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Abstract
Autoimmune vasculitis is an endothelial inflammatory disease that results from the deposition of immune-complexes (ICs) in blood vessels. The interaction between Fcgamma receptors (FcγRs) expressed on inflammatory cells with ICs is known to cause blood vessel damage. Hence, blocking the interaction of ICs and inflammatory cells is essential to prevent the IC-mediated blood vessel damage. Thus we tested if uncoupling the interaction of FcγRs and ICs prevents endothelium damage. Herein, we demonstrate that dimeric FcγR-Igs prevented nitric oxide (NO) mediated apoptosis of human umbilical vein endothelial cells (HUVECs) in an in vitro vasculitis model. Dimeric FcγR-Igs significantly inhibited the IC-induced upregulation of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) release by murine monocytic cell line. However, FcγR-Igs did not affect the exogenously added NO-induced upregulation of pro-apoptotic genes such as Bax (15 fold), Bak (35 fold), cytochrome-C (11 fold) and caspase-3 (30 fold) in HUVECs. In conclusion, these data suggest that IC-induced NO could be one of the major inflammatory mediator promoting blood vessel inflammation and endothelial cell death during IC-mediated vasculitis which can be effectively blocked by dimeric decoy FcγRs.
Highlights
The immune system has evolved to defend our body against invading pathogens, under certain conditions it attacks itself, leading to the development of autoimmune diseases
First we investigated whether aforementioned dimeric FcγR-Ig molecules compete with cell surface FcγRs expressed on inflammatory cells such as macrophages in vitro and block their binding to antibody coated endothelial cells, which is the hallmark of immune complexes (ICs)-mediated damage to the endothelial cells in an autoimmune vasculitis
To mimic the IC deposited in endothelial cell wall, the human umbilical vein endothelial cells (HUVECs) were coated with an antibody specific for fibronectin deposited on HUVECs
Summary
The immune system has evolved to defend our body against invading pathogens, under certain conditions it attacks itself, leading to the development of autoimmune diseases. During autoimmune vasculitis, circulating ICs deposit in the vascular endothelial walls leading to an infiltration of inflammatory cells [1, 2] causing weakening and narrowing of the blood vessels. This vascular inflammation results in vital organ damage including heart failure and neurological conditions such as stroke. The interaction of between ICs and the FcγRs expressed on inflammatory cells is a key event in the development of various IC-mediated diseases including vasculitis [5,6,7,8,9] and leads to the destruction of tissues/cells with IC-deposits through antibody dependent cellular cytotoxicity and phagocytosis [6, 10]. Inflammatory mediators released by activated cells are responsible for the endothelial cell inflammation, injury and subsequent vasculitis
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