interestingly, 25% of the families, most of them HLA-DRB1*1501 negative, showed no linkage to the MHC locus. We also detected an increased frequency of the DRB1*1501 susceptibility marker in families with many affecteds compared to families with smaller number of affecteds. Both observations suggest the presence of substantial

A model of inheritance

A simple model of inheritance for all MS is unlikely and cannot account for the nonlinear decrease in disease risk in families with increasing genetic distance from the proband. As summarized above, the available data is most compatible with a complex multifactorial etiology, including both genetic and environmental factors (Table 6). Recurrence risk estimates in multiplex families combined with twin data, predict that the MS-prone genotype results from multiple independent or interacting

Conclusions and future directions

The confluence of recent technological and analytical advances proposes a new experimental view to elucidate the pathogenic mechanisms of this disease. Specifically:

  • 1.

    Groups and consortia with the appropriate experimental, clinical and financial resources will continue the analysis of the MS genome using larger familial DNA datasets and dense and informative genetic markers to further narrow the chromosomal segments harboring disease genes. The potentially critical importance of identifying and

Acknowledgements

The authors are supported by the National Multiple Sclerosis Society, the National Institute of Health, and the Nancy Davis and Sandler Foundations. LFB is a National Multiple Sclerosis Society post-doctoral fellow. The concepts and discussion presented in this paper represent the invaluable continuous interactions with Drs. Jonathan L. Haines (Vanderbilt University), Margaret Pericak-Vance (Duke University) and their colleagues.

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