Alternative Pathway Activation of Complement by Shiga Toxin Promotes Exuberant C3a Formation That Triggers Microvascular Thrombosis

Morigi, Marina; Galbusera, Miriam; Gastoldi, Sara; Locatelli, Monica; Buelli, Simona; Pezzotta, Anna; Pagani, Chiara; Noris, Marina; Gobbi, Marco; Stravalaci, Matteo; Rottoli, Daniela; Tedesco, Francesco; Remuzzi, Giuseppe; Zoja, Carla

doi:10.4049/jimmunol.1100491

Cited by 209 publications

(205 citation statements)

References 61 publications

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“…In various hemolytic conditions complement deposition on RBCs contributes to the hemolysis. Complement activation occurs on blood cells and endothelial cells during Stx2-mediated infection (11,23), but the role of complement in hemolysis during HUS has not been addressed. We demonstrated deposition of C3 on RBCs from patients with acute HUS but no C5b-9, with the exception of one patient whose sample was taken early on in the course of disease and C5b-9 decreased 5 d later.…”

Section: Discussionmentioning

confidence: 99%

Shiga Toxin–Induced Complement-Mediated Hemolysis and Release of Complement-Coated Red Blood Cell–Derived Microvesicles in Hemolytic Uremic Syndrome

Arvidsson

Ståhl

Hedström

et al. 2015

The Journal of Immunology

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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 P1k and P2k phenotype RBCs, expressing high levels of the Pk 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.

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Section: Discussionmentioning

confidence: 99%

Shiga Toxin–Induced Complement-Mediated Hemolysis and Release of Complement-Coated Red Blood Cell–Derived Microvesicles in Hemolytic Uremic Syndrome

Arvidsson

Ståhl

Hedström

et al. 2015

The Journal of Immunology

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“…There is in vitro evidence that TM expression was decreased in human glomerular microvascular endothelial cells exposed to Stx2 after presensitization with inflammatory mediators (22). More recently, in a mouse model of HUS induced by coinjection of Stx2 and LPS, reduced glomerular TM expression was observed in association with fibrin(ogen) and platelet deposition (23).…”

mentioning

confidence: 94%

“…Mice were then maintained at Mario Negri Institute in conformity with the institutional guidelines that are in compliance with national and international laws and policies (23 …”

Section: Experimental Designmentioning

confidence: 99%

Lack of the Lectin-like Domain of Thrombomodulin Worsens Shiga Toxin-Associated Hemolytic Uremic Syndrome in Mice

Zoja

Locatelli

Pagani

et al. 2012

The Journal of Immunology

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Shiga toxin (Stx)-producing Escherichia coli is a primary cause of diarrhea-associated hemolytic uremic syndrome (HUS), a disorder of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. The pathophysiology of renal microvascular thrombosis in Stx-HUS is still ill-defined. Based on evidence that abnormalities in thrombomodulin (TM), an anticoagulant endothelial glycoprotein that modulates complement and inflammation, predispose to atypical HUS, we assessed whether impaired TM function may adversely affect evolution of Stx-HUS. Disease was induced by coinjection of Stx2/LPS in wild-type mice (TMwt/wt) and mice that lack the lectin-like domain of TM (TMLeD/LeD), which is critical for its anti-inflammatory and cytoprotective properties. After Stx2/LPS, TMLeD/LeD mice exhibited more severe thrombocytopenia and renal dysfunction than TMwt/wt mice. Lack of lectin-like domain of TM resulted in a stronger inflammatory reaction after Stx2/LPS with more neutrophils and monocytes/macrophages infiltrating the kidney, associated with PECAM-1 and chemokine upregulation. After Stx2/LPS, intraglomerular fibrin(ogen) deposits were detected earlier in TMLeD/LeD than in TMwt/wt mice. More abundant fibrin(ogen) deposits were also found in brain and lungs. Under basal conditions, TMLeD/LeD mice exhibited excess glomerular C3 deposits, indicating impaired complement regulation in the kidney that could lead to local accumulation of proinflammatory products. TMLeD/LeD mice with HUS had a higher mortality rate than TMwt/wt mice. If applicable to humans, these findings raise the possibility that genetic or acquired TM defects might have an impact on the severity of microangiopathic lesions after exposure to Stx-producing E. coli infections and raise the potential for using soluble TM in the treatment of Stx-HUS.

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“…Abnormalities in complement genes and anti-FH antibodies account for 60%-80% of all cases of aHUS. Additionally, accumulating data underline that complement dysregulation is involved in the pathogenesis of secondary forms of HUS (postrenal transplantation de novo HUS) (35) and even in typical verotoxin-induced HUS (28,36).…”

Section: Tma In Pregnancy: the Great Paradigm Shiftmentioning

confidence: 99%

Obstetric Nephrology

Fakhouri

Vercel

Frémeaux‐Bacchi

2012

Clinical Journal of the American Society of Nephrology

140

119

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Summary AKI in pregnancy remains a cause of significant fetomaternal mortality and morbidity, particularly in developing countries. Hypertensive complications of pregnancy (preeclampsia/eclampsia or hemolysis, elevated liver enzymes, and low platelets count syndrome) are the leading cause of AKI in pregnancy worldwide. Thrombotic microangiopathy is another peculiar and devastating cause of AKI in pregnancy. During the last decade, our understanding, and in some cases, our management, of these causes of AKI in pregnancy has dramatically improved. For instance, convincing data have linked pre-eclampsia/eclampsia to an increase in circulating antiangiogenic factors soluble Flt 1 and endoglin, which induce endothelial cell dysfunction, hypertension, and proteinuria. Several distinct pathogenic mechanisms underlying thrombotic microangiopathy, including thrombotic microangiopathy occurring during pregnancy, have been established. Thrombotic microangiopathy, which can present as hemolytic uremic syndrome or thrombotic thrombocytopenic purpura, can be reclassified in four potentially overlapping subtypes: disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 deficiency-related thrombotic microangiopathy, complement alternative pathway dysregulation-related thrombotic microangiopathy, secondary thrombotic microangiopathy (verotoxin and antiangiogenic drugs), and thrombotic microangiopathy of undetermined mechanism. In most cases, pregnancy is only a precipitating factor for thrombotic microangiopathy. Treatment of thrombotic microangiopathy occurring during pregnancy should be tailored to the underlying pathogenic mechanism: (1) restoration of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 serum activity in the setting of thrombotic thrombocytopenic purpura through plasma exchanges and in some cases, B cell-depleting therapy and (2) inhibition of complement alternative pathway activation in atypical hemolytic uremic syndrome using antiC5 blocking antibody (eculizumab).

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Alternative Pathway Activation of Complement by Shiga Toxin Promotes Exuberant C3a Formation That Triggers Microvascular Thrombosis

Cited by 209 publications

References 61 publications

Shiga Toxin–Induced Complement-Mediated Hemolysis and Release of Complement-Coated Red Blood Cell–Derived Microvesicles in Hemolytic Uremic Syndrome

Shiga Toxin–Induced Complement-Mediated Hemolysis and Release of Complement-Coated Red Blood Cell–Derived Microvesicles in Hemolytic Uremic Syndrome

Lack of the Lectin-like Domain of Thrombomodulin Worsens Shiga Toxin-Associated Hemolytic Uremic Syndrome in Mice

Obstetric Nephrology

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