Beta-2-glycoprotein 1-dependent macrophage uptake of apoptotic cells. Binding to lipoprotein receptor-related protein receptor family members.
ABSTRACT The recognition and removal of apoptotic cells is critical to development, tissue homeostasis, and the resolution of inflammation. Many studies have shown that phagocytosis is regulated by signaling mechanisms that involve distinct ligand-receptor interactions that drive the engulfment of apoptotic cells. Studies from our laboratory have shown that the plasma protein beta-2-glycoprotein 1 (beta2GP1), a member of the short consensus repeat superfamily, binds phosphatidylserine-containing vesicles and apoptotic cells and promotes their bridging and subsequent engulfment by phagocytes. The phagocyte receptor for the protein/apoptotic cell complex, however, is unknown. Here we report that a member of the low density lipoprotein receptor-related protein family on phagocytes binds and facilitates engulfment of beta2GP1-phosphatidylserine and beta2GP1-apoptotic cell complexes. Using recombinant beta2GP1, we also show that beta2GP1-dependent uptake is mediated by bridging of the target cell to the phagocyte through the protein C- and N-terminal domains, respectively.
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ABSTRACT: The Antiphospholipid Syndrome (APS) is characterized by thrombosis and pregnancy loss, clinical events mediated by pathogenic anti-phospholipid autoantibodies (aPL). β2-glycoprotein I (β2GPI) is the major autoantigens recognized by aPL. β2GPI is a cationic protein that binds to negatively charged surfaces such as those of apoptotic cells. This feature may lead to two major events: i) immunization with β2GPI fosters the Fc-receptor-mediated uptake by antigen presenting cells of apoptotic material decorated with β2GPIand the activation ofβ2GPI-specific T cells which in turn provide help to β2GPI-specific B cells for the production of anti-β2GPI; ii) apoptotic bodies decorated with β2GPI can be opsonized by anti-β2GPI and shifted towards a pro-inflammatory clearance by macrophages; epitope spread can occur with the generation of autoimmunity against nuclear autoantigens. In the presence of a predisposing genetic background and of a particular cytokine environment (type I interferons), the sequential emergence of autoantibodies can evolve into overt clinical disease. The spectrum of clinical phenotypes of the patients can be modulated by several factors affecting the pathogenicity of anti-β2GPI (e.g. domain specificity). We conclude that dying cells may play a dual role in APS: (I) as immunogen for the induction of aPL (etiology) and (II) as targets of aPL for the chronification of inflammation and the development of autoimmune diseases (pathology).Autoimmunity 05/2013; · 2.77 Impact Factor
- 04/2012; , ISBN: 978-953-51-0526-8
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ABSTRACT: Systemic lupus erythematosus is a multifactorial autoimmune disease which has been associated with several genetic, hormonal and environmental factors. TLRs are a group of innate immune system receptors and have been linked strongly to SLE development. Several lines of evidence support the significant role of TLR7 in initiation and progression of autoimmunity. The common presence of anti-β2GPI antibodies in SLE patients and the antagonizing effect of these antibodies on the physiologic roles of the β2GPI may suggest a function for this protein in the pathogenesis of SLE. In addition, a recent in vitro report on the role of anti-β2GPI antibodies in translocation and activation of TLR7 raised the suspicion about the possible interactions between TLR7 and β2GPI in development of SLE. By deleting the β2GPI gene from a TLR7-dependent mouse model of SLE, BXSByaa, we have shown that the absence of this protein causes acceleration of the disease development in these mice with presentation of a more severe phenotype including, large lymphadenopathy huge splenomegaly and increased mortality. Histological and serological studies showed that the absence of β2GPI led to formation of a very severe nephritis in BXSByaa mice and production of a high titer of autoantibodies and inflammatory cytokines including BAFF and IFN-I. Flowcytometery analysis also showed a significant proportional increase in the population of the immune cells involved in the pathogenesis of SLE. In vitro experiments did not show any direct inhibitory or enhancing interaction between β2GPI and TLR7. But we have shown that in the absence of β2GPI there is decreased phagocytosis of apoptotic cells by macrophages in vivo. Impaired phagocytosis has been proposed to be one of the main mechanisms involved in the pathogenesis of SLE. As one of the posttranslational modification reactions, oxidization of antigens has been linked to increase in their immunogenecity. Here we have shown that disrupting of the β2GPI gene causes an increase in the serum titer of anti-oxidized RNA antibodies. This observation which can be a reflection of higher titer of oxidized-RNA may imply the protective role of β2GPI in preventing the occurrence of posttranslational modifications of nucleic acid-containing antigens under pathologic conditions like oxidative stress. These findings may open new areas of research to further investigate the possible roles of β2GPI in inflammation and innate immunity and the autoimmune pathologies that may arise upon disruption of its function.07/2013, Degree: PhD, Supervisor: Steven Krilis