Immune regulation of complement components in vivo

Goldman, John N.; Bangalore, Shrikar; O'Rourke, K S; Goldman, Margaret B.

doi:10.1016/0008-8749(82)90137-x

Cited by 4 publications

(2 citation statements)

References 18 publications

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“…4). This latter result is consistent with a previous report indicating activation of the alternative complement pathway by CVF in EDTA-treated mouse and rat sera (26).…”

Section: Discussionsupporting

confidence: 94%

Complement activation in factor D-deficient mice

Ippolito

et al. 2001

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

176

158

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To assess the contribution of the alternative pathway in complement activation and host defense and its possible role in the regulation of systemic energy balance in vivo, factor D-deficient mice were generated by gene targeting. The mutant mice have no apparent abnormality in development and their body weights are similar to those of factor D-sufficient littermates. Complement activation could not be initiated in the serum of deficient mice by the alternative pathway activators rabbit erythrocytes and zymosan. Surprisingly, injection of cobra venom factor (CVF) caused a profound and reproducible reduction in serum C3 levels, whereas, as expected, there was no C3 reduction in factor B-deficient mice treated similarly. Studies of C3 and factor B activation in vitro by CVF demonstrated that in factor D-deficient serum the ␣ chain of C3 was cleaved gradually over a period of 60 min without detectable cleavage of factor B. CVF-dependent C3 cleavage in the deficient serum required the presence of Mg 2؉ , whereas in normal mouse serum the presence of divalent cations was not required. These results suggest that in mouse proteolytic cleavage of factor B by factor D is not an absolute requirement for the zymogen to active enzyme conformational transition of CVF-bound factor B. Kinetics of opsonization of Streptococcus pneumoniae by C3 fragments was much slower in factor D-deficient serum, suggesting a significant contribution of the alternative pathway to antibacterial host defense early after infection. T he alternative pathway (AP) of complement activation is a self-amplifying mechanism important for pathogen recognition and elimination in the absence of specific antibodies. The AP also amplifies complement activation initiated by the other two pathways of complement activation, classical and lectin (1). The dual function (recognition and amplification) of the AP underlines its importance for host defense against pathogens. The proximal result of complement activation is the formation of convertases, enzymes that activate C3 and C5, generating biologically active protein fragments and complexes (1). In the AP, assembly of the C3͞C5 convertase requires the initial attachment of the C3b fragment of C3 to the surface of a pathogen and proceeds through the formation of a complex with factor B (C3bB) and the subsequent cleavage of factor B by factor D to form C3bBb, the C3͞C5 convertase of the AP.Mouse factor D was initially recognized as a serine protease encoded by a differentiation-specific message present mainly in adipocytes and cells of the nervous system (2). Because its mRNA was significantly reduced in mouse and rat models of obesity, it was thought that the protein was involved in fat metabolism (3). These observations led to naming the protein adipsin, which soon was identified with mouse factor D (4). Subsequently it was demonstrated that adipocytes also synthesize and secrete C3 and factor B, leading to the formation of a C3 convertase in culture supernatants (5). Other results indicated that C3a desArg , the ...

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“…4). This latter result is consistent with a previous report indicating activation of the alternative complement pathway by CVF in EDTA-treated mouse and rat sera (26).…”

Section: Discussionsupporting

confidence: 94%

Complement activation in factor D-deficient mice

Ippolito

et al. 2001

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

176

158

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“…Anti-C4 Antibody C4D guinea pigs were immunized with normal guinea pig serum or purified C4 following published methods [3]. The antibody produced was fractionated into subclasses by ion-exchange chromatography on DEAE-cellulose.…”

Section: Preparation and Purification Of Igcf And F(ab)2mentioning

confidence: 99%

Effects of Anti-C4 Antibody on Complement Production by Splenic and Peritoneal Macrophages

Goldman

O'Rourke²,

McMannis³

et al. 1988

Complement

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We have previously shown that administration of anti-C4 antibody to cells in culture can suppress the synthesis and secretion of C4. Lymphoid cells must be present along with the C4 secreting macrophages to achieve suppression of full magnitude and long duration. In this publication we have demonstrated that treatment of peritoneal macrophages with intact anti-C4 antibody results in reduction of intracellular and secreted C4. Intracellular levels of pro-C4 rapidly returned to normal after removal of the suppressing antibody and extracellular levels of C4 secreted into the media returned to normal within 24-48 h. This is in marked contrast to our previously published results with splenic fragments where intracellular pro-C4 remained markedly reduced long after removal of anti-C4. Using pulse- chase experiments we now demonstrate that, after recovery from suppression, intracellular pro-C4 levels remain low in splenic macrophages because nascent C4 is processed through the cell more rapidly. This results in a smaller intracellular pool of C4, even in the face of normal or high levels of C4 synthesis in the postsuppression phase. Finally, we demonstrate that suppression of full magnitude and duration could only be achieved with intact anti-C4 antibody. F(ab')2 fragments were not capable of inducing complete suppression.

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