The quantitative role of alternative pathway amplification in classical pathway induced terminal complement activation

Abstract

SUMMARYComplement activation with formation of biologically potent mediators like C5a and the terminal C5b-9 complex (TCC) contributes essentially to development of inflammation and tissue damage in a number of autoimmune and inflammatory conditions. A particular role for complement in the ischaemia/ reperfusion injury of the heart, skeletal muscle, central nervous system, intestine and kidney has been suggested from animal studies. Previous experiments in C3 and C4 knockout mice suggested an important role of the classical or lectin pathway in initiation of complement activation during intestinal ischaemia/reperfusion injury while later use of factor D knockout mice showed the alternative pathway to be critically involved. We hypothesized that alternative pathway amplification might play a more critical role in classical pathway-induced C5 activation than previously recognized and used pathwayselective inhibitory mAbs to further elucidate the role of the alternative pathway. Here we demonstrate that selective blockade of the alternative pathway by neutralizing factor D in human serum diluted 1 : 2 with mAb 166-32 inhibited more than 80% of C5a and TCC formation induced by solid phase IgM and solid-and fluid-phase human aggregated IgG via the classical pathway. The findings emphasize the influence of alternative pathway amplification on the effect of initial classical pathway activation and the therapeutic potential of inhibiting the alternative pathway in clinical conditions with excessive and uncontrolled complement activation.

Candidate inhibitors of porcine complement

“…In the 50's properdin was proposed as an initiator of this pathway and recent evidence supports these early findings (61,62). Another and very important function of the AP is amplification of the complement respons initiated by the other two pathways (63). All the recognition molecules of the complement system (e. g. C1q, MBL, ficolins and properdin) are PRRs, as they recognize PAMPs and alarmins and mediate the danger signals through complement-activation (8).…”

Improved ex vivo blood compatibility of central venous catheter with noble metal alloy coating

“…The activation of the complement system is one of the most significant challenges when blood is exposed to foreign materials 16, 17, 18, 19. Measures of C3a and SC5b‐9, also called Terminal Complement Complex (TCC), are widely used as complement activation markers.…”

Cancer and the Complement Cascade

“…C3b has diverse effects that include opsonization of target surfaces and promotion of the alternative pathway amplification loop. In this loop, C3b generated by the alternative pathway C3 convertase or through the classic or mannose-binding lectin (MBL) pathways binds factor B to form the C3bBb convertase, propagating further C3b production and self-amplification (45,46). Because factor B is central to this amplification Abbreviations: BAD, bcl-xL/bcl-2-associated death promoter; Bcl-2, B-cell lymphoma-2; bFGF, basic fibroblast growth factor; BID, bcl-2 interacting domain; CDK, cyclin-dependent kinase; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; FasL, Fas ligand; HGF, hepatocyte growth factor; IGF, insulin-like growth factor; IGFBP, insulin-like growth factor binding protein; IL-6, interleukin-6; JAK-STAT, Janus activated kinase-signal transducer and activated transcription; JNK, c-jun amino terminal kinase; MAPK, mitogen-activated protein kinase; MDSC, myeloid-derived suppressor cells; MEK-1, mitogen-activated protein kinase or ERK kinase-1; METr, mesenchymal-epithelial transition receptor; MMP-9, matrix metalloproteinase 9; PI3K, phosphatidylinositol 3-kinase; PDGF, platelet-derived growth factor; PKC, protein kinase C; RGC, response gene to complement; ROS/RNS, reactive oxygen species/reactive nitrogen species; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α; VEGF, vascular endothelial growth factor.…”