title: Premature ageing of the immune system underlies immunodeficiency in ataxia telangiectasia.
abstract: ATM kinase modulates pathways implicated in premature ageing and ATM genotype predicts survival, yet immunodeficiency in ataxia telangiectasia is regarded as mild and unrelated to age. We address this paradox in a molecularly characterised sequential adult cohort with classical and mild variant ataxia telangiectasia. Immunodeficiency has the characteristics of premature ageing across multiple cellular and molecular immune parameters. This immune ageing occurs without previous CMV infection. Age predicts immunodeficiency in genetically homogeneous ataxia telangiectasia, and in comparison with controls, calendar age is exceeded by immunological age defined by thymic naïve CD4+ T cell levels. Applying ataxia telangiectasia as a model of immune ageing, pneumococcal vaccine responses, characteristically deficient in physiological ageing, are predicted by thymic naïve CD4+ T cell levels. These data suggest inherited defects of DNA repair may provide valuable insight into physiological ageing. Thymic naïve CD4+ T cells may provide a biomarker for vaccine responsiveness in elderly cohorts.
authors: Immunology Laboratory, Department of Pathology, Papworth Hospital NHS Foundation Trust, Cambridge University Health Partners, Cambridge CB23 3RE, UK. andrew.exley@papworth.nhs.uk
authors: Andrew Robert
authors: AR
authors: Exley
authors: Samantha
authors: S
authors: Buckenham
authors: Elizabeth
authors: E
authors: Hodges
authors: Robert
authors: R
authors: Hallam
authors: Phil
authors: P
authors: Byrd
authors: James
authors: J
authors: Last
authors: Claire
authors: C
authors: Trinder
authors: Susan
authors: S
authors: Harris
authors: Nicholas
authors: N
authors: Screaton
authors: Anthony P
authors: AP
authors: Williams
authors: A Malcolm R
authors: AM
authors: Taylor
authors: John M
authors: JM
authors: Shneerson
mesh_terms: D000328:Adult; D000375:Aging / Q000276:immunology*; D001260:Ataxia Telangiectasia / Q000235:genetics / Q000276:immunology*; D064007:Ataxia Telangiectasia Mutated Proteins; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002452:Cell Count; D018797:Cell Cycle Proteins / Q000235:genetics; D002469:Cell Separation; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases