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J Immunol ; 194(5): 2309-18, 2015 Mar 01.
Article in English | MEDLINE | ID: mdl-25637016

ABSTRACT

Shiga toxin (Stx)-producing Escherichia coli (STEC) cause hemolytic uremic syndrome (HUS). This study investigated whether Stx2 induces hemolysis and whether complement is involved in the hemolytic process. RBCs and/or RBC-derived microvesicles from patients with STEC-HUS (n = 25) were investigated for the presence of C3 and C9 by flow cytometry. Patients exhibited increased C3 deposition on RBCs compared with controls (p < 0.001), as well as high levels of C3- and C9-bearing RBC-derived microvesicles during the acute phase, which decreased after recovery. Stx2 bound to P1 (k) and P2 (k) phenotype RBCs, expressing high levels of the P(k) Ag (globotriaosylceramide), the known Stx receptor. Stx2 induced the release of hemoglobin and lactate dehydrogenase in whole blood, indicating hemolysis. Stx2-induced hemolysis was not demonstrated in the absence of plasma and was inhibited by heat inactivation, as well as by the terminal complement pathway Ab eculizumab, the purinergic P2 receptor antagonist suramin, and EDTA. In the presence of whole blood or plasma/serum, Stx2 induced the release of RBC-derived microvesicles coated with C5b-9, a process that was inhibited by EDTA, in the absence of factor B, and by purinergic P2 receptor antagonists. Thus, complement-coated RBC-derived microvesicles are elevated in HUS patients and induced in vitro by incubation of RBCs with Stx2, which also induced hemolysis. The role of complement in Stx2-mediated hemolysis was demonstrated by its occurrence only in the presence of plasma and its abrogation by heat inactivation, EDTA, and eculizumab. Complement activation on RBCs could play a role in the hemolytic process occurring during STEC-HUS.


Subject(s)
Coated Vesicles/drug effects , Erythrocytes/drug effects , Escherichia coli Infections/blood , Escherichia coli O157/pathogenicity , Hemolytic-Uremic Syndrome/blood , Shiga Toxin/toxicity , Adult , Aged , Antibodies, Monoclonal, Humanized/pharmacology , Child , Child, Preschool , Coated Vesicles/chemistry , Coated Vesicles/immunology , Complement Activation/drug effects , Complement C3/chemistry , Complement C9/chemistry , Complement Membrane Attack Complex/chemistry , Edetic Acid/pharmacology , Erythrocytes/chemistry , Erythrocytes/immunology , Erythrocytes/pathology , Escherichia coli Infections/immunology , Escherichia coli Infections/microbiology , Escherichia coli Infections/pathology , Escherichia coli O157/immunology , Escherichia coli O157/metabolism , Female , Gene Expression , Hemolysis/drug effects , Hemolytic-Uremic Syndrome/immunology , Hemolytic-Uremic Syndrome/microbiology , Hemolytic-Uremic Syndrome/pathology , Humans , Infant , L-Lactate Dehydrogenase/metabolism , Male , Middle Aged , Purinergic P2 Receptor Antagonists/pharmacology , Receptors, Purinergic P2/genetics , Receptors, Purinergic P2/immunology , Shiga Toxin/chemistry , Shiga Toxin/immunology , Suramin/pharmacology , Trihexosylceramides/immunology
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