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  • 1
    Abstract: Next-generation DNA sequencing has accelerated the genetic characterization of many human primary immunodeficiency diseases (PIDs). These discoveries can be lifesaving for the affected patients and also provide a unique opportunity to study the effect of specific genes on human immune function. In the past 18 months, a number of independent groups have begun to define novel PIDs caused by defects in the caspase recruitment domain family, member 11 (CARD11)-B-cell chronic lymphocytic leukemia/lymphoma 10 (BCL10)-mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1 [CBM]) signalosome complex. The CBM complex forms an essential molecular link between the triggering of cell-surface antigen receptors and nuclear factor kappaB activation. Germline mutations affecting the CBM complex are now recognized as the cause of novel combined immunodeficiency phenotypes, which all share abnormal nuclear factor kappaB activation and dysregulated B-cell development as defining features. For this "Current perspectives" article, we have engaged experts in both basic biology and clinical immunology to capture the worldwide experience in recognizing and managing patients with PIDs caused by CBM complex mutations.
    Type of Publication: Journal article published
    PubMed ID: 25087226
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  • 2
    ISSN: 1279-8509
    Keywords: Immunodeficiency ; Viral complications ; Adenovirus ; CMV ; EBV
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Patients undergoing bone marrow transplantation are susceptible to many different bacterial, fungal and viral infections. Among the viral pathogens, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and adenovirus cause the greatest morbidity and mortality and have been the most common infectious causes of death following the grafting of allogeneic marrow. This great susceptibility to viral infections is due to the immunodeficiency in cellular and humoral immune responses lasting for months to years. Contributing factors are high-dose chemo/radiotherapy, graft-versus-host disease (GVHD) prophylaxis/treatment, GVHD itself, the degree of HLA disparity between donor and recipient and the underlying disease. Defects of T cell helper and cytotoxic functions contribute to the great incidence of viral infections. We described here the kinetic of immunological reconstituion and the role of T cell immunodeficiency. At day 30 to 40 after BMT, a minority of patients had recovery of virus-specific CD8+ T-cell response. Between day 40 and day 90 recovery of deficient CD8+ and CD4+ T cell responses occured in the majority of the recipients of HLA identical BMT but only in the minority of the recipients of HLA partially incompatible BMT. New approaches should therefore be envisaged either to preserve donor T-cell-mediate immunity or tho accelerate immune reconstitution. Add-back of unmanipulated T-cells, or virus-specific T cells could improve antimicrobial defenses after BMT.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Oxford, UK; Malden, USA : Munksgaard International Publishers
    Immunological reviews 203 (2005), S. 0 
    ISSN: 1600-065X
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Summary:  Hyper-immunoglobulin M (IgM) syndromes are primary immunodeficiencies characterized by normal or elevated serum IgM levels with the absence of other isotypes, pinpointing to a defect in the Ig class switch recombination (CSR). The delineation of hyper-IgM syndromes made it possible to better define the mechanisms underlying the two major events of antibody maturation in humans, CSR and introduction of somatic hypermutation (SHM) in the variable region of immunoglobulins. The description of the activation-induced cytidine deaminase (AID) deficiency, characterized by a defect in both CSR and SHM, demonstrated for the first time that this molecule acts as a master player in the antigen-induced Ig gene-modification events responsible for both CSR and SHM. However, deleterious mutations located in the C-terminus lead to a CSR defect without affecting SHM, providing evidence for a role of AID in CSR distinct from the cytidine deaminase activity, likely by binding to a specific CSR cofactor. Molecular causes of two other hyper-IgM conditions have not yet been defined. However, they may be caused by either a defect in AID targeting on S regions or a CSR-specific DNA-repair defect. The mechanism of action of AID remains somewhat debated, but the observation that uracil-DNA-glycosylase deficiency leads to a severe hyper-IgM syndrome strongly argues in favor of a DNA-editing activity of AID.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1365-3083
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Human neonate B lymphocytes display unique phenotypic and functional characteristics: in addition to CD1c antigens, CD5+ and CD5- subsets both express activation markers such as CD23 and Bac-1. They proliferate strongly in the presence of various lymphokines (rIL-2, rIL-4, low molecular weight BCGF), but differentiate poorly in the presence of the same lymphokines, pokeweed mitogen and Epstein Barr virus. It has also been reported that human neonate B lymphocytes produce polyreactive autoantibodies after in vitro activation by Staphylococcus aureus Cowan I and transformation by Epstein Barr virus. We now show that, in the absence of in vitro stimulation, human neonate B lymphocytes produce polyreactive antibodies of the IgM isotype against several autoantigens. The B lymphocytes involved expressed membrane IgD, IgM, CD23 and CD11b molecules; CD5 expression was variable. This phenotype was consistently found on a minority of B lymphocytes and is similar to that of polyreactive autoantibody-producing B cells in mice. We also found that autoantibody production in vitro could occur in the absence of any T helper effectThe function of these autoantibodies is not clearly established, but their occurrence in a large proportion of human neonates strongly suggests that they play an important role in the development of the immune system.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1365-3083
