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Circulating T Cells of Patients with Nijmegen Breakage Syndrome Show Signs of Senescence.

ABSTRACT: The Nijmegen breakage syndrome (NBS) is an inherited genetic disorder characterized by a typical facial appearance, microcephaly, growth retardation, immunodeficiency, and a strong predisposition to malignancies, especially of lymphoid origin. NBS patients have a mutation in the NBN gene which involves the repair of DNA double-strand breaks (DSBs). Here we studied the peripheral T cell compartment of NBS patients with a focus on immunological senescence.The absolute numbers and frequencies of the different T cell subsets were determined in NBS patients from young age till adulthood and compared to age-matched healthy individuals (HI). In addition, we determined the expression of senescent T cell markers and the signal joint T cell receptor excision circles (sjTRECs) content.Our results demonstrate that NBS patients have reduced T cell numbers. NBS patients showed lower numbers of ??+ T cells, but normal ??+ T cell numbers compared to HI. Concerning the ??+ T cells, both CD4+ as well as CD8+ T cells were excessively reduced in numbers compared to aged-matched HI. In addition, NBS patients showed higher frequencies of the more differentiated T cells expressing the senescent cell marker CD57 and did not express co-stimulatory molecule CD28. These effects were already present in the youngest age group. Furthermore, NBS patients showed lower sjTREC content in their T cells possibly indicative of a lower thymic output.We conclude that circulating T cells from NBS patients show signs of a senescent phenotype which is already present from young age on and which might explain their T cell immune deficiency.

SUBMITTER: Meijers RWJ

PROVIDER: S-EPMC5325864 | biostudies-other | 2017 Feb

REPOSITORIES: biostudies-other

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Circulating T Cells of Patients with Nijmegen Breakage Syndrome Show Signs of Senescence.

Meijers Ruud W J RWJ Dzierzanowska-Fangrat Katarzyna K Zborowska Magdalena M Solarska Iwona I Tielemans Dennis D van Turnhout Bob A C BAC Driessen Gertjan G van der Burg Mirjam M van Dongen Jacques J M JJM Chrzanowska Krystyna H KH Langerak Anton W AW

Journal of clinical immunology 20161221 2

<h4>Purpose</h4>The Nijmegen breakage syndrome (NBS) is an inherited genetic disorder characterized by a typical facial appearance, microcephaly, growth retardation, immunodeficiency, and a strong predisposition to malignancies, especially of lymphoid origin. NBS patients have a mutation in the NBN gene which involves the repair of DNA double-strand breaks (DSBs). Here we studied the peripheral T cell compartment of NBS patients with a focus on immunological senescence.<h4>Methods</h4>The absolu ...[more]

PMID: 28000062

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Project description:Nijmegen breakage syndrome (NBS) is a rare autosomal recessive syndrome of chromosomal instability mainly characterized by microcephaly at birth, combined immunodeficiency and predisposition to malignancies. Due to a founder mutation in the underlying NBN gene (c.657_661del5) the disease is encountered most frequently among Slavic populations. The principal clinical manifestations of the syndrome are: microcephaly, present at birth and progressive with age, dysmorphic facial features, mild growth retardation, mild-to-moderate intellectual disability, and, in females, hypergonadotropic hypogonadism. Combined cellular and humoral immunodeficiency with recurrent sinopulmonary infections, a strong predisposition to develop malignancies (predominantly of lymphoid origin) and radiosensitivity are other integral manifestations of the syndrome. The NBN gene codes for nibrin which, as part of a DNA repair complex, plays a critical nuclear role wherever double-stranded DNA ends occur, either physiologically or as a result of mutagenic exposure. Laboratory findings include: (1) spontaneous chromosomal breakage in peripheral T lymphocytes with rearrangements preferentially involving chromosomes 7 and 14, (2) sensitivity to ionizing radiation or radiomimetics as demonstrated in vitro by cytogenetic methods or by colony survival assay, (3) radioresistant DNA synthesis, (4) biallelic hypomorphic mutations in the NBN gene, and (5) absence of full-length nibrin protein. Microcephaly and immunodeficiency are common to DNA ligase IV deficiency (LIG4 syndrome) and severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation due to NHEJ1 deficiency (NHEJ1 syndrome). In fact, NBS was most commonly confused with Fanconi anaemia and LIG4 syndrome. Genetic counselling should inform parents of an affected child of the 25% risk for further children to be affected. Prenatal molecular genetic diagnosis is possible if disease-causing mutations in both alleles of the NBN gene are known. No specific therapy is available for NBS, however, hematopoietic stem cell transplantation may be one option for some patients. Prognosis is generally poor due to the extremely high rate of malignancies.

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Circulating T Cells of Patients with Nijmegen Breakage Syndrome Show Signs of Senescence.

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Circulating T Cells of Patients with Nijmegen Breakage Syndrome Show Signs of Senescence.

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