Transient perturbation of endothelial integrity induced by natural antibodies and complement.

Abstract

SummaryThe barrier function of blood vessels is thought to be regulated at least in part by endothelium. This concept is supported by the dramatic loss of barrier function occurring in the hyperacute rejection of vascularized grafts mediated by anti-endothelial ceU (EC) antibodies and complement. In this process, the endothelium is not destroyed but instead loses the ability to retain blood cells and plasma proteins within capillaries. The noncytotoxic mechanism that allows this change in EC function has been unknown. Here we report that within 10 to 20 rain of exposure to human xenoreactive natural antibodies and complement, porcine EC undergo alterations in cell shape and in the cytoskeleton that disrupt monolayer integrity and lead to formation of intercellular gaps. Gap formation is not associated with cell death but requires the complement complex C5b67. The gaps induced by anti-EC antibodies and complement are transient; gap closure requires formation of C5b-9 complexes on the ceils and the rate of recovery depends on the release of cellular products into the medium. Preincubation of EC with dibutyryl cAMP (0.5 raM) prevents gap formation and disruption of the cytoskeleton caused by antibodies and complement. These results provide evidence that the integrity of endothelium is regulated by components of the complement system and suggest a mechanism that may explain the prominent loss of endothelial integrity seen in humoral immune responses.

Interleukin-4 Induces Up-regulation of Endothelial Cell Claudin-5 through Activation of FoxO1

“…Many substances are able to adversely modify the EC junction, including thrombin (23), antibodies and EC antigen-binding lectins (11,13), and the membrane attack complex of complement (24). Because the injury caused by complement can be prevented by IL-4 (5), we hypothesized that IL-4 modifies one or more components of the junction so that the EC monolayer can resist the deleterious effect of complement.…”

Entry and Integration of Transplanted Hepatocytes in Rat Liver Plates Occur by Disruption of Hepatic Sinusoidal Endothelium

“…Nondestructive endothelial cell separations may involve cytoskeletal alterations, 29 as well as increased endothelial permeability. It is well established that cytokines capable of affecting endothelial cells, e.g., interleukins and tumor necrosis factor ␣ may be released by infiltrating macrophages, 30 activated Kupffer cells, 23 or even endothelial cells themselves.…”

Pathogenesis of neurocognitive and neuropsychiatric manifestations in childhood-onset lupus: an overview

“…101,102 AECAs, have been reported to be found in approximately 40% of SLE patients compared to multiple sclerosis, stroke and healthy controls in one study by Saadi and Platt. 103 The IgG from the SLE patients caused increased IL-6 release from IL-1β pre-treated endothelial cells, compared to control IgG. Another study demonstrated the ability of a monoclonal AECA isolated from an SLE patient to recognize a 42kDa endothelial cell membrane protein and activate endothelial cells, leading to up regulation of the generegulatory protein NF-κB, which is also implicated in a pro-inflammatory milieu.…”