Claudia Grossi - Academia.edu (original) (raw)
Papers by Claudia Grossi
Frontiers in Immunology
Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by recurrent vasc... more Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by recurrent vascular thrombosis and miscarriages in the absence of known causes. Antibodies against phospholipid-binding proteins (aPL) are pathogenic players in both clotting and pregnancy APS manifestations. There is sound evidence that antibodies specific for beta2 glycoprotein I (β2GPI) trigger thrombotic and pregnancy complications by interacting with the molecule on the membranes of different cell types of the coagulation cascade, and in placenta tissues. In addition to the humoral response against β2GPI, both peripheral and tissue CD4+ β2GPI-specific T cells have been reported in primary APS as well as in systemic lupus erythematosus (SLE)-associated APS. While adaptive immunity plays a clear role in APS, it is still debated whether innate immunity is involved as well. Acute systemic inflammation does not seem to be present in the syndrome, however, there is sound evidence that complement activat...
The Journal of Immunology, 2020
β2-Glycoprotein I (β2-GPI) is an abundant plasma glycoprotein with unknown physiological function... more β2-Glycoprotein I (β2-GPI) is an abundant plasma glycoprotein with unknown physiological function and is currently recognized as the main target of antiphospholipid Abs responsible for complement activation and vascular thrombosis in patients with antiphospholipid syndrome (APS). In this study, we provide evidence that mannose-binding lectin (MBL) binds to β2-GPI in Ca++ and a dose-dependent manner and that this interaction activates complement and promotes complement-dependent thrombin generation. Surprisingly, a significant binding was observed between MBL and isolated domains II and IV of β2-GPI, whereas the carbohydrate chains, domain I and domain V, were not involved in the interaction, documenting a noncanonical binding mode between MBL and β2-GPI. Importantly, this interaction may occur on endothelial cells because binding of MBL to β2-GPI was detected on the surface of HUVECs, and colocalization of MBL with β2-GPI was observed on the endothelium of a biopsy specimen of a fem...
Nature reviews. Rheumatology, 2018
Recurrent thrombosis and miscarriages are the main clinical manifestations of antiphospholipid sy... more Recurrent thrombosis and miscarriages are the main clinical manifestations of antiphospholipid syndrome (APS). Although most patients display both clinical signs, some patients can have isolated vascular or obstetric variants. Emerging data raise the question of whether obstetric and vascular APS are the same or different diseases. An important difference between the two conditions is that a thrombophilic state is a common feature in vascular APS, whereas clot occlusions of the decidual spiral arteries are seldom observed in obstetric APS, and infarctions are found in only one-third of APS placentae. Conversely, inflammation, which is undetectable in vascular APS, is frequently observed in the placentae of patients with obstetric APS and has been documented in the placentae of pregnant mice with fetal loss mediated by antiphospholipid antibodies. Attempts to identify different antibodies or epitopes responsible for the two clinical manifestations of APS have so far been unsuccessful...
Journal of Cerebral Blood Flow & Metabolism
Beta-2 Glycoprotein I (β2-GPI) is the main target of anti-phospholipid antibodies (aPL) in the au... more Beta-2 Glycoprotein I (β2-GPI) is the main target of anti-phospholipid antibodies (aPL) in the autoimmune anti-phospholipid syndrome, characterized by increased risk of stroke. We here investigated the antibody independent role of β2-GPI after ischemia/reperfusion, modeled in vivo by transient middle cerebral artery occlusion (tMCAo) in male C57Bl/6J mice; in vitro by subjecting immortalized human brain microvascular endothelial cells (ihBMEC) to 16 h hypoxia and 4 h re-oxygenation. ApoH (coding for β2-GPI) was upregulated selectively in the liver at 48 h after tMCAo. At the same time β2-GPI circulating levels increased. β2-GPI was detectable in brain parenchyma and endothelium at all time points after tMCAo. Parenchymal β2-GPI recognized apoptotic neurons (positive for annexin V, C3 and TUNEL) cleared by CD68+ brain macrophages. Hypoxic ihBMEC showed increased release of IL-6, over-expression of thrombomodulin and IL-1α after re-oxygenation with β2-GPI alone. β2-GPI interacted with...
