Classical ataxia telangiectasia patients have a congenitally aged immune system with high expression of CD95.
Ataxia-telangiectasia (A-T) is a rare neurodegenerative immunodeficiency disorder caused by mutations in the ataxia telangiectasia mutated gene. Patients commonly have lymphopenia and Ig-production abnormalities. We used multicolor flow cytometry and IL-7 ELISA to investigate the effect of A-T and age on the proportions of major lymphocyte subsets and their pattern of CD95 expression in relation to IL-7 levels in 15 classical A-T patients. We also analyzed the sensitivity of T cells from four classical A-T patients to CD95-mediated apoptosis using TUNEL and caspase-activation assays. Our results confirmed lymphopenia and a deficiency in naive T and B cells in A-T patients. In contrast to controls, the proportions of naive and memory T and B cell subsets in A-T patients did not vary in relation to age. There was no evidence of a deficiency in plasma IL-7 or IL-7R expression, and IL-7 concentration correlated positively with CD95 expression on CD4(+) T cells. CD95 expression on unstimulated A-T lymphocytes was high, and the apoptotic sensitivity of activated naive and central memory T cells was increased. These findings show that the immunodeficiency in A-T patients may be described as congenitally aged and is not progressive. The naive cell deficiency is not related to a deficiency in IL-7 or its receptor. However, IL-7 may upregulate CD95 on A-T lymphocytes. High CD95 expression and increased apoptotic sensitivity of activated naive and central memory T cells may result in an increased level of CD95-mediated apoptosis, which could contribute to the congenital lymphopenia in A-T.
School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
Ellen F
EF
Carney
Venkataramanan
V
Srinivasan
Paul A
PA
Moss
A Malcolm
AM
Taylor
D000293:Adolescent; D000328:Adult; D000375:Aging / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D017209:Apoptosis / Q000276:immunology; D001260:Ataxia Telangiectasia / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D002648:Child; D005260:Female; D006801:Humans; D007223:Infant; D008231:Lymphopenia / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D015854:Up-Regulation / Q000276:immunology*; D055815:Young Adult; D019014:fas Receptor / Q000096:biosynthesis* / Q000502:physiology
C491901:FAS protein, human; D019014:fas Receptor