Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Abstract

Multiple sclerosis (OMIM 126200) is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability.1 Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals;2,3 and systematic attempts to identify linkage in multiplex families have confirmed that variation within the Major Histocompatibility Complex (MHC) exerts the greatest individual effect on risk.4 Modestly powered Genome-Wide Association Studies (GWAS)5-10 have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects play a key role in disease susceptibility.11 Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the Class I region. Immunologically relevant genes are significantly over-represented amongst those mapping close to the identified loci and particularly implicate T helper cell differentiation in the pathogenesis of multiple sclerosis.

CTLA4 as Immunological Checkpoint in the Development of Multiple Sclerosis

“…Moreover, they provide functional support for GWAS that implicated T‐cell costimulatory and coinhibitory molecular networks as genetic risk factors of MS 1, 3, 4, 5, 6. A comprehensive Web‐based human genetics resource, ImmunoBase (https://www.immunobase.org), yields strong MS‐related hits for CD86 and CD80 .…”

“…Specifically, genome‐wide association studies (GWAS) identified numerous risk variants implicated in the regulation, differentiation, or activation of T lymphocytes 5, 6. The strongest genetic risk factor is HLA‐DRB1*15:01 , which encodes a molecule that presents peptide antigens to CD4 + T lymphocytes.…”

“…The strongest genetic risk factor is HLA‐DRB1*15:01 , which encodes a molecule that presents peptide antigens to CD4 + T lymphocytes. Additional genetic risk variants include CD80 and CD86 , which are the binding partners of costimulatory (CD28) and coinhibitory (CTLA4) molecules expressed on T cells 1, 3, 4, 5, 6. Molecular candidates revealed by GWAS need to be corroborated by functional evidence.…”

Heterogeneity in association of remote herpesvirus infections and pediatric MS

“…Whole‐genome single‐nucleotide polymorphism (SNP) analysis was performed on Illumina OmniExpress BeadChip or Illumina Infinium Human OmniExpress Exome. 17. Standard quality control (QC) was performed.…”

Genomics implicates adaptive and innate immunity in Alzheimer's and Parkinson's diseases

“…We used MS33 as a positive control, as it is a disease affecting the brain with known immune etiology. All studies were conducted in European populations, and are summarized in Table 1.…”