Thrombosis and Haemostasis, 2009
[
Clinical Reviews in Allergy & Immunology, 2007
... 30. Out, HJ, Kooijman, CD, Bruinse, HW, and Derksen, RH (1991), Histopathological findings in... more ... 30. Out, HJ, Kooijman, CD, Bruinse, HW, and Derksen, RH (1991), Histopathological findings in placentae from patients with intra-uterine fetal death and antiphospholipid antibodies. Eur J Obstet Gynecol Reprod Biol 41, 179186. ... 39. Ikematsu, W., Luan, FL, La Rosa, L., et al. ...
Thrombosis and haemostasis, 2009
Handbook of Systemic Autoimmune Diseases, 2009
Antiphospholipid antibodies (aPL) are both diagnostic and pathogenic antibodies. aPL may: (1) int... more Antiphospholipid antibodies (aPL) are both diagnostic and pathogenic antibodies. aPL may: (1) interfere with anticoagulant mechanisms and fibrinolysis favoring a prothrombotic state, and (2) interact with cells of the coagulation cascade (i.e. endothelial cells, monocytes, and platelets) inducing a procoagulant phenotype. These pathogenic mechanisms have been reproduced in in vivo animal models. Thrombotic events explain in part the fetal losses
Lupus, 2008
The anti-phospholipid syndrome (APS) is a systemic autoimmune disease characterized by an adaptiv... more The anti-phospholipid syndrome (APS) is a systemic autoimmune disease characterized by an adaptive immune response against self phospholipid (PL)--binding proteins. Although APS is considered as an autoantibody-mediated disease, there is now evidence that anti-phospholipid antibodies (aPL) are necessary but not sufficient to trigger some of the clinical manifestations of the syndrome. For example, mediators of the innate immunity are recognized to be additional second hits able to induce the thrombotic events in the presence of aPL. Finally, environmental agents - in particular infectious ones - were reported to act as triggers for the production of autoantibodies cross-reacting with PL-binding proteins as well as inflammatory stimuli that potentiate the aPL thrombogenic effect. Altogether, these findings suggest a role for the innate immunity in APS pathogenesis. Toll-like receptors (TLR) are receptors that induce prompt inflammatory responses and mediate functional activation in immune effector cells. There is evidence that aPL, and in particular anti-beta(2) glycoprotein I (beta(2)GPI) antibodies, may activate endothelial cells and monocytes through TLR-4-dependent signalling. Whether or not TLR may behave as surface receptors for beta(2)GPI is still matter of research. Drugs or molecules able to interfere with TLR involvement may represent new therapeutic approaches for APS.
Journal of Autoimmunity, 2010
Background: There is strong evidence that antiphospholipid antibodies (aPL) perturb endothelium b... more Background: There is strong evidence that antiphospholipid antibodies (aPL) perturb endothelium both in vitro and in experimental animal models. by inducing a vasculopathy and an endothelial pro-inflammatory/coagulant phenotype. However, few contrasting studies raised the issue about the possibility to detect a comparable endothelial perturbation in anti-phospholipid syndrome (APS) patients. The aim of this observational case-control study was to evaluate several parameters of endothelial perturbation in patients with APS and without any other atherosclerosis risk factor. Patients and Methods: We investigated plasma levels of soluble adhesion molecules (s-ICAM-1, s-VCAM-1, s-E-selectin), soluble thrombomodulin (sTM), von Willebrand factor (vWF) and tissue plasminogen activator (t-PA) by solid-phase assays in 40 selected APS patients and 40 age-and sex-matched healthy subjects. In addition, we evaluated circulating endothelial cells by flow cytometry and brachial artery flow-mediated vasodilation. Patients and controls were free of conditions known to affect both the biological and the functional endothelial parameters. Results: Plasma levels of sTM, s-E-selectin and s-VCAM-1 did not differ from controls, while a significant increase in s-ICAM-1 (P ¼ 0.029), t-PA (P ¼ 0.003) and vWF titres (P ¼ 0.002) was found. Circulating mature endothelial cells were also significantly higher in patients than in controls (P ¼ 0.05) and decreased during both vitamin K antagonists (P ¼ 0.001) and antiplatelet (P ¼ 0.032) treatments. Mean brachial artery flow-mediated vasodilation responses were significantly impaired compared to healthy subjects (P ¼ 0.0001). Conclusions: As a whole these findings indicate that APS patients display an endothelial perturbation in the absence of other detectable traditional risk factors for atherosclerosis.
