title: Idiopathic CD4+ T lymphopenia without autoimmunity or granulomatous disease in the slipstream of RAG mutations.
abstract: A girl presented during childhood with a single course of extensive chickenpox and moderate albeit recurrent pneumonia in the presence of idiopathic CD4+ T lymphocytopenia (ICL). Her clinical condition remained stable over the past 10 years without infections, any granulomatous disease, or autoimmunity. Immunophenotyping demonstrated strongly reduced naive T and B cells with intact proliferative capacity. Antibody reactivity on in vivo immunizations was normal. T-cell receptor-Vβ repertoire was polyclonal with a very low content of T-cell receptor excision circles (TRECs). Kappa-deleting recombination excision circles (KRECs) were also abnormal in the B cells. Both reflect extensive in vivo proliferation. Patient-derived CD34+ hematopoietic stem cells could not repopulate RAG2(-/-)IL2Rγc(-/-) mice, indicating the lymphoid origin of the defect. We identified 2 novel missense mutations in RAG1 (p.Arg474Cys and p.Leu506Phe) resulting in reduced RAG activity. This report gives the first genetic clue for ICL and extends the clinical spectrum of RAG mutations from severe immune defects to an almost normal condition.
authors.affiliation: Emma Children's Hospital, Academic Medical Center, Meibergdreef 9, Amsterdam, The Netherlands. t.w.kuijpers@amc.nl
authors.forename: Taco W
authors.initials: TW
authors.lastname: Kuijpers
authors.forename: Hanna
authors.initials: H
authors.lastname: Ijspeert
authors.forename: Ester M M
authors.initials: EM
authors.lastname: van Leeuwen
authors.forename: Machiel H
authors.initials: MH
authors.lastname: Jansen
authors.forename: Mette D
authors.initials: MD
authors.lastname: Hazenberg
authors.forename: Kees C
authors.initials: KC
authors.lastname: Weijer
authors.forename: Rene A W
authors.initials: RA
authors.lastname: van Lier
authors.forename: Mirjam
authors.initials: M
authors.lastname: van der Burg
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000502:physiology; D005260:Female; D006105:Granulomatous Disease, Chronic / Q000276:immunology*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D015375:Receptors, Interleukin-2 / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D018344:T-Lymphocytopenia, Idiopathic CD4-Positive / Q000235:genetics* / Q000276:immunology*
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C499308:Rag2 protein, mouse; D015375:Receptors, Interleukin-2; C064658:RAG-1 protein