title: The MS Risk Allele of CD40 Is Associated with Reduced Cell-Membrane Bound Expression in Antigen Presenting Cells: Implications for Gene Function.
abstract: Human genetic and animal studies have implicated the costimulatory molecule CD40 in the development of multiple sclerosis (MS). We investigated the cell specific gene and protein expression variation controlled by the CD40 genetic variant(s) associated with MS, i.e. the T-allele at rs1883832. Previously we had shown that the risk allele is expressed at a lower level in whole blood, especially in people with MS. Here, we have defined the immune cell subsets responsible for genotype and disease effects on CD40 expression at the mRNA and protein level. In cell subsets in which CD40 is most highly expressed, B lymphocytes and dendritic cells, the MS-associated risk variant is associated with reduced CD40 cell-surface protein expression. In monocytes and dendritic cells, the risk allele additionally reduces the ratio of expression of full-length versus truncated CD40 mRNA, the latter encoding secreted CD40. We additionally show that MS patients, regardless of genotype, express significantly lower levels of CD40 cell-surface protein compared to unaffected controls in B lymphocytes. Thus, both genotype-dependent and independent down-regulation of cell-surface CD40 is a feature of MS. Lower expression of a co-stimulator of T cell activation, CD40, is therefore associated with increased MS risk despite the same CD40 variant being associated with reduced risk of other inflammatory autoimmune diseases. Our results highlight the complexity and likely individuality of autoimmune pathogenesis, and could be consistent with antiviral and/or immunoregulatory functions of CD40 playing an important role in protection from MS.
authors.affiliation: Multiple Sclerosis Division, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria., Australia.
authors.forename: Judith
authors.initials: J
authors.lastname: Field
authors.affiliation: Centre for Immunology and Allergy Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Fernando
authors.initials: F
authors.lastname: Shahijanian
authors.affiliation: Centre for Immunology and Allergy Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Schibeci
authors.affiliation: Multiple Sclerosis Division, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria., Australia.
authors.forename: Laura
authors.initials: L
authors.lastname: Johnson
authors.affiliation: Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Parkville, Australia; Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Melissa
authors.initials: M
authors.lastname: Gresle
authors.affiliation: Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Parkville, Australia; Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Louise
authors.initials: L
authors.lastname: Laverick
authors.affiliation: Centre for Immunology and Allergy Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Grant
authors.initials: G
authors.lastname: Parnell
authors.affiliation: Centre for Immunology and Allergy Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Graeme
authors.initials: G
authors.lastname: Stewart
authors.affiliation: Centre for Immunology and Allergy Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Fiona
authors.initials: F
authors.lastname: McKay
authors.affiliation: Multiple Sclerosis Division, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria., Australia; Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Parkville, Australia; Melbourne Neuroscience Institute, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Trevor
authors.initials: T
authors.lastname: Kilpatrick
authors.affiliation: Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Parkville, Australia; Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Helmut
authors.initials: H
authors.lastname: Butzkueven
authors.affiliation: Centre for Immunology and Allergy Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Booth
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000235:genetics* / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism*; D015331:Cohort Studies; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D005838:Genotype; D006801:Humans; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D009103:Multiple Sclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000737:chemistry / Q000378:metabolism; D055815:Young Adult
chemical_list: D019013:CD40 Antigens; D012333:RNA, Messenger