Selective deficiency of CD4+/CD45RA+ lymphocytes in patients with ataxia-telangiectasia

Paganelli, Roberto; Scala, Enrico; Scarselli, Elisa; Ortolani, Claudio; Cossarizza, Andrea; Carmini, Daniela; Aiuti, F; Fiorilli, Massimo

doi:10.1007/bf00918137

Cited by 46 publications

(46 citation statements)

References 31 publications

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“…Thus, it is possible that a reduced output of T cells from the thymus leads to the accumulation of memory T cells in the periphery. This also occurs in AT patients, in whom dysplastic changes or the absence of the thymus is constantly found (19). The reasons for the large numbers of NK cells observed throughout the first set of studies (Table 1) remain unknown, but a relatively large number of NK cells was noted in other NBS patients (5).…”

Section: Discussionmentioning

confidence: 94%

“…responded to chromosome bands containing immunologically relevant genes (T-cell-receptor ␣, ␤, and ␥ chains and the immunoglobulin heavy chain) (19).…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, T-cell-B-cell cooperation, as measured by PWM-induced mitogenesis (which acts by contact of T cells and B cells) was also affected. Naive T cells (CD4 ϩ CD45RA ϩ ) are supposed to proliferate better with classical mitogens (PHA, ConA, PWM), and these response patterns (low-level proliferative responses to PHA, Con A and PWM) strongly correlate with the very low proportion of CD4 ϩ CD45RA ϩ T cells in the patient (19). The immune consequences of a deficiency of the NBS gene product in many ways resemble the abnormalities seen in AT: hypogammaglobulinemia, alteration of the proportions of lymphocyte subpopulations, and similar defective blastogeneses.…”

Section: Discussionmentioning

confidence: 99%

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Role of Nijmegen Breakage Syndrome Protein in Specific T-Lymphocyte Activation Pathways

Garcı́a-Pérez

Allende

Corell

et al. 2001

Clin Diagn Lab Immunol

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Nijmegen breakage syndrome (NBS) is a genetic disorder characterized by immunodeficiency, microcephaly, and "bird-like" facies. NBS shares some clinical features with ataxia telangiectasia (AT), including increased sensitivity to ionizing radiation, increased spontaneous and induced chromosome fragility, and strong predisposition to lymphoid cancers. The mutated gene that results in NBS codes for a novel double-stranded DNA break repair protein, named nibrin. In the present work, a Spanish NBS patient was extensively characterized at the immunological and the molecular DNA levels. He showed low CD3 ؉ -cell numbers and an abnormal low CD4؉ naive cell/CD4 ؉ memory cell ratio, previously described in AT patients and also described in the present report in the NBS patient. The proliferative response of peripheral blood lymphocytes in vitro to mitogens is deficient in NBS patients, but the possible link among NBS mutations and the abnormal immune response is still unknown.Nijmegen breakage syndrome (NBS) is a rare, autosomal recessive disorder characterized by microcephaly, immunodeficiency, and a predisposition to cancer (27). It shares some striking clinical and cellular similarities to the genetic disease ataxia telangiectasia (AT), and for this reason, NBS has been classified as a variant of AT (12). However, NBS patients have neither ataxia nor telangiectasia, and microcephaly is absent from AT patients (25, 27). The serum ␣-fetoprotein concentration is within the normal range in NBS patients, in contrast to AT patients, about 90% of whom are found to have elevated serum ␣-fetoprotein concentrations (31). In addition, different defective genes in patients with AT and NBS have been identified (3,23,28) and have been mapped in chromosomes 11q23 (8) and 8q21-24, respectively (22), which demonstrates that NBS is a genetic entity distinct from AT.Patients with both NBS and AT display chromosome instability, hypersensitivity to ionizing radiation, and a lack of DNA replication delay in response to radiation, which is governed, in normal cells, by the protein kinase C (PKC)-mediated upregulation of tumor suppresor protein p53 (9,13,14,15,18). These similarities suggest that ATM and nibrin, the proteins responsible for AT and NBS, respectively, may play a role in common functions, which appear to be defective in both diseases.Both ATM and nibrin participate in the processing of double-stranded breaks in DNA (3, 25). It has recently been shown that nibrin, in particular, forms a trimolecular complex, together with Rad50 (a protein similar to those required for the structural maintenance of chromosomes) and Mre11 (with both structural and catalytic activities, including single-stranded DNA endonuclease and double-stranded DNA exonuclease activities). The complex participates in the repair of doublestranded DNA breaks induced by radiation, and the Mre11 hyperphosphorylation observed after DNA damage is dependent on the presence of intact nibrin (6, 7). Recently, it has been shown that the phosphorylation of nibrin induced ...

