Genetic and Molecular Approaches to the Immunopathogenesis of Multiple Sclerosis: An Update

Abstract

Although the aetiology of MS remains elusive, several genetic approaches have provided clues to the underlying molecular pathogenesis. In addition to the well known association to HLA class II alleles, weak but highly significant association to the interleukin-7 receptor and interleukin-2 receptor genes has recently been established. A series of other promising candidate genes identified in large genome screens are under evaluation. The genetic predisposition to MS is so far shown to be mediated by common polymorphisms in genes encoding molecules involved in T cell activation and homeostasis, but only a small proportion of the potential susceptibility genes have yet been identified. Analyses of transcribed immune receptor genes have revealed evidence of antigen-driven clonal expansion of lymphocytes, and may also provide tools for charting their specificites. Recently, attempts to identify disease-associated genes through transcriptional profiling have revealed new candidate players in MS pathogenesis. Whereas genetic studies in humans may identify individual molecular players, transgenic animal models allow detailed examination of molecular pathways. These studies have shown that in addition to altered protein function, alteration of gene expression may contribute to disease development. We here review how different genetic approaches can be combined to elucidate the immuno-pathogenesis of MS.

Cytokine gene polymorphisms in multiple sclerosis: a meta-analysis of 45 studies including 7379 cases and 8131 controls

“…However, even for the well‐established effect of the human leucocyte antigen (HLA) DRB1*1501 class II allele [13], the predicted contribution on MS genetics appears to be modest [12,13,69]. Recently, the genome‐wide association methodology and large studies using the classic candidate‐gene approach have identified SNPs (interleukin‐2 receptor A on chromosome 10 and interleukin‐7 receptor A on chromosome 5) located outside the MHC gene region that were related to MS [11,70–75]. Once again, the mutant alleles explained only a small fraction of the variance in the risk of the development of MS [11].…”

“…Recently, the genome-wide association methodology and large studies using the classic candidate-gene approach have identified SNPs (interleukin-2 receptor A on chromosome 10 and interleukin-7 receptor A on chromosome 5) located outside the MHC gene region that were related to MS [11,[70][71][72][73][74][75]. Once again, the mutant alleles explained only a small fraction of the variance in the risk of the development of MS [11].…”

Fingolimod

“…Die Bedeutung des B-Zell-Arms für die Pathogenese der MS rückt ebenfalls in den Fokus (14,27). Obwohl die genauen Ursachen, die zur Störung der Schrankenfunktion des Endothels führen, noch unklar sind, werden verschiedene infektiöse und genetische Mechanismen diskutiert, die zur remittierenden Entzündungsreaktion führen können (13,19,40). Die Kontrolle dieser Entzündungsreaktionen und ihrer lokalen Komplikationen stellt damit die wichtigste therapeutische Intervention für die MS dar.…”

Myelin matters: proteomic insights into white matter disorders

“…MS is believed to be caused by a combination of factors including genetic susceptibility, gender and environmental influences such as toxins or bacterial/viral infection [15][16][17]. The typical demyelination of tissue plaques goes along with a complex neuro pathology that includes axonal degeneration, the invasion of activated autoantigen-specific T lymphocytes into the central nervous system, astrogliosis, microglial activation, alterations regarding several molecular networks including chemokines and cytokines and autoantibodies directed against myelin components [18][19][20].…”

“…The typical demyelination of tissue plaques goes along with a complex neuro pathology that includes axonal degeneration, the invasion of activated autoantigen-specific T lymphocytes into the central nervous system, astrogliosis, microglial activation, alterations regarding several molecular networks including chemokines and cytokines and autoantibodies directed against myelin components [18][19][20]. It is of note, however, that the established MS-susceptibility genes of the major histocompatibility complex as well as those with weaker associations [21,22,15] are not 'myelin genes' but 'immune genes'. …”