RESUMEN
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.
Asunto(s)
Empalme Alternativo/genética , Predisposición Genética a la Enfermedad , Antígenos Comunes de Leucocito/genética , Polimorfismo Genético , Linfocitos T/inmunología , Pueblo Asiatico/genética , Linfocitos T CD4-Positivos/química , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/química , Linfocitos T CD8-positivos/inmunología , Estudios de Cohortes , Citoplasma/química , Exones/genética , Frecuencia de los Genes , Hepatitis B/genética , Hepatitis C/genética , Heterocigoto , Homocigoto , Humanos , Memoria Inmunológica/genética , Interferón gamma/análisis , Interferón gamma/metabolismo , Antígenos Comunes de Leucocito/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Tiroiditis Autoinmune/genéticaRESUMEN
The CD45 (leucocyte common) antigen is a haemopoietic cell specific tyrosine phosphatase essential for antigen receptor signalling in lymphocytes, and expression of different CD45 isoforms is associated with distinct functions. Here we describe a novel polymorphism in exon 4 (A54G) of the gene encoding CD45 (PTPRC) that results in an amino acid substitution of Thr-19 to Ala in exon 4. The 54G allele was identified in African Ugandan populations and was found with a suggestive but not statistically significant increase in frequency amongst HIV-seropositive Ugandans. This suggests that the 54G variant and CD45 splicing abnormalities might be associated with HIV infection.
Asunto(s)
Exones/genética , Predisposición Genética a la Enfermedad , Infecciones por VIH/genética , VIH-1 , Antígenos Comunes de Leucocito/genética , Polimorfismo Genético/genética , Empalme Alternativo , Sustitución de Aminoácidos , Frecuencia de los Genes , Infecciones por VIH/inmunología , Seropositividad para VIH , Humanos , Antígenos Comunes de Leucocito/metabolismo , Leucocitos Mononucleares/inmunología , UgandaRESUMEN
CD45 (leukocyte common) antigen is a hemopoietic cell-specific tyrosine phosphatase essential for antigen receptor-mediated signaling in lymphocytes. The molecule undergoes complex alternative splicing in the extracellular domain, and different patterns of CD45 splicing are associated with distinct functions. Lack of CD45 leads to severe combined immunodeficiency, and alterations of CD45 splicing, because of a polymorphism in exon 4, have been associated with altered immune function. Here we describe a polymorphism in exon 6 (A138G) of the gene encoding CD45 that interferes with alternative splicing. The polymorphism results in an amino acid substitution of Thr-47 to Ala in exon 6, a potential O- and N-linked glycosylation site. This exon 6 A138G variant is present at a frequency of 23.7% in the Japanese population but is absent in Caucasoids. Peripheral blood T cells from individuals carrying the A138G variant show a significant decrease in the proportion of cells expressing the A, B, and C CD45 isoforms and a high frequency of CD45R0+ cells. These phenotypic alterations in the A138G carriers may lead to changes in ligand binding, homodimerization of CD45, and altered immune responses, suggesting the involvement of natural selection in controlling the A138G carrier frequency.