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Section: Discussionmentioning

confidence: 94%

“…responded to chromosome bands containing immunologically relevant genes (T-cell-receptor ␣, ␤, and ␥ chains and the immunoglobulin heavy chain) (19).…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Role of Nijmegen Breakage Syndrome Protein in Specific T-Lymphocyte Activation Pathways

Garcı́a-Pérez

Allende

Corell

et al. 2001

Clin Diagn Lab Immunol

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“…+ lymphopenia [21][22][23][24]. However, our patient did not have clinical features consistent with any of these syndromes, a personal or family history of malignancy or a karyotypical analysis consistent with chromosomal instability.…”

Section: Methodsmentioning

confidence: 98%

Safety and efficacy of treatment using interleukin-2 in a patient with idiopathic CD4+ lymphopenia andMycobacterium avium-intracellulare

Trojan

Collins

Khan

2009

Clinical and Experimental Immunology

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SummaryWe present the case of a 39-year-old white man with a Myobacterium aviumintracellulare pulmonary infection found to have a CD4+ count of 172 cells/ mm 3 and diagnosed subsequently with idiopathic CD4 + lymphopenia (ICL). After receiving clathromycin for 4 months with minimal improvement, the patient was started on pegylated subcutaneous interleukin (IL)-2 at 600 000 units daily. Later, he received incrementally higher pegylated IL-2 doses until he reached a maintenance dose 3 months later of 11 million units weekly divided into three equal doses. After 5 months of therapy, the patient's chronic cough resolved completely, sputum cultures became negative for Myobacterium avium-intracellulare and the CD4 + T cell count increased to 553 cells/mm 3 . After 35 months of well-tolerated IL-2 treatments and no recurrence of any opportunistic infections, IL-2 treatment was stopped. CD4 + counts 6 and 9 months after discontinuing IL-2 treatment were 596 and 378 cells/mm 3 respectively, and he remains asymptomatic. This report supports IL-2 treatment for ICL-associated opportunistic infections as a safe and potentially efficacious treatment option, especially when combined with more traditional treatment regimens.

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“…Elevated serum IgM levels may occasionally progress to a high blood viscosity syndrome, with splenomegaly, lymphoadenopathy, neutropenia, thrombocytopenia, and congestive heart failure. T-cell deficiencies occur in half the patients, with abnormal skin test antigen and PHA responses (Paganelli et al, 1992). In a British study of 70 patients (Woods and Taylor, 1992), 10% had severe immunodeficiencies, while nearly 40% had normal immunologic function.…”

Section: Biological Featuresmentioning

confidence: 99%

Ataxia-Telangiectasia and variants

Uhrhammer¹,

Bay²,

Perlman³

et al. 2011

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Selective deficiency of CD4+/CD45RA+ lymphocytes in patients with ataxia-telangiectasia

Cited by 46 publications

References 31 publications

Role of Nijmegen Breakage Syndrome Protein in Specific T-Lymphocyte Activation Pathways

Role of Nijmegen Breakage Syndrome Protein in Specific T-Lymphocyte Activation Pathways

Safety and efficacy of treatment using interleukin-2 in a patient with idiopathic CD4+ lymphopenia andMycobacterium avium-intracellulare

Ataxia-Telangiectasia and variants

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