The role of C5a and antibody in the release of heparan sulfate from endothelial cells

Platt, Jeffrey L.; Dalmasso, Agustin P.; Lindman, Bonnie J.; Ihrcke, Nathan S.; Bach, Fritz H.

doi:10.1002/eji.1830211135

Cited by 126 publications

(72 citation statements)

References 25 publications

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“…HS proteoglycans are rapidly released under conditions of inflammation and tissue damage (17)(18)(19). The release of HS is mediated by proteolytic cleavage of the protein core or by endoglycolytic cleavage of the HS chains (18,20).…”

mentioning

confidence: 99%

The Complement Inhibitor Low Molecular Weight Dextran Sulfate Prevents TLR4-Induced Phenotypic and Functional Maturation of Human Dendritic Cells

Spirig¹,

Kooten

Obregon

et al. 2008

The Journal of Immunology

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Low molecular weight dextran sulfate (DXS) has been reported to inhibit the classical, alternative pathway as well as the mannan-binding lectin pathway of the complement system. Furthermore, it acts as an endothelial cell protectant inhibiting complement-mediated endothelial cell damage. Endothelial cells are covered with a layer of heparan sulfate (HS), which is rapidly released under conditions of inflammation and tissue injury. Soluble HS induces maturation of dendritic cells (DC) via TLR4. In this study, we show the inhibitory effect of DXS on human DC maturation. DXS significantly prevents phenotypic maturation of monocyte-derived DC and peripheral myeloid DC by inhibiting the up-regulation of CD40, CD80, CD83, CD86, ICAM-1, and HLA-DR and down-regulates DC-SIGN in response to HS or exogenous TLR ligands. DXS also inhibits the functional maturation of DC as demonstrated by reduced T cell proliferation, and strongly impairs secretion of the proinflammatory mediators IL-1β, IL-6, IL-12p70, and TNF-α. Exposure to DXS leads to a reduced production of the complement component C1q and a decreased phagocytic activity, whereas C3 secretion is increased. Moreover, DXS was found to inhibit phosphorylation of IκB-α and activation of NF-κB. These findings suggest that DXS prevents TLR-induced maturation of human DC and may therefore be a useful reagent to impede the link between innate and adaptive immunity.

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mentioning

confidence: 99%

The Complement Inhibitor Low Molecular Weight Dextran Sulfate Prevents TLR4-Induced Phenotypic and Functional Maturation of Human Dendritic Cells

Spirig¹,

Kooten

Obregon

et al. 2008

The Journal of Immunology

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“…Structural modifications of the saccharide residues, especially sulfation, confer manifold biological activities, including regulation of cell adhesion, proliferation, development, anticoagulant, and chemical mediator functions (18 -21). Injury of tissues (22) or exposure of endothelial cells and, perhaps, other cells to activated complement or to neutrophils or platelets causes rapid cleavage and shedding of heparan sulfate proteoglycans and glycosaminoglycan fragments (23)(24)(25)(26). The release of heparan sulfate is postulated to be mediated by proteolytic cleavage of the protein core or by endoglycolytic cleavage of the heparan sulfate chains (25,(27)(28)(29).…”

mentioning

confidence: 99%

Phenotypic and Functional Maturation of Dendritic Cells Mediated by Heparan Sulfate

Kodaira¹,

Nair

Wrenshall

et al. 2000

The Journal of Immunology

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105

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Primary immune responses are thought to be induced by dendritic cells. To promote such responses, dendritic cells must be activated by exogenous agonists, such as LPS, or by products of activated leukocytes, such as TNF-α and IL-1. How dendritic cells might be activated in the absence of exogenous stimuli, or without the immediate presence of activated leukocytes, as might occur in immunity to tumor cells or transplants, is unknown. We postulated that heparan sulfate, an acidic, biologically active polysaccharide associated with cell membranes and extracellular matrices, which is rapidly released under conditions of inflammation and tissue damage, might provide such a stimulus. Incubation of immature murine dendritic cells with heparan sulfate induced phenotypic maturation evidenced by up-regulation of I-A, CD40, CD54 (ICAM-1), CD80 (B7-1), and CD86 (B7-2). Dendritic cells exposed to heparan sulfate exhibited a markedly lowered rate of Ag uptake and increased allostimulatory capacity. Stimulation of dendritic cells with heparan sulfate induced release of TNF-α, IL-1β, and IL-6, although the maturation of dendritic cells was independent of these cytokines. These results suggest that soluble heparan sulfate chains, as products of the degradation of heparan sulfate proteoglycan, might induce maturation of dendritic cells without exogenous stimuli, thus contributing to the generation and maintenance of primary immune responses.

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“…Various C fragments may participate in production of tissue pathology in hyperacute rejection. We found that C5a in conjunction with natural antibodies causes the cleavage and loss of heparan sulfate from the endothelium (12). The loss of heparan sulfate might contribute to disruption of blood vessel integrity and also to intravascular coagulation, which are components of hyperacute rejection.…”

Section: Discussionmentioning

confidence: 83%

“…Heparan sulfate release correlated with serum levels of IgM antibodies that bound to porcine endothelial cells and also with deposition of iC3b on the cells, but not with serum C activity (11). The loss of heparan sulfate was found to be triggered by C5a and natural antibody acting in combination on endothelial cells (12).…”

Section: Endothelial Cell Activation By Antibody and Complement: Relementioning

confidence: 85%

Reaction of Complement With Endotheual Cells in a Model of Xen0transplantation

Dalmasso

Platt²,

Bach

1991

Clinical and Experimental Immunology

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SUMMARYWe review our studies on the role of complement (C) as mediator of xenograft hyperacute rejection using an in vitro model consisting of porcine endothelial cells as target and human serum as source of natural antibodies and C. Cytotoxicity of endothelial cells required IgM antibodies to porcine endothelial cells, and the classical pathway and membrane attack complex of C. These findings correlated with in vivo results of porcine organs transplanted into rhesus monkeys, which showed a) co-deposition of IgM, C3, C4 and C9, along blood vessels of rejecting organs, with trace deposits of factors B or P, and b) minimal deposition of IgM and C components in transplants with prolonged survival that were performed in rtiesus monkeys depleted of natural antibodies but with normal C levels. Human serum causes activation of porcine endothelial cells manifested by release of heparan sulfate proteogiycan. Heparan sulfate release was induced by C5a alone. A new approach to avert xenograft hyperacute rejection was tested. To inhibit cytotoxicity of porcine endothelial cells by human C, the membrane-associated C inhibitor decay-accelerating factor (DAF) of human origin was incorporated into endothelial cells. Human DAF was able to efficiently inhibit C-mediated killing of porcine endothelial cells, suggesting that the use of DAF and other C inhibitors could be used to interfere with C-mediated xenograft hyperacute rejection.

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The role of C5a and antibody in the release of heparan sulfate from endothelial cells

Cited by 126 publications

References 25 publications

The Complement Inhibitor Low Molecular Weight Dextran Sulfate Prevents TLR4-Induced Phenotypic and Functional Maturation of Human Dendritic Cells

The Complement Inhibitor Low Molecular Weight Dextran Sulfate Prevents TLR4-Induced Phenotypic and Functional Maturation of Human Dendritic Cells

Phenotypic and Functional Maturation of Dendritic Cells Mediated by Heparan Sulfate

Reaction of Complement With Endotheual Cells in a Model of Xen0transplantation

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