title: Disease associations and altered immune function in CD45 138G variant carriers.
abstract: The CD45 antigen is a haemopoietic cell specific tyrosine phosphatase essential for antigen receptor mediated signalling in lymphocytes. Expression of different patterns of alternatively spliced CD45 isoforms is associated with distinct functions. We recently identified a polymorphism in exon 6 (A138G) of the gene encoding CD45 (PTPRC) that results in altered CD45 splicing. The 138G allele is present at a high frequency among Japanese (23.7%), with 5.1% individuals homozygous for the G allele. In this study we show that the A138G polymorphism is the cause of altered CD45 isoform expression, promoting splicing towards low molecular weight CD45 isoforms. We further report that the frequency of A138G heterozygotes is significantly reduced in number in cohorts of patients with autoimmune Graves' disease or hepatitis B infection, whereas G138G homozygotes are absent from a cohort of Hashimoto's thyroiditis patients. We also show that 138G individuals exhibit altered cytokine production in vitro and an increased proportion of memory T cells. These data suggest that the 138G variant allele strongly influences these diseases by modulation of immune mechanisms and may have achieved its high frequency as a result of a natural selection probably related to pathogen resistance.
authors.affiliation: The Edward Jenner Institute for Vaccine Research, Compton, Berkshire RG20 7NN, UK.
authors.forename: Sally
authors.initials: S
authors.lastname: Boxall
authors.forename: Tara
authors.initials: T
authors.lastname: Stanton
authors.forename: Kouzo
authors.initials: K
authors.lastname: Hirai
authors.forename: Victoria
authors.initials: V
authors.lastname: Ward
authors.forename: Tomoyo
authors.initials: T
authors.lastname: Yasui
authors.forename: Hideki
authors.initials: H
authors.lastname: Tahara
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tamori
authors.forename: Shuhei
authors.initials: S
authors.lastname: Nishiguchi
authors.forename: Susumu
authors.initials: S
authors.lastname: Shiomi
authors.forename: Osamu
authors.initials: O
authors.lastname: Ishiko
authors.forename: Masaaki
authors.initials: M
authors.lastname: Inaba
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Nishizawa
authors.forename: Ritu
authors.initials: R
authors.lastname: Dawes
authors.forename: Walter
authors.initials: W
authors.lastname: Bodmer
authors.forename: Peter C L
authors.initials: PC
authors.lastname: Beverley
authors.forename: Elma Z
authors.initials: EZ
authors.lastname: Tchilian
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology; D015331:Cohort Studies; D003593:Cytoplasm / Q000737:chemistry; D005091:Exons / Q000235:genetics; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006509:Hepatitis B / Q000235:genetics; D006526:Hepatitis C / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007156:Immunologic Memory / Q000235:genetics; D007371:Interferon-gamma / Q000032:analysis / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D013967:Thyroiditis, Autoimmune / Q000235:genetics
chemical_list: D020033:Protein Isoforms; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens