title: The CD6 multiple sclerosis susceptibility allele is associated with alterations in CD4+ T cell proliferation.
abstract: Genome-wide association studies have revealed a large number of genetic associations with autoimmune diseases. Despite this progress, the mechanisms underlying the contribution of allelic variants to the onset of immune-related diseases remain mostly unknown. Our recent meta-analysis of genome-wide association studies of multiple sclerosis (MS) identified a new susceptibility locus tagged by a single nucleotide polymorphism, rs17824933 (p = 3.8 × 10(-9)), that is found in a block of linkage disequilibrium containing the CD6 gene. Because CD6 plays an important role in maintenance of T cell activation and proliferation, we examined the biologic phenotypes of the risk-associated allele. In this article, we report that the MS susceptibility allele in CD6 is associated with decreased expression of full-length CD6 in CD4(+) and CD8(+) T cells. As a consequence, proliferation is diminished during long-term activation of CD4(+) T cells from subjects with the risk allele. Selective knockdown of full-length CD6 using exon 5-specific small interfering RNA induces a similar proliferation defect of CD4(+) T cells from subjects homozygous for the protective allele. Exon 5 encodes for the extracellular binding site of the CD6 ligand ALCAM, which is required for CD6 stimulation. In CD4(+) T cells from subjects with the risk allele, exon 5 is consistently underexpressed, thereby providing a mechanism by which the allele affects proliferation of CD4(+) T cells. These findings indicate that the MS risk allele in the CD6 locus is associated with altered proliferation of CD4(+) T cells and demonstrate the influence of a disease-related allelic variant on important immunological characteristics.
authors.affiliation: Department of Neurology, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Kofler
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Severson
authors.forename: Narine
authors.initials: N
authors.lastname: Mousissian
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
authors.forename: David A
authors.initials: DA
authors.lastname: Hafler
mesh_terms: D000483:Alleles; D015703:Antigens, CD / Q000235:genetics* / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D049109:Cell Proliferation; D002469:Cell Separation; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D009103:Multiple Sclerosis / Q000235:genetics* / Q000276:immunology; D010641:Phenotype; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; C062279:CD6 antigen; D034741:RNA, Small Interfering