Journal of clinical immunology
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X-linked agammaglobulinemia (XLA) is caused by mutations in the gene encoding the cytoplasmic Bruton's tyrosine kinase (Btk). Btk has been shown to play an essential role in the development of B1 (CD5+) and conventional circulating mature B cells (B2) in mouse and man. It has been shown in earlier studies that Btk is involved in both the BCR- and CD40-mediated signaling pathways. ⋯ Our findings demonstrate that INK activation via the CD40 signaling pathway is intact in EBV-transformed B cells of most if not all XLA patients, independent of the mutation and its effect on Btk expression and kinase activity. We suggest that Btk is not necessary for the activation of INK upon CD40 stimulation, at least in the B cell subpopulation we had studied. We cannot exclude that these B cells belong to a "leaky" B-cell subpopulation in which the CD40 signaling pathway has become independent of Btk function.
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Clinical Trial
Umbilical cord blood transplantation in severe T-cell immunodeficiency disorders: two-year experience.
Hematopoietic stem cell transplantation is the treatment of choice for severe primary T-cell immunodeficiencies. When an HLA-identical sibling as the donor is not available, an alternative donor stem cell source is needed. In primary T-cell immunodeficiencies, T-cell-depleted HLA-haploidentical bone marrow transplantation has been particularly successful in reconstituting the immune system in many but not all of the severe T-cell immune deficiency disorders. ⋯ B cells engrafted early, and study of functional B-cell antibody responses revealed that five of six patients in whom intravenous immune globulin has been discontinued have low detectable antibody responses to tetanus and diphtheria toxoid immunizations at 18 to 24 months posttransplantation. Unrelated umbilical donor cord blood is an alternative source of stem cells for transplantation in children with severe T-cell immune deficiency disorders when a suitable HLA-matched donor is not available and when a T-depleted haploidentical preparation is not beneficial. Benefits of UCB include rapid and reliable recovery of immune function, low risk of GvHD, and low viral transmission rate.
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Comparative Study
Clinical and biological significance of interleukin-10 plasma levels in patients with septic shock.
Interleukin-10 is a potent macrophage-deactivating cytokine that inhibits lipopolysaccharide-induced tumor necrosis factor production. We determined the plasma levels of immunoreactive interleukin-10 in 16 patients with septic shock and in 11 patients with circulatory shock of nonseptic origin. In septic shock, interleukin-10 levels peaked during the first 24 h (median: 48 pg/ml) and decreased progressively till Day 5. ⋯ In septic shock patients, interleukin-10 plasma levels were positively correlated with tumor necrosis factor (r = 0.8, p = 0.01) and with parameters of shock severity including lactate levels (r = 0.56, p < 0.05) and correlated negatively with blood platelet counts (r = -0.65, p < 0.05). The decreased production of tumor necrosis factor-alpha and interleukin-6 after in vitro incubation of whole blood from septic shock patients with lipopolysaccharide was not influenced by in vitro neutralization of interleukin-10. We conclude that interleukin-10 is produced in patients with circulatory shock of septic and nonseptic origin and that the production of this anti-inflammatory cytokine during septic shock correlates positively with the intensity of the inflammatory response.
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To elucidate potential mechanisms of the acute lung injury associated with endotoxemia, we evaluated the effect of intravenously administered endotoxin on the ability of alveolar macrophages isolated by bronchoalveolar lavage from normal subjects to produce inflammatory mediators. Within 1 hr of endotoxin (4 ng/kg body weight) administration, all 12 study subjects developed constitutional symptoms and leukopenia, and within 3 hr, low-grade fever. Resolution of symptoms and fever by 6 hr was accompanied by systemic granulocytosis. ⋯ In contrast, intravenous endotoxin primed the alveolar macrophages for enhanced lipopolysaccharide-induced secretion of interleukin-1 (11.8 to 25.8 U/ml; P = 0.04), tumor necrosis factor-alpha (titer, 6.8 to 13.6; P = 0.20), and prostaglandin E2 (38.4 to 116.3 ng/ml; P = 0.035). These results demonstrate that low-dose intravenous endotoxin primes human alveolar macrophages, which are already differentiated in situ, for enhanced secretion of inflammatory mediators. Such mediators may contribute to the pulmonary changes associated with endotoxemia and acute lung injury.
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To explore possible mechanisms for the association between elevated immunoglobulin levels and lower pulmonary function in cystic fibrosis patients, we measured serum IgG subclass levels and anti-P. aeruginosa IgG subclass titers and correlated levels with neutrophil phagocytosis and chemotaxis. Serum was obtained from 13 cystic fibrosis patients colonized with the same serotype of P. aeruginosa, 12 noncolonized patients, and 12 normal volunteers. All anti-P. aeruginosa IgG subclass titers were elevated in serum from colonized patients. ⋯ Chemotactic index directly correlated with anti-P. aeruginosa IgG3 titer and serum IgG3. These data demonstrate that cystic fibrosis patients with increased IgG3 levels are in poorer clinical condition and that their serum enhances neutrophil function. Such patients may have increased pulmonary inflammation with subsequent lung damage.