Curvature of Synthetic and Natural Surfaces Is an Important Target Feature in Classical Pathway Complement Activation

Abstract

The binding of Abs to microbial surfaces followed by complement activation constitutes an important line of defense against infections. In this study, we have investigated the relationship between complement activation and the binding of human IgM Abs to surfaces with different curvatures. IgM Abs to dextran were shown to activate complement potently on dextran-coated particles having a diameter around 250 nm, whereas larger (600 nm) particles were less potent activators. This selectivity regarding particle dimension was also found for complement activation by colloidal substances of microbial origin. Peptidoglycan (PGN) is the major chemical component in the cell wall of Gram-positive bacteria. Fragments of purified PGN with sizes of ∼100 nm promoted complement activation effectively through the classical pathway. By contrast, larger or smaller fragments of PGN did not activate complement strongly. A careful analysis of PGN fragments released during planctonic growth of Staphylococcus aureus showed that these include curvatures that would permit strong IgM-mediated complement activation, whereas the curvature of intact cells would be less effective for such activation. Consistently, we found that the suspended PGN fragments were strong activators of complement through the classical pathway. We suggest that these fragments act as decoy targets for complement activation, providing protection for S. aureus against the host immune response to infection.

The Nanoscience of Polyvalent Binding by Proteins in the Immune Response

“…Furthermore, the ability of Perkins et al to obtain a full-size envelope from the SAXS studies [27] suggests a level of rigidity in the soluble molecule, which would be inconsistent with a highly fluctuating structure. Finally, functional data supported by structural calculations presented by Pedersen et al [29] also support the idea that appropriate conformational change in IgM is critical for complement activation. In these studies, human sera were incubated with iron oxide nanoparticles (NPs) coated with dextran.…”

Liposome-induced complement activation and related cardiopulmonary distress in pigs: factors promoting reactogenicity of Doxil and AmBisome

“…The coffee-bean, or American football-like oval appearance of Doxil is widely documented in the literature; what our presented cryo-TEM images highlight for the first time to our knowledge is that this shape change may be related to the length and bulkiness of doxorubicin crystals within liposomes. Considering that C activation proceeds on membrane surfaces whose curvature is an important factor 45 in determining the buildup of multimolecular complexes, such as the C3 convertases (C4b2b or C3bBb) and C5 convertases (C4b2b3b or C3bBb3b), the low-curvature parts in the case of oval Doxil vesicles, together with the visibly large, incongruent surfaces on aggregates, may explain, at least in part, the increased reactogenicity of Doxil.…”

The Role of Nanometer-Scaled Ligand Patterns in Polyvalent Binding by Large Mannan-Binding Lectin Oligomers

“…Consequently, the sensitivity of the MBL 3 oligomers to ligand spacing in the nanometer range is likely to play a role with regard to the binding of MBL to microbial surfaces and, hence, the function of MBL in the immune system. Similar to the surface binding by other large proteins of the humoral immune system, such as IgM (70,71), for MBL there also appears to be a close link between the topological presentation of ligand and the outcome in terms of MBL deposition.…”