Journal of Autoimmunity, 2014
The thrombogenic effect of b2-glycoprotein I (b2GPI)-dependent anti-phospholipid antibodies (aPL)... more The thrombogenic effect of b2-glycoprotein I (b2GPI)-dependent anti-phospholipid antibodies (aPL) in animal models was found to be LPS dependent. Since b2GPI behaves as LPS scavenger, LPS/b2GPI complex was suggested to account for in vitro cell activation through LPS/TLR4 involvement being LPS the actual bridge ligand between b2GPI and TLR4 at least in monocytes/macrophages. However, no definite information is available on the interaction among b2GPI, LPS and endothelial TLR4 in spite of the main role of endothelial cells (EC) in clotting. To analyse at the endothelial level the need of LPS, we investigated the in vitro interaction of b2GPI with endothelial TLR4 and we assessed the role of LPS in such an interaction.
Clinical Reviews in Allergy & Immunology, 2007
... 30. Out, HJ, Kooijman, CD, Bruinse, HW, and Derksen, RH (1991), Histopathological findings in... more ... 30. Out, HJ, Kooijman, CD, Bruinse, HW, and Derksen, RH (1991), Histopathological findings in placentae from patients with intra-uterine fetal death and antiphospholipid antibodies. Eur J Obstet Gynecol Reprod Biol 41, 179186. ... 39. Ikematsu, W., Luan, FL, La Rosa, L., et al. ...
Clinical Reviews in Allergy & Immunology, 2008
Anti-phospholipid antibodies (aPL) are risk factor for recurrent pregnancy loss and obstetrical c... more Anti-phospholipid antibodies (aPL) are risk factor for recurrent pregnancy loss and obstetrical complications. The mechanisms of aPL-mediated pregnancy failure are still a matter of research. Although aPL are associated with thrombosis, thrombotic events cannot explain all the miscarriages. There is evidence for a direct in vitro aPL effect on the trophoblast as shown by their binding; reduction of proliferation, human chorionic gonadotrophin release, in vitro invasiveness, adhesion molecule expression; and increased apoptosis. Such a direct reactivity is supported by the expression of beta2 glycoprotein (β2GP) I on trophoblast cell membranes. aPL/anti-β2GPI antibodies also bind to human decidual/endometrial cells in vitro and induce a pro-inflammatory phenotype. APL-mediated inflammatory processes at the placental level are apparently responsible for fetal loss at least in animal models. Both complement activation and pro-inflammatory cytokine/chemokine secretion have been shown to play a role. More recently, complement-induced tissue factor expression on infiltrating neutrophils was described as an additional pathogenic mechanisms mediated by aPL. As a whole, these findings do suggest that aPL may induce a defective placentation by acting at different levels without involving necessarily thrombotic events.
Blood, 2011
In vitro studies have documented β2 glycoprotein I (β2GPI) binding to endothelial cells (ECs) and... more In vitro studies have documented β2 glycoprotein I (β2GPI) binding to endothelial cells (ECs) and trophoblast using antiphospholipid antibodies. The in vivo binding of β2GPI to these cells and the conditions that favor their interaction have not been investigated. We analyzed the in vivo distribution of cyanine 5.5-labeled β2GPI in mice and evaluated the effect of pregnancy and circulating antibodies on its tissue localization. The signal was detected in the liver by whole body scan and ex vivo analysis. The β2GPI failed to bind to the vascular endothelium and reacted only with the ECs of uterine vessels. In pregnant mice the protein was localized on ECs and trophoblast at the embryo implantation sites. Immunized mice showed a similar β2GPI biodistribution to naive mice but the immunized pregnant animals exhibited a significant increase in fetal loss associated with C3 and C9 deposition at the implantation sites. Treatment of mice with LPS after β2GPI-Cy5.5 injection promoted protein localization on gut and brain ECs associated with IgG, C1q, and C9 deposition in immunized mice. These findings indicate that β2GPI binding to EC requires priming with pro-inflammatory factors which is not needed for uterine and placental localization probably dependent on hormonal changes.