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: T-cell subsets have been analysed in 23 cases of primary immunodeficiency with monoclonal antibodies. Functional assays investigating T-cell function—proliferative response to mitogens, antigens, and allogeneic cells, cytotoxicity generated against allogeneic target cells and helper function to pokeweed mitogen-induced immunoglobulin synthesis—were performed in parallel in the same patients. The results enabled us to delineate four groups of patients. The first group consisted of patients in whom marker and function studies show concordant data, with either normal or strongly decreased T-cell number and function. The second group consisted of patients in whom various degrees of functional abnormality coexist with subnormal T-cell number and increased suppressor T-cell proportion. In the third group, we collected all patients who showed functional deficiencies without marker abnormalities. Finally, there was a small group composed of patients whose T-cell pattern was strongly suggestive of abnormal differentiation.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1540-8191
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1573-2592
    Keywords: MHC class II deficient B lymphocytes ; B lymphocyte activation ; immunoglobulins
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract It has been suggested that MHC class II molecules can transduce signals required for B-cell activation. Enhancement or inhibition of B-cell stimulation by anti-MHC class II molecule antibodies has likewise been reported. The study of B cells from patients with a combined immune deficiency due to a defective expression of MHC class II genes provides a useful tool for approaching the functional role of B-cell HLA class II molecules. We have thus analyzed the specific and nonspecific, cognate and noncognate B-cell activation of genetically HLA class II-deficient lymphocytes. B lymphocytes from 14 tested patients were able to synthesize RNA following stimulation with ionomycin and phorbol myristate acetate or anti-μ antibodies and with mannan, a T cell-independent polysaccharidic antigen. They were also able to synthetize DNA following the addition of ionomycin and PMA or of anti-μ antibodies in the presence of recombinant interleukin 2. Pokeweed mitogen failed to induce B-lymphocyte terminal differentiation into immunoglobulin-producing cells in the presence of normal T lymphocytes, while a combination of anti-CD2 antibodies were capable of triggering IgG synthesis. B-cell activation, whatever the condition used, did not induce HLA class II expression. Mannan-specific T cell-dependent antibody production (IgM) was detected in 6 of 14 patients. Anti-influenza virus antibody production was always found absent. These results are compatible with the hypothesis that B-cell activation events that do not require a cognate interaction with T cells can occur in the absence of HLA class II molecule expression, while the absence of HLA class II molecule expression prevents T-B cognate interaction.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1573-2592
    Keywords: Di George syndrome ; suppressor T cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We have studied thein vitro B-cell maturation induced by pokeweed mitogen of lymphocytes from seventeen patients with partial Di George syndrome. These patients were characterized by a low number of T8(+) lymphocytes. They had normal immune functions with an increased level of serum IgE for most of them. These patients were investigated before the age of 1 month. In contrast to age-matched subjects, their lymphocytes were able to producein vitro immunoglobulins, although the level of immunoglobulin production was lower than in adults. These data were explained by a lack of T-cell mediated suppressor activity normally found in newborns. There was a strong correlation between the low number of T8(+) lymphocytes and the magnitude of thein vitro immunoglobulin production by patients' cells. This was further demonstrated by the ability of residual T8(+) lymphocytes isolated from patients to normally suppress the PWM driven B cell maturation on a per cell basis. The defective T-cell mediated suppression progressively disappears within 5 months. It is possible that this phenomenon is secondary to a delayed differentiation of suppressor T-cells in patients with partial Di George syndrome.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1573-2592
    Keywords: Chronic mucocutaneous candidiasis ; mannan ofCandida albicans ; mannan-induced T- and B-cell responses ; specific T suppressive activity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We have studied T- and B-cell responses to antigens ofCandida albicans in 18 patients suffering from chronic mucocutaneous candidiasis. We have shown thatin vitro production of antibody to one of these antigens, mannan, was absent during the active phase of the disease and that this absence was consequent to the activation of specific CD8(+) and CD8(−) suppressor T lymphocytes. Such activation was also observed when control T lymphocytes were incubated in the presence of monocytes and a high concentration of mannan. This suppressive effect was specific to antigens ofCandida albicans, was radiosensitive, and was not consequent to the secretion of prostaglandin E2. It appeared as well that the induction of these suppressor T cells was HLA-DQ restricted. The suppressor T-cell activity induced by antigens ofCandida albicans in vitro is thus comparable to the suppressor T-cell activity observedin vivo in patients affected with chronic mucocutaneous candidiasis. Defective handling of mannan by monocytes could result in the accumulation of mannan, resulting in the activation of specific T suppressor cells and in the consequent cellular immunodeficiency specific toCandida albicans. Successful treatment of the candidiasis resulted in complete correction of the immune abnormalities.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1546-1718
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Medicine
    Notes: [Auszug] The molecular basis of X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) has remained elusive. Here we report hypomorphic mutations in the gene IKBKG in 12 males with EDA-ID from 8 kindreds, and 2 patients with a related and hitherto unrecognized syndrome of EDA-ID ...
    Type of Medium: Electronic Resource
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