title: Defective dendritic cell maturation in a child with nucleotide excision repair deficiency and CD4 lymphopenia.
abstract: We report a case of a combined immunodeficiency (CID) in a child affected by trichothiodystrophy (TTD) characterized by an altered response to ultraviolet (UV) light due to a defect in the XPD gene. The XPD gene encodes a subunit of the transcription factor II H (TFIIH), a complex involved in nucleotide-excision repair (NER) and basal transcription. Our patient showed neurological and immune system abnormalities, including CD4 + lymphopenia never previously reported in TTD patients. In vitro immunological studies revealed a marked reduction in T-cell proliferation in response to mitogens and CD3 cross-linking which was partially recovered by the addition of anti-CD28 antibody or exogenous interleukin-2. The patient's T cells displayed alterations in T-cell receptor (TCR/CD3) proximal signalling characterized by marked reduction in Lck kinase activity coupled with a constitutive hyperactivation of Fyn kinase. Despite these alterations, normal levels of Lck and Fyn proteins were detected. The role of antigen-presenting cells (APCs) in the pathogenesis of the T-cell defect was investigated by analysing dendritic cells (DCs) generated from the patient's blood monocytes. In these cells, flow cytometry revealed significantly reduced expression of the CD86 co-stimulatory molecules and HLA glycoproteins. In addition, the patient's DCs showed a decreased ability to stimulate naive T lymphocytes. Overall, the results of our study suggest that a defective TFIIH complex might result in alterations in T cells and DC functions leading to a severe immunodeficiency.
authors.affiliation: Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli Federico II, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Racioppi
authors.forename: C
authors.initials: C
authors.lastname: Cancrini
authors.forename: M L
authors.initials: ML
authors.lastname: Romiti
authors.forename: F
authors.initials: F
authors.lastname: Angelini
authors.forename: S
authors.initials: S
authors.lastname: Di Cesare
authors.forename: E
authors.initials: E
authors.lastname: Bertini
authors.forename: S
authors.initials: S
authors.lastname: Livadiotti
authors.forename: M G
authors.initials: MG
authors.lastname: Gambarara
authors.forename: G
authors.initials: G
authors.lastname: Matarese
authors.forename: F
authors.initials: F
authors.lastname: Lago Paz
authors.forename: M
authors.initials: M
authors.lastname: Stefanini
authors.forename: P
authors.initials: P
authors.lastname: Rossi
mesh_terms: D015496:CD4-Positive T-Lymphocytes; D002454:Cell Differentiation; D002675:Child, Preschool; D004265:DNA Helicases; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D005808:Genes, Recessive; D006197:Hair / Q000002:abnormalities; D006801:Humans; D007057:Ichthyosis / Q000235:genetics; D008607:Intellectual Disability / Q000235:genetics; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D008297:Male; D010787:Photosensitivity Disorders / Q000235:genetics; D011506:Proteins / Q000235:genetics; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction; D013577:Syndrome; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000235:genetics; D019473:Transcription Factors, TFII; D051759:Xeroderma Pigmentosum Group D Protein
chemical_list: D004268:DNA-Binding Proteins; D011506:Proteins; D014157:Transcription Factors; D019473:Transcription Factors, TFII; D051758:Transcription Factor TFIIH; D004265:DNA Helicases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human