C3 binds covalently to the C<i>γ</i>3 domain of IgG immune aggregates during complement activation by the alternative pathway

Antón, Luis C.; Alcolea, JoséM.; Sánchez-Corral, Pilar; Marqués, Guillermo; Sánchez, Angel; Vivanco, Fernando

doi:10.1042/bj2570831

Cited by 30 publications

(14 citation statements)

References 35 publications

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“…At the macromolecular level, the covalent binding of C3 to immune complexes had been studied. It was shown that C3b mainly bound to the antibodies (Gadd & Reid, 1981) and at multiple sites (Anton et al, 1989(Anton et al, , 1994. Using heat-aggregated IgG, obtained from a myeloma patient, Shohet et al (1993) showed that C3b, activated via the alternative pathway, bound to one major region of the heavy chain of IgG containing six potential acceptor sites, in the form of serine and threonine residues.…”

Section: Ska Law and Aw Doddsmentioning

confidence: 99%

The internal thioester and the covalent binding properties of the complement proteins C3 and C4

1997

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The covalent binding of complement components C3 and C4 is critical for their activities. This reaction is made possible by the presence of an internal thioester in the native protein. Upon activation, which involves a conformational change initiated by the cleavage of a single peptide bond, the thioester becomes available to react with molecules with nucleophilic groups. This description is probably sufficient to account for the binding of the C4A isotype of human C4 to amino nucleophiles. The binding of the C4B isotype, and most likely C3, to hydroxyl nucleophiles, however, involves a histidine residue, which attacks the thioester to form an intramolecular acyl-imidazole bond. The released thiolate anion then acts as a base to catalyze the binding of hydroxyl nucleophiles, including water, to the acyl function. This mechanism allows the complement proteins to bind to the hydroxyl groups of carbohydrates found on all biological surfaces, including the components of bacterial cell walls. In addition, the fast hydrolysis of the thioester provides a means to contain this very damaging reaction to the immediate proximity of the site of activation.

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Section: Ska Law and Aw Doddsmentioning

confidence: 99%

The internal thioester and the covalent binding properties of the complement proteins C3 and C4

1997

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“…Clq purification and labeling. Clq was purified from NHS by high-pH precipitation, ion-exchange chromatography on BioRex 70, and gel filtration on Bio-Gel A5m (27, 45) as described previously (2). The purity of the isolated Clq was verified by polyacrylamide gel electrophoresis (PAGE).…”

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C1q binding and activation of the complement classical pathway by Klebsiella pneumoniae outer membrane proteins

et al. 1993

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Both the classical and alternative complement pathways were effective in the elimination of K pneumoniae serumsensitive strains in nonimmune serum, although bacterial killing was more effective when both pathways were active. Activation of the classical pathway by these strains was studied in more detail, and we have identified two bacterial outer membrane proteins (OMP) that bind Clq and activate this pathway in nonimmune serum and in agammaglobulinemic (agamma) serum. MATERIALS AND METHODS Bacteria, bacteriophage, and media. The serum-sensitive K pneumoniae strain KT793 (0-:K-) used in this study is a double mutant obtained from the serum-resistant K pneumoniae strain C3 (serotypes O1:K66). It was made unencapsulated (K-) after UV mutagenesis and selection with anticapsular serum, as described before (5). Spontaneous LPSdeficient mutants (O-) were obtained from the Kmutant strain by selection with the LPS-specific bacteriophage FC3-2, as described previously (48). The other serum-sensitive strains used were KT701, KT702, and KT707, which were derived from the wild-type C3 strain and which were serotypes 0-:K66 (47). Strain KT707 shows only one OMP with an Mr of about 36,000 in the range of 35,000 to 40,000 (47). Strains KT717 (47) and KT791 (an isogenic mutant from strain C3) (5) are serum-resistant O1:Kstrains. Luria broth or nutrient broth was used for bacterial growth and phage propagation (33). Human sera. A pool of nonimmune human sera (NHS) was obtained from healthy volunteers. NHS diluted 1/100 did not react with OMP from K pneumoniae KT793 in Western blot (immunoblot) experiments. NHS was made deficient in Clq Vol. 61, No. 3

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“…14 Because this complement-attenuating effect of IVIG might represent an important therapeutic effect in clinical applications where complement is involved in the pathogenic process, we addressed the question whether IVIG stimulated inactivation of C3b-containing complexes in vivo. C3b-containing complexes comprise a population of ester-linked complexes 14,[17][18][19][20][21][22] of which the most abundant ones carry 2 C3b and another plasma protein, primarily IgG. 14,17,21 We selected dermatomyositis (DM) for our studies because it is associated with complement activation beyond C3, with deposition of C5b to 9 to endomysial capillaries, 13 and patients may profit from high-dose IVIG treatment.…”

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

Lutz

Stammler

Bianchi

et al. 2004

Blood

104

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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...

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C3 binds covalently to the Cγ3 domain of IgG immune aggregates during complement activation by the alternative pathway

Cited by 30 publications

References 35 publications

The internal thioester and the covalent binding properties of the complement proteins C3 and C4

The internal thioester and the covalent binding properties of the complement proteins C3 and C4

C1q binding and activation of the complement classical pathway by Klebsiella pneumoniae outer membrane proteins

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

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