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Immune defects in families and patients with xeroderma pigmentosum and trichothiodystrophy
E Mariani1, A Facchini, M C Honorati
1Laboratorio di Immunologia e Genetica, Istituto di Ricerca Codivilla Putti, I.O.R., Bologna, Italy.
Abstract:
Xeroderma pigmentosum (XP) is a rare autosomal recessive disease characterized by photosensitivity, a high incidence of cancer in sun-exposed portions of the skin and a reduced capacity to repair the u.v.-induced DNA damage. One of the XP mutations (XP-D) has also been identified in patients affected by trichothiodystrophy (TTD), a rare autosomal recessive disease characterized by brittle hair, mental and physical retardation, peculiar face and ichthyosis. However, in these patients there is no evidence of increased skin tumour incidence. Since an impairment of cell-mediated immunity has been proposed as a co-factor in the cancer proneness of XP patients, we investigated the involvement of immune defect(s) in five XP patients, five TTD patients, their parents, and 24 TTD relatives. We evaluated the phenotype of circulating lymphocytes, natural killer (NK) cell lytic activity, target cell binding of NK cells at single cell level and the effect of interferons (IFN) alpha and beta on NK cell activity. The relative proportion of CD3+ and CD4+ circulating lymphocytes was reduced in XP but not in TTD patients. NK cell lytic activity was decreased in XP patients and their mothers, but their fathers showed normal lytic activity. NK activity varied among TTD families: four out of five patients and their relatives presented low NK cell activity, and one family was normal. In TTD family members, NK activity increased after incubation with IFN-alpha or IFN-beta, but never reached normal values. In contrast, in XP patients and their mothers, the defect was almost completely corrected after in vitro incubation with IFN-alpha or IFN-beta. Our study indicates impaired NK lytic activity in the majority of TTD and XP patients and that this defect is present also in members of their families. In addition, XP patients present a low number of circulating T cells. These multiple abnormalities, together with DNA repair defects, could be related to the increased cancer risk in XP patients.
Insights
Xeroderma pigmentosum (XP) and trichothiodystrophy (TTD) patients show impaired natural killer (NK) cell activity, with XP patients also having reduced T cells. Immune defects may contribute to cancer risk in XP.
Area of Science:
- Immunology
- Genetics
- Dermatology
Background:
- Xeroderma pigmentosum (XP) is a rare genetic disorder causing photosensitivity and high skin cancer rates due to DNA repair defects.
- Trichothiodystrophy (TTD) shares a mutation (XP-D) with XP but lacks increased skin cancer risk, suggesting other factors are involved.
- Impaired cell-mediated immunity is a potential co-factor in XP's cancer proneness.
Purpose of the Study:
- To investigate immune system defects in XP and TTD patients and their families.
- To evaluate lymphocyte phenotypes, natural killer (NK) cell activity, and interferon responses.
- To explore the relationship between immune dysfunction, DNA repair, and cancer risk in XP.
Main Methods:
- Assessed circulating lymphocyte proportions (CD3+, CD4+).
- Measured NK cell lytic activity and target cell binding.
- Tested the effect of interferon-alpha and interferon-beta on NK cell activity in vitro.
Main Results:
- XP patients exhibited reduced CD3+ and CD4+ lymphocytes and decreased NK cell activity.
- NK cell activity was impaired in most TTD patients and their relatives, with variable responses to interferons.
- Interferon treatment partially or fully corrected NK cell defects in XP patients and their mothers, but not in TTD families.
Conclusions:
- The majority of TTD and XP patients display impaired NK cell activity, often present in family members.
- XP patients have additional T cell deficiencies, contributing to their immune dysfunction.
- Combined DNA repair and immune defects likely increase cancer risk in Xeroderma pigmentosum.