Interactions of the platelets in paroxysmal nocturnal hemoglobinuria with complement. Relationship to defects in the regulation of complement and to platelet survival in vivo.

Devine, Dana V.; Siegel, Robert S.; Rosse, Wendell F.

doi:10.1172/jci112773

Cited by 62 publications

(18 citation statements)

References 33 publications

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“…This platelet-associated factor H resides in ␣ granules, is functionally active, and is released upon complement activation or other stimuli (63,64). Our data show that rodent platelets are different from their human counterparts as they contain factor H on their surface.…”

Section: Table IImentioning

confidence: 80%

A Protein with Characteristics of Factor H Is Present on Rodent Platelets and Functions as the Immune Adherence Receptor

Alexander

Hack

Cunningham

et al. 2001

Journal of Biological Chemistry

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Complement-coated particles interact with specific immune adherence receptors (IAR). In primates, this function is served by complement receptor 1 (CR1) on erythrocytes. In contrast, rodent platelets bear IAR distinct from CR1, the identity of which was studied here. A 150-kDa C3b-binding protein was isolated from rat platelets, which had immunochemical and biochemical identity to plasma factor H. Immunofluorescence microscopy and flow cytometry demonstrated that factor H was present on the surface of rat and mouse platelets, which could be removed by treatment with neuraminidase. Sheep erythrocytes bearing C3b underwent immune adherence with rat and mouse platelets, which was blocked with anti-factor H F(ab) 2 antibodies, but not with antibodies binding to the complement regulator, Crry, on the platelet surface. By reverse transcription-polymerase chain reaction using rat platelet RNA and primers designed from mouse factor H, a 472-base pair product was generated that was identical in sequence to that produced from rat liver RNA. The translated protein product was 85% similar to mouse liver factor H. The 3-nucleotide sequence from platelets predicted a soluble factor H protein. By Northern analysis, liver and platelets had identically sized factor H mRNA. Thus, rat and mouse platelets have a membrane protein with characteristics of factor H that is linked via sialic acid residues and functions as the IAR. Whether platelet factor H is acquired by passive adsorption from sera and/or is produced by platelets remains to be determined.

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Section: Table IImentioning

confidence: 80%

A Protein with Characteristics of Factor H Is Present on Rodent Platelets and Functions as the Immune Adherence Receptor

Alexander

Hack

Cunningham

et al. 2001

Journal of Biological Chemistry

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“…This activity could be removed from the sonicates with antiserum to factor H (17). Studies from this laboratory on the activity of the alternative pathway C3 convertase on the platelets of patients with PNH demonstrated that not all patients have the increased C3bBb activity that might be expected from platelets deficient in DAF (15). In studies reported here we demonstrate that normal human platelets contain factor H, which can be secreted from platelet a granules and can regulate the activity of platelet-bound C3bBb.…”

mentioning

confidence: 57%

“…min at 370C with 1 mg of C3 and cobra venom factor-factor Bb complexes. These complexes were prepared using purified cobra venom factor, factor B, and factor D as described (15). The amount of platelet-bound C3b at this step was measured by monoclonal anti-C3c antibody binding assay similar to that described (15).…”

Section: Methodsmentioning

confidence: 99%

“…These complexes were prepared using purified cobra venom factor, factor B, and factor D as described (15). The amount of platelet-bound C3b at this step was measured by monoclonal anti-C3c antibody binding assay similar to that described (15). These platelets (PC3b) were then washed into GVB containing 2.5 mM MgCI2 and exposed to factor B, factor D, and C3 nephritic factor for 10 min at 370C to create platelet-bound C3 convertase complexes.…”

Section: Methodsmentioning

confidence: 99%

“…Human platelets contain DAF (13,14) but not CR1. Although platelet DAF is biochemically and immunologically similar to erythrocyte DAF (13,15), the ability of platelet DAF to regulate the C3 convertases of the alternative and classical pathways on the platelet surface has not been demonstrated. The importance of DAF in the regulation of the classical pathway C3 convertase on platelets can be inferred from studies demonstrating that the platelets from patients with paroxysmal nocturnal hemoglobinuria (PNH) lack DAF and are readily lysed by complement that has been activated by anti-platelet antibodies (16).…”

mentioning

confidence: 99%

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Regulation of the activity of platelet-bound C3 convertase of the alternative pathway of complement by platelet factor H.

Devine¹,

Rosse²

1987

Proc. Natl. Acad. Sci. U.S.A.

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The alternative pathway of complement is regulated on the surface of homologous blood cells at the C3 amplification step by the membrane protein decay-accelerating factor, as well as by the plasma protein factor H. We have reported elsewhere that platelets from patients with paroxysmal nocturnal hemoglobinuria regulate the activity of the C3 convertase C3bBb, even though they lack decay-accelerating factor. We now report that normal human platelets contain factor H, which was released from the platelet in response to complement deposition or thrombin stimulation. Factor H was localized to the platelet at granules by immunocytochemical techniques. As determined by a solid-phase radioimmunoassay, thrombin-stimulated platelets released -54 ng of factor H per 108 platelets. The release of factor H in response to complement or thrombin was inhibited by treating the platelets with metabolic inhibitors. Such inhibition resulted in a 3-fold increase in the activity of C3bBb. Platelets that released factor H bound only half as many molecules of radiolabeled factor B to platelet-bound C3b than platelets that could not release factor H. Treatment of platelets with anti-decay-accelerating factor antibody had no effect on the activity of C3bBb unless the release of factor H was blocked. Therefore, so far as we know, human platelets have a unique mechanism for the regulation of the alternative pathway of complement.

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Altered expression of host‐encoded complement regulators on human cytomegalovirus‐infected cells

et al. 1996

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Human cytomegalovirus (HCMV)-infected cells persist in the presence of anti-HCMV antibody, suggesting that HCMV has evolved mechanisms to evade host immune defenses. Insofar as no virus-encoded complement inhibitors have been identified for HCMV, we hypothesized that HCMV infection may alter the expression of host-encoded cell surface complement inhibitors. Herein, we report that cell surface expression of two complement regulator proteins, CD55 and CD46, which are members of the regulators of complement activation (RCA) gene cluster, increased up to eightfold following infection of fibroblasts or glioblastoma cells with HCMV, but not after infection with HSV-1 or adenovirus. However, the cell surface expression of a third complement regulator, CD59, which is not a member of the RCA gene cluster, was not altered during HCMV infection. Functional studies using purified complement components demonstrated that up-regulation of CD55 suppressed the activity of cell-associated C3 convertases on HCMV-infected cells. Furthermore, increased CD55 expression protected infected cells from complement-mediated lysis, an effect which directly correlated with the length of HCMV infection. Increased expression of host-encoded complement regulator proteins may provide protection of HCMV-infected cells from the host immune response in vivo, through increasing the resistance of infected cells to complement-mediated lysis and decreasing the deposition of C3-derived products on the cell surface.

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Interactions of the platelets in paroxysmal nocturnal hemoglobinuria with complement. Relationship to defects in the regulation of complement and to platelet survival in vivo.

Cited by 62 publications

References 33 publications

A Protein with Characteristics of Factor H Is Present on Rodent Platelets and Functions as the Immune Adherence Receptor

A Protein with Characteristics of Factor H Is Present on Rodent Platelets and Functions as the Immune Adherence Receptor

Regulation of the activity of platelet-bound C3 convertase of the alternative pathway of complement by platelet factor H.

Altered expression of host‐encoded complement regulators on human cytomegalovirus‐infected cells

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