Coexistence of Anti-Phospholipid Antibodies and Endothelial Perturbation in Systemic Lupus Erythematosus Patients With Ongoing Prothrombotic State

Ferro, Domenico; Pittoni, V.; Quintarelli, C.; Basili, Stefania; Saliola, Mirella; Caroselli, Costantino; Valesini, Guido; Violi, Francesco

doi:10.1161/01.cir.95.6.1425

Cited by 63 publications

(54 citation statements)

References 37 publications

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“…The signal peptide [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] is underlined in the figure. The protein was further subjected to PROSITE and ASC analyses (see "Bioinformatic analysis"), which indicated that the following cysteine residues are likely to be involved in disulfide bond formation and to be responsible for the Sushi domain secondary structure: C23-C66, C51-C79, C84-C124, C110-C137, C142-C188, C174-C200, C205-C248, and C234-C260.…”

Section: Resultsmentioning

confidence: 99%

“…3 This glycoprotein is also the most common target for antiphospholipid antibodies frequently associated with vascular cell dysfunction, 4 thrombotic events, and pro-atherogenic mechanisms. [5][6][7][8] In chronic disorders related to endothelial cell dysfunction, such as systemic lupus erythematosus, antiphospholipid antibody syndrome (APS), and atherosclerosis, ␤ 2 GPI plays a role as a target antigen for an immune-mediated attack, possibly influencing the progression of disease. 9-13 ␤ 2 GPI stimulates a vigorous adaptive humoral response, but also a cellular immune response.…”

Section: Introductionmentioning

confidence: 99%

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Advanced glycation end products of human β2 glycoprotein I modulate the maturation and function of DCs

Buttari

Profumo

Capozzi

et al. 2011

Blood

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In chronic disorders related to endothelial cell dysfunction, plasma ␤ 2 glycoprotein I (␤ 2 GPI) plays a role as a target antigen of pathogenetic autoimmune responses. However, information is still lacking to clarify why ␤ 2 GPI triggers autoimmunity. It is possible that posttranslational modification of the protein, such as nonenzymatic glycosylation, leads to the formation of advanced glycation end products (AGEs). The aim of our study was to explore whether glucose-modified ␤ 2 GPI is able to interact and activate monocytederived immature dendritic cells (iDCs) from healthy human donors. SDS-PAGE and spectrofluorometric analyses indicated that ␤ 2 GPI incubated with glucose was sugar modified, and that this modification likely consisted of AGE formation, resulting in AGE-␤ 2 GPI. AGE-␤ 2 GPI caused phenotypical and functional maturation of iDCs involving the activation of p38 MAPK, ERK, and NF-B. It also induced on DCs a significant up-regulation of RAGE, the receptor for AGEs. Evidence for RAGE involvement comes from blocking experiments with an anti-RAGE mAb, confocal analysis, and coimmunoprecipitation experiments. AGE-␤ 2 GPI-stimulated DCs had increased allostimulatory ability and primed naive T lymphocytes toward a Th2 polarization. These findings might explain in part the interactive role of ␤ 2 GPI, AGEs, and DCs in chronic disorders related to endothelial cell dysfunction. (Blood. 2011;117(23):6152-6161) Introduction ␤ 2 Glycoprotein I (␤ 2 GPI) or apolipoprotein H is an abundant plasma glycoprotein that binds to negatively charged phospholipids and is involved in clotting mechanisms and lipid pathways. 1 Studies performed in healthy individuals have shown a correlation between plasma ␤ 2 GPI and fasting glucose, lipids, and lipoprotein levels. 2 ␤ 2 GPI plasma concentrations are strongly associated with the metabolic syndrome and cardiovascular disease in type 2 diabetic patients and could be considered as a clinical marker of cardiovascular risk. 3 This glycoprotein is also the most common target for antiphospholipid antibodies frequently associated with vascular cell dysfunction, 4 thrombotic events, and pro-atherogenic mechanisms. [5][6][7][8] In chronic disorders related to endothelial cell dysfunction, such as systemic lupus erythematosus, antiphospholipid antibody syndrome (APS), and atherosclerosis, ␤ 2 GPI plays a role as a target antigen for an immune-mediated attack, possibly influencing the progression of disease. 9-13 ␤ 2 GPI stimulates a vigorous adaptive humoral response, but also a cellular immune response. 14-15 Cellular immunity to ␤ 2 GPI exists in patients with APS 14 and in healthy individuals. 16 Recently, we showed that ␤ 2 GPI is a T-cell target in patients with advanced carotid atherosclerotic plaques. 17 Although much is known about ␤ 2 GPI as a cofactor in autoimmune diseases, crucial information is still lacking to clarify why this abundant self-plasma protein is the target of autoimmune responses.The molecular structure and location of the major epitopic region(s) on the...

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Advanced glycation end products of human β2 glycoprotein I modulate the maturation and function of DCs

Buttari

Profumo

Capozzi

et al. 2011

Blood

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“…42 The conversion of a normal nonthrombotic state into a prothrombotic state may be the primary pathophysiological event in APS. In a recent study, Ferro et al 44 illustrated that in patients with systemic lupus erythematosus (SLE), aPL positivity is associated with an ongoing prothrombotic state only in the presence of EC perturbation, which can be measured by elevated levels of tissue plasminogen activator and von Willebrand factor. More recently, Martini and colleagues, 45 in a series of 22 SLE patients and 20 healthy individuals, evaluated the presence of aCL, LA, and/or aCL compared with SLE patients without LA and/or aCL and with controls.…”

