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Defective dendritic cell maturation in a child with nucleotide excision repair deficiency and CD4 lymphopenia
L Racioppi1, C Cancrini, M L Romiti
1Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli Federico II, Italy.
Insights
This study details a child with trichothiodystrophy (TTD) and combined immunodeficiency (CID) due to an XPD gene defect affecting DNA repair and transcription. The findings reveal novel immune cell dysfunction in TTD, impacting T-cell signaling and antigen-presenting cells.
Area of Science:
- Genetics and Molecular Biology
- Immunology
- Cell Biology
Background:
- Trichothiodystrophy (TTD) is a rare genetic disorder.
- Xeroderma pigmentosum group D (XPD) gene defects cause TTD and affect DNA repair.
- Combined immunodeficiency (CID) is characterized by impaired immune function.
Observation:
- A pediatric patient with TTD presented with neurological and immune abnormalities, including CD4+ lymphopenia.
- The patient exhibited reduced T-cell proliferation and altered T-cell receptor signaling.
- Dendritic cells (DCs) showed reduced co-stimulatory molecule and HLA glycoprotein expression.
Findings:
- The XPD gene defect impacts the transcription factor II H (TFIIH) complex, crucial for DNA repair and transcription.
- Patient T-cells displayed reduced Lck kinase activity and hyperactivated Fyn kinase.
- Antigen-presenting cells, specifically DCs, demonstrated impaired ability to stimulate naive T-cells.
Implications:
- Defective TFIIH complex function can lead to significant T-cell and DC dysfunction.
- This dysfunction contributes to the severe combined immunodeficiency observed in the patient.
- Highlights a novel link between XPD gene mutations, TFIIH complex, and immune system impairment.
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.