Annals of the New York Academy of Sciences, 1997
Frontiers in Immunology
Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by recurrent vasc... more Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by recurrent vascular thrombosis and miscarriages in the absence of known causes. Antibodies against phospholipid-binding proteins (aPL) are pathogenic players in both clotting and pregnancy APS manifestations. There is sound evidence that antibodies specific for beta2 glycoprotein I (β2GPI) trigger thrombotic and pregnancy complications by interacting with the molecule on the membranes of different cell types of the coagulation cascade, and in placenta tissues. In addition to the humoral response against β2GPI, both peripheral and tissue CD4+ β2GPI-specific T cells have been reported in primary APS as well as in systemic lupus erythematosus (SLE)-associated APS. While adaptive immunity plays a clear role in APS, it is still debated whether innate immunity is involved as well. Acute systemic inflammation does not seem to be present in the syndrome, however, there is sound evidence that complement activat...
The Journal of Immunology, 2020
β2-Glycoprotein I (β2-GPI) is an abundant plasma glycoprotein with unknown physiological function... more β2-Glycoprotein I (β2-GPI) is an abundant plasma glycoprotein with unknown physiological function and is currently recognized as the main target of antiphospholipid Abs responsible for complement activation and vascular thrombosis in patients with antiphospholipid syndrome (APS). In this study, we provide evidence that mannose-binding lectin (MBL) binds to β2-GPI in Ca++ and a dose-dependent manner and that this interaction activates complement and promotes complement-dependent thrombin generation. Surprisingly, a significant binding was observed between MBL and isolated domains II and IV of β2-GPI, whereas the carbohydrate chains, domain I and domain V, were not involved in the interaction, documenting a noncanonical binding mode between MBL and β2-GPI. Importantly, this interaction may occur on endothelial cells because binding of MBL to β2-GPI was detected on the surface of HUVECs, and colocalization of MBL with β2-GPI was observed on the endothelium of a biopsy specimen of a fem...
Nature reviews. Rheumatology, 2018
Recurrent thrombosis and miscarriages are the main clinical manifestations of antiphospholipid sy... more Recurrent thrombosis and miscarriages are the main clinical manifestations of antiphospholipid syndrome (APS). Although most patients display both clinical signs, some patients can have isolated vascular or obstetric variants. Emerging data raise the question of whether obstetric and vascular APS are the same or different diseases. An important difference between the two conditions is that a thrombophilic state is a common feature in vascular APS, whereas clot occlusions of the decidual spiral arteries are seldom observed in obstetric APS, and infarctions are found in only one-third of APS placentae. Conversely, inflammation, which is undetectable in vascular APS, is frequently observed in the placentae of patients with obstetric APS and has been documented in the placentae of pregnant mice with fetal loss mediated by antiphospholipid antibodies. Attempts to identify different antibodies or epitopes responsible for the two clinical manifestations of APS have so far been unsuccessful...
Journal of Cerebral Blood Flow & Metabolism
Beta-2 Glycoprotein I (β2-GPI) is the main target of anti-phospholipid antibodies (aPL) in the au... more Beta-2 Glycoprotein I (β2-GPI) is the main target of anti-phospholipid antibodies (aPL) in the autoimmune anti-phospholipid syndrome, characterized by increased risk of stroke. We here investigated the antibody independent role of β2-GPI after ischemia/reperfusion, modeled in vivo by transient middle cerebral artery occlusion (tMCAo) in male C57Bl/6J mice; in vitro by subjecting immortalized human brain microvascular endothelial cells (ihBMEC) to 16 h hypoxia and 4 h re-oxygenation. ApoH (coding for β2-GPI) was upregulated selectively in the liver at 48 h after tMCAo. At the same time β2-GPI circulating levels increased. β2-GPI was detectable in brain parenchyma and endothelium at all time points after tMCAo. Parenchymal β2-GPI recognized apoptotic neurons (positive for annexin V, C3 and TUNEL) cleared by CD68+ brain macrophages. Hypoxic ihBMEC showed increased release of IL-6, over-expression of thrombomodulin and IL-1α after re-oxygenation with β2-GPI alone. β2-GPI interacted with...
