Intravenously applied normal human immunoglobulin G (IgG) has anti-inflammatory effects in the treatment of autoimmune diseases. Systemic inflammation can originate from an overreacting amplification loop of the complement system. In blood, C3b 2 -containing complexes maintain complement amplification much better than the extremely short-lived C3b. Therefore, in patients with the complement-dependent autoimmune disease, dermatomyositis, we studied whether intravenously applied normal human IgG (IVIG) stimulated in vivo inactivation of these complexes. In the course of IVIG treatment, clinically effective in 6 of 8 patients, the concentration of C3b 2 -containing complexes dropped to 37% ؎ 14% (n ؍ 6) of the pretreatment level when having infused 0.5 g IgG/kg body weight, increased marginally and in parallel to factor Bb thereafter until full-dose IgG was infused. By day 14 following infusion of 2 g IgG/kg body weight the concentration of C3b 2 -containing complexes was 66% ؎ 19%. The plasma concentration of C3 remained constant in myopathic or increased by 15% to 20% in amyopathic patients. In contrast to this, IVIG infusion was associated with consumption of up to 40% of plasma C4 at day 1 to 2 after completion of IVIG infusion. Thus, IVIG had an immediate and long-lasting attenuating effect on complement amplification in vivo, despite the fact that it induced classical complement pathway activation. IntroductionIntravenously applied human immunoglobulin G (IgG) has an immunomodulatory potential. 1 This effect might in part be due to modulation of phagocytic cells either by altering autocrine or paracrine cytokines through the action of anticytokine antibodies 2,3 or alterations of cell receptor functions 4 or expression. 5,6 Intravenously applied human IgG (IVIG) is, however, similarly beneficial in autoimmune diseases that are associated with excessive complement activation via the classical pathway and the amplification loop. [7][8][9] Such complement activation is proinflammatory by generating C3b in excess. C3b, the active form of C3, binds covalently to targets and promotes generation of C3 convertases, which, in turn, consume C3 and allow assembly of C5 convertase. Elevated C3/C5 convertase activity 10 produces locally proinflammatory anaphylatoxins, C3a/C5a, and generates C5b that can initiate formation of the membrane attack complex on target cells. Finally, insertion of C5b to 7 and C9 into membranes of nucleated cells can result in activation of the arachidonic acid pathway that forms mediators of inflammation. 11 IVIG at high doses is able to displace nascent C3b from tissue-bound immune complexes to the fluid phase 12,13 by serving as a preferential binding site for C3b. 14 Although this process reduces local complement activation, it does not stop systemic complement amplification. Indeed, nascent C3b deposited to fluid-phase IgG primarily forms C3b 2 -IgG complexes. 14 These complexes represent potent activators of the amplification loop and are, on a molar basis, more efficient activators tha...
Liposomal formulations of some drugs, most importantly pegylated lipo-soma1 doxorubicin (Doxil@), have been reported to cause immediate hypersensitivity reactions that cannot be explained with the conventional paradigm of IgE-mediated (type I) allergy. Here we present a rationale and experimental evidence for the concept that these reactions represent a novel type of druginduced hypersensitivity that can be called complement (C) activation-related pseudoallergy (CARPA). The theoretical foundation includes the facts that 1) some liposomes have been known to activate C, 2) most of the clinical symptoms of liposome-induced reactions coincide with those caused by C activation by other activators, and 3) the C mechanism explains those manifestations which are atypical for type 1 reactions. The experimental the observations that 1 ) Doxil caused massive C activati (4/10) of normal human sera, 2) high dose IgG attenuated Doxil-induced C activation in serum and prevented further C activation by amplification, and 3) intravenous injection of therapeutically relevant doses of Doxil in pigs caused Journal of Liposome Research Downloaded from informahealthcare.com by The University of Manchester on 11/19/14 For personal use only. -168 SZERENI ET AL.significant pulmonary hypertension with consequent systemic hypotension and decline of cardiac output, which changes mimicked the cardiovascular manifestations of the human reaction and were shown to be triggered by C activation. As for the question how Doxil, a long-circulating "stealth" liposome forniulation, avoids phagocytic uptake by macrophages despite its potential opsonization by C3b, we demonstrated efficient inactivation of Doxil-bound and free C3b to iC3b in human serum. Thus, it i s unlikely that PEG would interfere with CDI 1 b/CD18-mediated phagocytosis by inhibiting the formation of its main ligand, iC3b.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.