FcgammaRIIIb and complement component C7 codeficiency in a patient with recurrence of fulminant meningococcal septic shock.
ABSTRACT Individuals with deficiencies of the late components of complement exhibit a susceptibility to the recurrence of meningococcal disease with a usually mild clinical presentation. We report the recurrence of fulminant meningococcal disease in a complement component C7-deficient patient. We found a total deficiency of FcgammaRIIIb on neutrophils, which could partially explain the unusually severe clinical presentation.
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ABSTRACT: Two classes of receptors for IgG, Fc gamma RIIa and Fc gamma RIIIb, both of which exist in two allelic forms, are expressed on human neutrophils. Neutrophils from normal donors, homozygous for the different allelic phenotypes of Fc gamma RIIIb, have significantly different levels of Fc gamma receptor-mediated phagocytosis of IgG-opsonized erythrocytes (EA). However, the observation that Fc gamma RIIIb mediates phagocytosis of specific mAb-targeted erythrocytes poorly suggests that this receptor may influence EA internalization by Fc gamma RIIa in an allele-sensitive fashion. Donors homozygous for the NA1 allele of Fc gamma RIIIb showed greater activation of Fc gamma RIIa after Fc gamma RIIIb cross-linking than donors homozygous for the NA2 allele of Fc gamma RIIIb. This increase in receptor-specific internalization reflects both an increase in ligand binding by Fc gamma RIIa and an increase in internalization efficiency of targets bound. Activation of Fc gamma RIIa by Fc gamma RIIIb is transferable by supernatants from activated cells and is blocked by inhibitors of reactive oxygen species and the H2O2-myeloperoxidase-chloride system and by serine protease inhibitors. Thus, cross-linking of Fc gamma RIIIb, which leads to neutrophil degranulation and the generation of reactive oxygen intermediates, in turn alters Fc gamma RIIa avidity and efficiency. These oxidant-mediated changes in Fc gamma RIIa function provide a novel mechanism for receptors to collaborate in both an autocrine and paracrine fashion. The allele sensitivity of these effects suggests that Fc gamma receptor polymorphisms may be inherited disease susceptibility factors in host defense against infection and in the development of autoimmunity.Journal of Clinical Investigation 07/1995; 95(6):2877-85. · 12.81 Impact Factor
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ABSTRACT: The aim of this study was to determine if there is a correlation between the activity of a MoAb as an agonist and its ability to bind to the Fc platelet receptor, Fc gamma RIIa. A polymorphism at amino acid 131 [arginine (Arg) or histidine (His)] of Fc gamma RIIa was first shown to be determinant for MoAb-IgG1 binding on monocytes. To clarify the role of this polymorphism in platelet activation by MoAb-IgG1 we (i) established the Fc gamma RIIa polymorphism at the gene level by adapting the denaturating gradient gel electrophoresis method, (ii) analyzed the binding affinity of the MoAbs to Fc gamma RIIa on platelets from homozygous Arg, homozygous His, and heterozygous Arg/His donors, and (iii) characterized the different reactivities of platelets according to the Fc gamma RIIA polymorphism. Among 167 caucasian donors we found 46% heterozygous Arg/His, 36% homozygous His and 18% homozygous Arg. ALB6, and anti CD9, P256 an anti GPIIb-IIIa, and AP3 an anti-GPIIIa were chosen according to their ability (ALB6, P256) or not (AP3) to activate platelets. These 3 MoAbs-IgG1 bind to Fc gamma RIIa with a stronger affinity for the Arg-form of Fc gamma RIIa, a result which was confirmed with the use of diverse MoAbs directed against various antigens. The different abilities of MoAbs to bind to the two Fc gamma RIIa forms were well correlated to the different platelet responses induced by ALB6 and P256. However, low concentrations of ALB6, which allow full activation of platelets from homozygous Arg donors, as did P256, did not induce any activation of platelets from homozygous His donors, whereas P256 is able to induce a low aggregation. The results further define the respective roles of the antigen and the Fc receptor, depending on the MoAb, and the role of the Fc gamma RIIa polymorphism in platelet activation induced by MoAbs. In addition, the results obtained with MoAbs unable to induce platelet activation provided evidence that the binding of a MoAb on Fc gamma RIIa does not predict its ability to activate platelets.Thrombosis and Haemostasis 01/1996; 74(6):1557-63. · 6.09 Impact Factor
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ABSTRACT: A biallelic polymorphism within the human interleukin (IL)-6 gene promoter region (-174 G/C) has been shown to affect IL-6 transcription in vitro and IL-6 plasma levels in healthy adults. Because IL-6 is excessively released into the circulation during sepsis and closely correlates with the clinical course, we studied whether this promoter polymorphism has an effect on the incidence and/or outcome of sepsis. Population-based association study in critically ill patients and healthy controls. Surgical intensive care unit (ICU) in a German university hospital. Surgical patients (n = 326) of German Caucasian origin with an ICU stay of at least 3 days admitted between 1997 and 1999 were prospectively enrolled. In a subset of 50 patients, sepsis was diagnosed according to consensus criteria (American College of Chest Physicians 1992). Healthy sex-matched adults of the same ethnic and geographic background served as controls. Blood sampling. The (-174 G/C) polymorphism was genotyped by an allele-specific polymerase chain reaction. IL-6 plasma levels were determined by enzyme-linked immunosorbent assay. Genotype distribution and allele frequencies did not differ significantly between patients with or without sepsis and healthy controls. In patients who finally succumbed to sepsis, significantly less GG homozygotes were observed compared with survivors (p = .008). Median systemic IL-6 levels in septic patients closely correlated with outcome (p < .0001) but were not associated with the IL-6 promoter genotype. The IL-6 promoter polymorphism (-174 G/C) does not affect the incidence of sepsis. However, the GG homozygous genotype is significantly associated with an improved survival in sepsis. Because this association is independent from the systemic IL-6 response, we suggest that other genetically linked polymorphisms may be the primary cause.Critical Care Medicine 02/2002; 30(1):32-7. · 6.12 Impact Factor