Intravenously applied IgG stimulates complement attenuation in a complement-dependent autoimmune disease at the amplifying C3 convertase level

Abstract

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...

Presensitization

“…IVIg products are derived from the plasma of thousands of donors, thereby ensuring a wide diversity of antibody repertoire. Numerous proposed mechanisms of action may be relevant to the modification of allosensitization: (1) Modification of autoantibody and alloantibody levels through induction of anti-idiotypic circuits (5,9 -12,14), (2) inhibition of cytokine gene activation and anticytokine activity (14), (3) anti-T cell receptor activity (14), (4) Fc receptor-mediated interactions with antigen-presenting cells (APC) to block T cell activation (14 -16), (5) anti-CD4 activity (15), (6) stimulation of cytokine receptor antagonists (14), and (7) inhibition of complement activity (14,17,18). Using the mixed lymphocyte culture system, we have shown that IVIg can significantly inhibit T cell activation and reduce the expression of CD40, CD19, intracellular adhesion molecule-1, CD86, and MHC class II on APC in the mixed lymphocyte reaction (15).…”

“…This beneficial effect was through inhibition of complement-mediated endothelial cell injury by IVIg. The Fc portion of IVIg has high affinity for activated complement components (C3b and C4b) and could represent a novel mechanism for inhibition of complement-mediated injury to allografts that was described recently for both acute rejection and chronic rejection in humans (18,20,21). Other investigators showed recently that IVIg inhibits the generation of C5b-C9 membrane attack complex, thereby preventing AMR.…”

“…Other investigators showed recently that IVIg inhibits the generation of C5b-C9 membrane attack complex, thereby preventing AMR. IVIg also inactivates C3b and accelerates C3b catabolism (14,18). IVIg can inhibit the activation of endothelial cells in in vitro models of inflammation.…”

Treatment Update of Sensitized Pediatric Kidney Transplant Recipients: A Review

“…Other mechanisms of IVIG are down-regulating B cell differentiation, B cell apoptosis, and ultimately reducing antibody production, inhibiting T cell proliferation, and activating and inhibiting ϒ-IFN, complement system inhibition, suppression of dendritic cells, and anticytokine activity. 17,18 Intravenous immunoglobulin also can inhibit memory cells. The suppressive effect of IVIG on antibody production persists long term.…”

Characteristics, Detection, and Clinical Relevance of Alloantibodies in Kidney Transplantation

“…In addition, IVIGs contain antibodies against CMV, T cell receptor idiotypes, and some cytokines, including GM-CSF and IL-1 (Jordan et al, 2003). The primary mechanisms of IVIG-mediated immunomodulation are summarized as the following: first, the inhibition of complement binding through blockage of C3 convertase (Kazatchkine & Kaveri, 2001;Lutz et al, 2004;Watanabe & Scornik, 2005); second, the neutralization of circulating antibodies through idiotype-anti-idiotype interactions (Glotz et al, 2004;Jordan et al, 2004Jordan et al, , 2006Watanabe & Scornik, 2005); third, the inhibition of IL-2 and IFN-secretion (Glotz et al, 2004;Fig. 7.…”