Genetics of Demyelinating Diseases

Abstract

Multiple sclerosis (MS), the prototypic demyelinating disease in humans, is the most common cause of acquired neurological dysfunction arising between early to mid adulthood. MS is an inflammatory disorder and is believed to result from an autoimmune response, directed against myelin proteins and perhaps other antigens, resulting in demyelination and dense astrogliosis. A genetic component in MS is indicated by an increased relative risk to siblings compared to the general population (lambda s) of 20-40, and an increased concordance rate in monozygotic compared to dizygotic twins. Association and/or linkage studies to candidate genes have yielded a considerable number of reports showing significant genetic effects for the major histocompatibility complex (MHC), immunoglobulin heavy chain, T cell antigen receptor, and myelin basic protein loci. With the exception of the MHC, however, these results have been difficult to replicate or apply beyond isolated populations. Recently, a multi-analytical genomic screen effort was completed to identify genomic regions potentially harboring MS susceptibility genes. Nineteen such regions were identified. The data confirm the reported genetic effect of the MHC region. However, no single locus generated overwhelming evidence of linkage. These results suggest a multifactorial etiology, including both environmental and multiple genetic factors of moderate effect.

T Cells of Multiple Sclerosis Patients Target a Common Environmental Peptide that Causes Encephalitis in Mice

“…Similar mono-and dizygotic twin concordance rates of 30 and 4%, respectively, in both MS and diabetes suggest that environmental factors trigger and/or sustain autoimmunity through interaction with the products of predisposing genes (5,6). The search for viral triggers of autoimmunity has continued for decades.…”

Association of CCR5 Δ32 deletion with early death in multiple sclerosis

“…21 Genetic studies indicate MS is likely to be a polygenic disorder, due to multiple gene associations. [22][23][24] Some of the genes reported to be associated with MS include interleukin, 25,26 CTLA4, 27 HLA-DRB1*1501, and apolipoprotein E. 28 Early-published reports 29,30 of epidemiological studies of MS concluded that the disease was common in persons of Scandinavian descent: an ethnic group that exhibits a high prevalence of CCR5 ⌬32 mutation. Among the European white population there is a north to south gradient of prevalence of the CCR5 ⌬32 mutant allele, with the allelic frequencies highest in Scandinavia (16%) and lowest in Sardinia (4%), with a mean allelic frequency across the whole of Europe of 9.1%, where as this variant was found in only 1% in individuals of African origin, 0% in Asians, and 9.8% in Caucasians.…”

“…21 Genetic studies indicate MS is likely to be a polygenic disorder, due to multiple gene associations. [22][23][24] Some of the genes reported to be associated with MS include interleukin, 25,26 CTLA4, 27 HLA-DRB1*1501, and apolipoprotein E. 28 Early- …”

Engineering High-Affinity T Cell Receptor/ Cytokine Fusions for Therapeutic Targeting

“…Pathogenic CD4 + T cells in these diseases are thought to express T cell receptors (TCRs) that recognize specific peptides bound to class II major histocompatibility complex (MHC) proteins on the surface of antigen-presenting cells (APCs), where the presented peptide is derived not from a pathogen, but from an allergen, transplant antigen, or self protein. Specific peptides derived from allergens or "self" proteins have been identified as linked to the pathological responses in many cases (Haselden et al 1999;Hemmer et al 1998;Jahn-Schmid et al 2002;Muraro et al 1997;Reijonen et al 2002;Vergelli et al 1997), and links between particular class II MHC alleles and disease susceptibility have been identified (Ebers et al 1996;Oksenberg et al 1996;Wucherpfennig & Sethi 2011). Hence, one attractive option would be to selectively inhibit only those CD4 + T cells that initiate or sustain pathological inflammation.…”