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Publications (44)
Sustained macroautophagy/autophagy favors the differentiation of fibroblasts into myofibroblasts. Cellular senescence, another means of responding to long-term cellular stress, has also been linked to myofibroblast differentiation and fibrosis. Here, we evaluate the relationship between senescence and myofibroblast differentiation in the context of...
Mitochondria are organelles that govern energy supply and control cell death. Mitochondria also express bacterial features, such as the presence of inner membrane cardiolipin and a circular genome rich in hypomethylated CpG motifs. While mitochondrial extrusion by damaged organs or activated cells is thought to trigger innate immunity, it is unclea...
Endothelial cells have multifaceted interactions with the immune system, both as initiators and targets of immune responses. In vivo, apoptotic endothelial cells release two types of extracellular vesicles upon caspase-3 activation: apoptotic bodies and exosome-like nanovesicles (ApoExos). Only ApoExos are immunogenic: their injection causes inflam...
Tertiary lymphoid structures (TLS) accumulate at sites of chronic injury where they function as an ectopic germinal center, fostering local autoimmune responses. Vascular injury leads to the release of endothelial‐derived apoptotic exosome‐like vesicles (ApoExo) that contribute to rejection in transplanted organs. The purpose of the study was to ev...
Ischemic, immunologic or pharmacological stressors can induce vascular injury and endothelial apoptosis in organ donors, in transplant candidates due to the impact of end stage organ failure on the vasculature, and in association with peri-transplantation events. Vascular injury may shape innate and adaptive immune responses, leading to dysregulati...
Independent of the initial cause of kidney disease, microvascular injury to the peritubular capillary network appears to play a central role in the development of interstitial fibrosis in both native and transplanted kidney disease. This association is explained by mechanisms such as the upregulation of pro-fibrotic genes and epigenetic changes ind...
Autoantibodies against perlecan/LG3 (anti‐LG3) have been associated with increased risks of delayed graft function, acute rejection and reduced long‐term survival. High titers of anti‐LG3 antibodies have been found in de novo renal transplants recipients in absence of allosensitizing or autoimmune conditions. Here, we seek to understand the pathway...
Background Ischemia-reperfusion injury (IRI) is a major risk factor for chronic renal failure. Here, we characterize the different modes of programmed cell death in the tubular and microvascular compartments during the various stages of IRI-induced AKI, and their relative importance to renal fibrogenesis.
Methods We performed unilateral renal arter...
Kidney transplantation entails a high likelihood of endothelial injury. The endothelium is a target of choice for injury by ischemia-reperfusion, alloantibodies, and autoantibodies. A certain degree of ischemia-reperfusion injury inevitably occurs in the immediate posttransplant setting and can manifest as delayed graft function. Acute rejection ep...
Antibody-mediated injury is a major cause of allograft dysfunction and loss. Antibodies to ABH(O) blood group antigens are classical mediators of ABO-incompatible (ABOi) graft rejection, while donor-specific anti-HLA antibodies and, more recently, autoantibodies are appreciated as important contributors to allograft inflammation and dysfunction. In...
Antibodies that are specific to organ donor HLA have been involved in the majority of cases of antibody-mediated rejection in solid organ transplant recipients. However, recent data show that production of non-HLA autoantibodies can occur before transplant in the form of natural autoantibodies. In contrast to HLAs, which are constitutively expresse...
Pretransplant autoantibodies to LG3 and angiotensin II type 1 receptors (AT1R) are associated with acute rejection in kidney transplant recipients, whereas antivimentin autoantibodies participate in heart transplant rejection. Ischemia-reperfusion injury (IRI) can modify self-antigenic targets. We hypothesized that ischemia-reperfusion creates perm...
Autoantibodies to components of apoptotic cells, such as anti-perlecan antibodies, contribute to rejection in organ transplant recipients. Mechanisms of immunization to apoptotic components remain largely uncharacterized. Here, we use large-scale proteomics with validation by electron microscopy and biochemical methods for comparing protein profile...
Transplant vasculopathy is associated with neointimal accumulation of recipient-derived mesenchymal stem cells. Increased circulating levels of LG3, a C-terminal fragment of perlecan, were found in renal transplant patients with vascular rejection. Here, we evaluated whether LG3 regulates the migration and homing of mesenchymal stem cells and the a...
Microparticles, also called microvesicles, are submicron extracellular vesicles produced by plasma membrane budding and shedding recognized as key actors in numerous physio(patho)logical processes. Since they can be released by virtually any cell lineages and are retrieved in biological fluids, microparticles appear as potent biomarkers. However, t...
Recent evidence suggests that autophagy may favor fibrosis through enhanced differentiation of fibroblasts in myofibroblasts. Here, we sought to characterize the mediators and signaling pathways implicated in autophagy-induced myofibroblast differentiation. Fibroblasts, serum starved for up to 4 d, showed increased LC3-II/-I ratios and decreased SQ...