Thrombosis and Haemostasis, 2009
[
Clinical Reviews in Allergy & Immunology, 2007
... 30. Out, HJ, Kooijman, CD, Bruinse, HW, and Derksen, RH (1991), Histopathological findings in... more ... 30. Out, HJ, Kooijman, CD, Bruinse, HW, and Derksen, RH (1991), Histopathological findings in placentae from patients with intra-uterine fetal death and antiphospholipid antibodies. Eur J Obstet Gynecol Reprod Biol 41, 179186. ... 39. Ikematsu, W., Luan, FL, La Rosa, L., et al. ...
Thrombosis and haemostasis, 2009
Handbook of Systemic Autoimmune Diseases, 2009
Antiphospholipid antibodies (aPL) are both diagnostic and pathogenic antibodies. aPL may: (1) int... more Antiphospholipid antibodies (aPL) are both diagnostic and pathogenic antibodies. aPL may: (1) interfere with anticoagulant mechanisms and fibrinolysis favoring a prothrombotic state, and (2) interact with cells of the coagulation cascade (i.e. endothelial cells, monocytes, and platelets) inducing a procoagulant phenotype. These pathogenic mechanisms have been reproduced in in vivo animal models. Thrombotic events explain in part the fetal losses
Lupus, 2008
The anti-phospholipid syndrome (APS) is a systemic autoimmune disease characterized by an adaptiv... more The anti-phospholipid syndrome (APS) is a systemic autoimmune disease characterized by an adaptive immune response against self phospholipid (PL)--binding proteins. Although APS is considered as an autoantibody-mediated disease, there is now evidence that anti-phospholipid antibodies (aPL) are necessary but not sufficient to trigger some of the clinical manifestations of the syndrome. For example, mediators of the innate immunity are recognized to be additional second hits able to induce the thrombotic events in the presence of aPL. Finally, environmental agents - in particular infectious ones - were reported to act as triggers for the production of autoantibodies cross-reacting with PL-binding proteins as well as inflammatory stimuli that potentiate the aPL thrombogenic effect. Altogether, these findings suggest a role for the innate immunity in APS pathogenesis. Toll-like receptors (TLR) are receptors that induce prompt inflammatory responses and mediate functional activation in immune effector cells. There is evidence that aPL, and in particular anti-beta(2) glycoprotein I (beta(2)GPI) antibodies, may activate endothelial cells and monocytes through TLR-4-dependent signalling. Whether or not TLR may behave as surface receptors for beta(2)GPI is still matter of research. Drugs or molecules able to interfere with TLR involvement may represent new therapeutic approaches for APS.
Journal of Autoimmunity, 2010
Background: There is strong evidence that antiphospholipid antibodies (aPL) perturb endothelium b... more Background: There is strong evidence that antiphospholipid antibodies (aPL) perturb endothelium both in vitro and in experimental animal models. by inducing a vasculopathy and an endothelial pro-inflammatory/coagulant phenotype. However, few contrasting studies raised the issue about the possibility to detect a comparable endothelial perturbation in anti-phospholipid syndrome (APS) patients. The aim of this observational case-control study was to evaluate several parameters of endothelial perturbation in patients with APS and without any other atherosclerosis risk factor. Patients and Methods: We investigated plasma levels of soluble adhesion molecules (s-ICAM-1, s-VCAM-1, s-E-selectin), soluble thrombomodulin (sTM), von Willebrand factor (vWF) and tissue plasminogen activator (t-PA) by solid-phase assays in 40 selected APS patients and 40 age-and sex-matched healthy subjects. In addition, we evaluated circulating endothelial cells by flow cytometry and brachial artery flow-mediated vasodilation. Patients and controls were free of conditions known to affect both the biological and the functional endothelial parameters. Results: Plasma levels of sTM, s-E-selectin and s-VCAM-1 did not differ from controls, while a significant increase in s-ICAM-1 (P ¼ 0.029), t-PA (P ¼ 0.003) and vWF titres (P ¼ 0.002) was found. Circulating mature endothelial cells were also significantly higher in patients than in controls (P ¼ 0.05) and decreased during both vitamin K antagonists (P ¼ 0.001) and antiplatelet (P ¼ 0.032) treatments. Mean brachial artery flow-mediated vasodilation responses were significantly impaired compared to healthy subjects (P ¼ 0.0001). Conclusions: As a whole these findings indicate that APS patients display an endothelial perturbation in the absence of other detectable traditional risk factors for atherosclerosis.
