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  • 1
    Keywords: ACTIVATION ; T-CELL ; IMMUNITY ; DEFICIENCY ; CARD11
    Abstract: BACKGROUND: Combined immunodeficiency (CID) is characterized by severe recurrent infections with normal numbers of T and B lymphocytes but with deficient cellular and humoral immunity. Most cases are sporadic, but autosomal recessive inheritance has been described. In most cases, the cause of CID remains unknown. OBJECTIVE: We wanted to identify the genetic cause of CID in 2 siblings, the products of a first-cousin marriage, who experienced recurrent bacterial and candidal infections with bronchiectasis, growth delay, and early death. METHODS: We performed immunologic, genetic, and biochemical studies in the 2 siblings, their family members, and healthy controls. Reconstitution studies were performed with T cells from mucosa-associated lymphoid tissue lymphoma-translocation gene 1-deficient (Malt1(-/-)) mice. RESULTS: The numbers of circulating T and B lymphocytes were normal, but T-cell proliferation to antigens and antibody responses to vaccination were severely impaired in both patients. Whole genome sequencing of 1 patient and her parents, followed by DNA sequencing of family members and healthy controls, showed the presence in both patients of a homozygous missense mutation in MALT1 that resulted in loss of protein expression. Analysis of T cells that were available on one of the patients showed severely impaired IkappaBalpha degradation and IL-2 production after activation, 2 events that depend on MALT1. In contrast to wild-type human MALT1, the patients' MALT1 mutant failed to correct defective nuclear factor-kappaB activation and IL-2 production in MALT1-deficient mouse T cells. CONCLUSIONS: An autosomal recessive form of CID is associated with homozygous mutations in MALT1. If future patients are found to be similarly affected, they should be considered as candidates for allogeneic hematopoietic cell transplantation.
    Type of Publication: Journal article published
    PubMed ID: 23727036
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  • 2
    ISSN: 0248-4900
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1365-2133
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background  The role of cytotoxic cells in the control of cancer is now well established.Objectives  To evaluate the expression of perforin and granzyme A in cytotoxic cells of patients with melanoma and to look for a link between this expression and natural tumour progression; to check if interferon (IFN)-α administration increased expression of cytotoxic mediators; and to evaluate if this increase was correlated with the antitumoral effect of IFN-α.Methods  To determine in patients with melanoma the expression of the cytotoxic mediators perforin and granzyme A in peripheral blood natural killer (NK) and T cells, we used flow cytometry before and after IFN-α administration.Results  Compared with healthy volunteers, we observed in 82 patients a low percentage of NK cells harbouring perforin [75% (95% confidence interval (CI) 70–79) vs. 92% (95% CI 89–95), P 〈 0·001] and granzyme A [48% (95% CI 41–55) vs. 73% (95% CI 66–81), P 〈 0·001]. By contrast, a high percentage of T cells, and particularly of CD56+ T cells, expressed perforin [56% (95% CI 41–71) vs. 28% (95% CI 18–38), P 〈 0·001], whereas a low percentage of CD56+ T cells expressed granzyme A [30% (95% CI 24–36) vs. 54% (95% CI 43–65), P 〈 0·001]. In untreated patients, the percentage of CD56+ T cells expressing granzyme A was higher in progressors than in nonprogressors [49% (95% CI 39–58) vs. 16% (95% CI 0–33), P = 0·003]. We followed cytotoxic mediator expression in 17 patients treated with IFN-α. IFN-α administration increased granzyme A expression in NK cells [44% (95% CI 27–61) and 65% (95% CI 54–76) before and after treatment, respectively, P = 0·010], rather than perforin expression, whereas expression of both perforin [46% (95% CI 30–62), and 58% (95% CI 44–73), P = 0·112] and especially granzyme A [27% (95% CI 14–40) vs. 45% (95% CI 26–64), P = 0·016] was increased in CD56+ T cells after IFN-α administration. Yet, this effect was not correlated with the clinical response to IFN-α.Conclusions  Thus, the expression of cytotoxic mediators is altered in cytotoxic cells of patients with melanoma, and increased under IFN-α administration.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1365-2133
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background The usually protracted and indolent course of cutaneous T-cell lymphoma (CTCL) is consistent with an accumulation of lymphocytes rather than being a true proliferative disorder, perhaps as the result of defective lymphocyte apoptosis. Fas (CD95) is the main signalling membrane molecule involved in postactivation T-lymphocyte apoptosis. Objectives To evaluate expression of Fas on circulating CD4+ lymphocytes in patients with CTCL. Methods Fas expression on peripheral blood CD4+ T cells in 16 patients with mycosis fungoides (patch and infiltrated plaque stages) and in four patients with Sézary syndrome was compared with that in 25 matched patients with lymphocyte-mediated cutaneous benign inflammatory disorders and in 15 subjects without inflammatory cutaneous diseases. Results Fas expression on peripheral CD4+ lymphocytes was significantly lower in patients with CTCL compared with subjects with benign inflammatory cutaneous disorders and with healthy donors. Conclusions This pattern supports the hypothesis that a defect in T-cell apoptosis may play a part in the pathophysiology of CTCL, perhaps through abnormalities of the Fas/Fas ligand system. Alternatively, this decrease could be the result of the presence of the soluble Fas ligand molecule in the sera of patients with CTCL.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1365-2133
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Summary Background The presence of a significant percentage of circulating atypical lymphocytes in peripheral blood has already been demonstrated in systemic CD30+ anaplastic large cell lymphoma (ALCL), which implies that a leukaemic component may be present in this subset of lymphomas. However, no similar data are available for the cutaneous counterpart of this particular lymphoproliferation. Objectives To assess the presence of atypical cells, CD30+ lymphocytes and of a dominant T-cell clone in peripheral blood in a series of patients with cutaneous CD30+ ALCL. Materials and methods Nine patients with either primary (four) or secondary (five) cutaneous CD4+ CD30+ ALCL were selected. The percentage of CD30+ CD4+ lymphocytes among peripheral blood mononuclear cells (PBMC) was determined by flow cytometry and the presence of a dominant circulating T-cell clone was assessed by polymerase chain reaction targeting the T-cell receptor γ chain. A control group composed of apparently healthy individuals was similarly studied at the same time. Results The mean percentage of CD30+ cells in PBMC was slightly higher in patients than in controls (3·9% vs. 2·7%) but the difference was not statistically significant. Only two patients displayed more than 5% CD30+ cells, both of whom had a minor tumour burden. A dominant circulating T-cell clone was detected in only three cases, including these two latter patients. Conclusions The occurrence of a significant percentage of CD30+ CD4+ circulating cells is rare in active cutaneous CD30+ ALCL, either primary or secondary. This percentage is not related to the apparent skin tumour burden but a significant figure appeared to be correlated with the detection of a dominant T-cell clone in peripheral blood. Overall, these data show that, unlike mycosis fungoides, peripheral blood involvement seems infrequent in cutaneous CD30+ ALCL. The hypothesis that a high percentage of CD30+ circulating cells might be related to the presence of a cryptic systemic disease cannot be ruled out.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1365-2133
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Type of Medium: Electronic Resource
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