Non-HLA antibodies against the angiotensin II type 1 receptor (AT1 R) and the C-terminal fragment of perlecan (i.e., LG3) are associated with the development of renal allograft rejection. It is currently unknown how humans develop anti-AT1 R or anti-LG3 antibodies. The aim of this study was to investigate whether pregnancy-as a model of sensitizati...
BACKGROUND: The stress status of the apoptotic cell can promote phenotypic changes that have important consequences on the immunogenicity of the dying cell. Autophagy is one of the biological processes that are activated in response to a stressful condition. It is an important mediator of intercellular communications, both by regulating the unconve...
Acute vascular rejection (AVR) is characterized by immune-mediated vascular injury and heightened endothelial cell (EC) apoptosis. We reported previously that apoptotic ECs release a bioactive C-terminal fragment of perlecan referred to as LG3. Here, we tested the possibility that LG3 behaves as a neoantigen, fuelling the production of anti-LG3 ant...
Stem cells are highly plastic cells characterized by the capacity to differentiate into various cells types of importance in tissue repair and immune regulation. Stem cells are released from the bone marrow and home to sites of injury where they differentiate and regulate various aspects of the immune response and tissue regeneration. Under sustain...
Transplanted organs have to cope with diverse immunologic and metabolic stressors that augment the percentage of stressed and dying cells. Cell death, whether apoptotic or necrotic, is crucial in various transplantation-associated conditions. Necrosis, a proinflammatory type of cell death classically considered as accidental, is increasingly recogn...
Endothelial apoptosis is increased in association with acute and chronic vascular rejection (VR) of solid allografts. Apoptotic endothelial cells (EC) release LG3, a C-terminal fragment of perlecan of potential importance in vascular remodeling and neointima formation.
Our 2 goals were to determine whether circulating levels of LG3 are increased in...
β2-Glycoprotein I (β2GPI) is an abundant plasma protein that binds to the surface of cells and particles expressing negatively charged lipids,
but its physiological role remains unknown. Antibodies to β2GPI are found in patients with anti-phospholipid syndrome, a systemic autoimmune disease associated with vascular thrombosis
and pregnancy morbidit...
Anti-heat shock protein 60 autoantibodies (anti-Hsp60) are associated with cardiovascular disease and are known to affect endothelial cells in vitro, and we have recently shown that anti-Hsp60 promote thrombosis in a murine model of arterial injury. Based on those findings, we undertook the present study to investigate the hypothesis that the prese...
Cardiolipin (CL), a major phospholipid in bacterial cell walls, is sequestered from the immune system in mammalian mitochondria and is, therefore, a potential danger signal. Based on growing evidence that phospholipids constitute natural ligands for CD1 and that CD1d-restricted T cells recognize phospholipids, we hypothesized that CD1d binds and pr...
The antiphospholipid syndrome (APS), as both a primary syndrome and a syndrome in association with systemic lupus erythematosus (SLE), can be a devastating disease. It is unclear what factors (genetic and/or environmental) lead to the generation of antiphospholipid antibodies (aPL). It is equally unclear why only certain individuals with aPL develo...
Anti-phospholipid syndrome (APS) is an autoimmune disorder characterized by the presence of autoantibody (AAb) to phospholipid (PL)-binding proteins, such as beta2-glycoprotein I (beta2GPI), and clinical manifestations including thrombosis and/or recurrent pregnancy loss. beta2GPI-reactive T cells are clearly implicated in the generation of these A...
Anti-heat shock protein (HSP)60 autoantibodies are associated with atherosclerosis and are known to affect endothelial cells in vitro. However, their role in thrombus formation remains unclear. We hypothesized that anti-HSP60 autoantibodies could potentiate thrombosis, and evaluated the effect of anti-murine HSP60 antibodies in a ferric chloride (F...
Anti-phospholipid syndrome (APS) is an autoimmune disorder characterized by the presence of autoantibody (AAb) to phospholipid (PL)-binding proteins, such as β2-glycoprotein I (β2GPI), and clinical manifestations including thrombosis and/or recurrent pregnancy loss. β2GPI-reactive T cells are clearly implicated in the generation of these AAb, but t...
Physicians who provide care to patients with systemic sclerosis (SSc, scleroderma) ask themselves several questions: Is SSc the correct diagnosis? Can the disease course be predicted? Is there a greater risk for involvement of certain organs? Can the vital prognosis be predicted? In this brief review, we answer these questions by excerpting data fr...
To determine whether anti-endothelial cell autoantibodies (AECAs) from systemic lupus erythematosus (SLE) patients with the antiphospholipid syndrome are involved in the initial endothelial cell (EC) membrane perturbation effect that is postulated to provide a target for antiphospholipid antibody (aPL) binding and, hence, to trigger the thrombotic...
Objective:
To demonstrate the association between autoantibodies to nuclear lamin B1 (aLB1) and protection against thrombosis ("thromboprotection") in patients with systemic lupus erythematosus (SLE), and to elucidate the mechanism by which aLB1 cause thromboprotection in vivo. Since a number of autoantigens in SLE have been localized specifically...