Journal of Autoimmunity, 2014
The thrombogenic effect of b2-glycoprotein I (b2GPI)-dependent anti-phospholipid antibodies (aPL)... more The thrombogenic effect of b2-glycoprotein I (b2GPI)-dependent anti-phospholipid antibodies (aPL) in animal models was found to be LPS dependent. Since b2GPI behaves as LPS scavenger, LPS/b2GPI complex was suggested to account for in vitro cell activation through LPS/TLR4 involvement being LPS the actual bridge ligand between b2GPI and TLR4 at least in monocytes/macrophages. However, no definite information is available on the interaction among b2GPI, LPS and endothelial TLR4 in spite of the main role of endothelial cells (EC) in clotting. To analyse at the endothelial level the need of LPS, we investigated the in vitro interaction of b2GPI with endothelial TLR4 and we assessed the role of LPS in such an interaction.
Clinical Reviews in Allergy & Immunology, 2007
... 30. Out, HJ, Kooijman, CD, Bruinse, HW, and Derksen, RH (1991), Histopathological findings in... more ... 30. Out, HJ, Kooijman, CD, Bruinse, HW, and Derksen, RH (1991), Histopathological findings in placentae from patients with intra-uterine fetal death and antiphospholipid antibodies. Eur J Obstet Gynecol Reprod Biol 41, 179186. ... 39. Ikematsu, W., Luan, FL, La Rosa, L., et al. ...
Clinical Reviews in Allergy & Immunology, 2008
Anti-phospholipid antibodies (aPL) are risk factor for recurrent pregnancy loss and obstetrical c... more Anti-phospholipid antibodies (aPL) are risk factor for recurrent pregnancy loss and obstetrical complications. The mechanisms of aPL-mediated pregnancy failure are still a matter of research. Although aPL are associated with thrombosis, thrombotic events cannot explain all the miscarriages. There is evidence for a direct in vitro aPL effect on the trophoblast as shown by their binding; reduction of proliferation, human chorionic gonadotrophin release, in vitro invasiveness, adhesion molecule expression; and increased apoptosis. Such a direct reactivity is supported by the expression of beta2 glycoprotein (β2GP) I on trophoblast cell membranes. aPL/anti-β2GPI antibodies also bind to human decidual/endometrial cells in vitro and induce a pro-inflammatory phenotype. APL-mediated inflammatory processes at the placental level are apparently responsible for fetal loss at least in animal models. Both complement activation and pro-inflammatory cytokine/chemokine secretion have been shown to play a role. More recently, complement-induced tissue factor expression on infiltrating neutrophils was described as an additional pathogenic mechanisms mediated by aPL. As a whole, these findings do suggest that aPL may induce a defective placentation by acting at different levels without involving necessarily thrombotic events.
Blood, 2011
In vitro studies have documented β2 glycoprotein I (β2GPI) binding to endothelial cells (ECs) and... more In vitro studies have documented β2 glycoprotein I (β2GPI) binding to endothelial cells (ECs) and trophoblast using antiphospholipid antibodies. The in vivo binding of β2GPI to these cells and the conditions that favor their interaction have not been investigated. We analyzed the in vivo distribution of cyanine 5.5-labeled β2GPI in mice and evaluated the effect of pregnancy and circulating antibodies on its tissue localization. The signal was detected in the liver by whole body scan and ex vivo analysis. The β2GPI failed to bind to the vascular endothelium and reacted only with the ECs of uterine vessels. In pregnant mice the protein was localized on ECs and trophoblast at the embryo implantation sites. Immunized mice showed a similar β2GPI biodistribution to naive mice but the immunized pregnant animals exhibited a significant increase in fetal loss associated with C3 and C9 deposition at the implantation sites. Treatment of mice with LPS after β2GPI-Cy5.5 injection promoted protein localization on gut and brain ECs associated with IgG, C1q, and C9 deposition in immunized mice. These findings indicate that β2GPI binding to EC requires priming with pro-inflammatory factors which is not needed for uterine and placental localization probably dependent on hormonal changes.
Annals of the New York Academy of Sciences, 1997