Section: Discussionmentioning

confidence: 99%

Antiphospholipid Antibodies From Antiphospholipid Syndrome Patients Activate Endothelial Cells In Vitro and In Vivo

et al. 1999

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Background —Antiphospholipid (aPL) antibodies are associated with thrombosis in patients diagnosed with antiphospholipid syndrome (APS) and enhance thrombus formation in vivo in mice, but the mechanism of thrombosis by aPL is not completely understood. Although aPL antibodies have been shown to inhibit protein C activation and activate endothelial cells (ECs) in vitro, no study has examined whether these antibodies activate ECs in vivo. Therefore, human affinity-purified aPL (ap aPL) antibodies from APS patients were tested in a mouse model of microcirculation using the cremaster muscle that allows direct microscopic examination of thrombus formation and adhesion of white blood cells (WBCs) to ECs as an indication of EC activation in vivo. Adhesion molecule expression on human umbilical vein endothelial cells (HUVECs) after aPL exposure was performed to confirm EC activation in vitro. Methods and Results —All 6 ap aPL antibodies significantly increased the expression of VCAM-1 (2.3- to 4.4-fold), with one of the antibodies also increasing the expression of E-selectin (1.6-fold) on HUVECs in vitro. In the in vivo experiments, each ap aPL antibody except for 1 preparation increased WBC sticking (mean number of WBCs ranged from 22.7 to 50.6) compared with control (14.4), which correlated with enhanced thrombus formation (mean thrombus size ranged from 1098 to 6476 versus 594 μm 2 for control). Conclusions —Activation of ECs by aPL antibodies in vivo may create a prothrombotic state on ECs, which may be the first pathophysiological event of thrombosis in APS.

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“…Patient eligibility criteria included an established diagnosis of SLE and 1 of the following 5 features: World Health Organization class III or class IV glomerulonephritis (7), uncontrolled with treatment according to the National Institutes of Health short-course CYC protocol (8); parenchymal disease of the heart or lung with biopsy-proven vasculitis, uncontrolled with IV CYC; cerebritis or transverse myelitis, uncontrolled with IV CYC; profound, refractory autoimmune cytopenias; or catastrophic antiphospholipid syndrome (9)(10)(11)(12).…”

Section: Methodsmentioning

confidence: 99%

Hematopoietic stem cell transplantation for severe and refractory lupus

Traynor¹,

Barr²,

Rosa³

et al. 2002

Arthritis & Rheumatism

116

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Objective. To determine the safety and long-term efficacy of immune ablation and autologous hematopoietic stem cell transplantation (HSCT) in severe systemic lupus erythematosus (SLE).Methods. Fifteen patients with persistently active SLE after intravenous (IV) cyclophosphamide (CYC) therapy underwent HSCT. Stem cells were mobilized with CYC (2.0 gm/m 2 ) and granulocyte colonystimulating factor (5 g/kg/day). Lymphocytes were depleted from the graft by selection of CD34-positive cells. The conditioning regimen used was CYC (200 mg/kg), antithymocyte globulin (90 mg/kg), and methylprednisolone (3 mg/kg). Outcome was evaluated by the SLE Disease Activity Index (SLEDAI), serum complement levels, serologic features, function of diseased organs, and immunosuppressive medication requirements.Results. Fifteen patients with persistent, severe SLE, 7 of whom were critically ill, were treated. No deaths occurred following treatment. The median followup after HSCT has been 36 months (range 12-66 months). All patients demonstrated a gradual, but marked, improvement. The SLEDAI score has declined to <5 in 12 patients. Complement and anti-doublestranded DNA levels have normalized and marked improvements in end organ function have occurred in all subjects. Of the 12 patients followed up for >1 year after HSCT, 10 have discontinued immunosuppressive medications, and the prednisone dosage has been tapered to 15 mg/day in 1. Only 2 patients have demonstrated clinical evidence of recurrence of active lupus. One of these patients currently requires no immunosuppressive medication and has a normal performance status. The other patient is currently receiving IV CYC.Conclusion. In patients experiencing the persistence of organ-threatening lupus following standard, aggressive therapy, HSCT may be performed safely, with marked improvement and sustained withdrawal of all immunosuppressive medication for most patients. A phase III randomized trial is warranted to determine the relative efficacy and durability of remission of HSCT compared with standard therapies. Hematopoietic stem cell transplantation (HSCT)is most commonly applied to chemotherapy-sensitive "malignant" hematologic diseases, such as lymphoma or multiple myeloma. These malignancies are characterized by invasive or injurious clonal or oligoclonal lymphocyte proliferation. Diseases for which autologous stem cell transplants are used successfully are believed to be environmentally induced in a setting of genetic susceptibility. HSCT allows for normal, healthy hematopoietic stem cells to repopulate the bone marrow and peripheral blood after chemotherapy-induced elimination of the malignant clones. It may be anticipated that disease-mediating lymphocytes in patients with systemic lupus erythematosus (SLE) should be at least as prone to therapeutic eradication as malignant lymphocytes. If human SLE is also triggered by the hormonal and environmental milieu in a genetically susceptible host, then high-dose chemotherapy and HSCT should also induce sustained lupus-free remissions.

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Coexistence of Anti-Phospholipid Antibodies and Endothelial Perturbation in Systemic Lupus Erythematosus Patients With Ongoing Prothrombotic State

Abstract: This study shows that in SLE patients, aPL positivity is associated with an ongoing prothrombotic state only in the presence of endothelial perturbation. Our findings also suggest that aPLs and TNF-alpha might cooperate in inducing endothelial perturbation.

Cited by 63 publications

References 37 publications

Advanced glycation end products of human β2 glycoprotein I modulate the maturation and function of DCs

Advanced glycation end products of human β2 glycoprotein I modulate the maturation and function of DCs

Antiphospholipid Antibodies From Antiphospholipid Syndrome Patients Activate Endothelial Cells In Vitro and In Vivo

Hematopoietic stem cell transplantation for severe and refractory lupus

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