Complement classical pathway components are all important in clearance of apoptotic and secondary necrotic cells

Abstract

SummaryInherited deficiencies in components of the classical complement pathway are strong disease susceptibility factors for the development of systemic lupus erythematosus (SLE) and there is a hierarchy among deficiency states, the strongest association being with C1q deficiency. We investigated the relative importance of the different complement pathways regarding clearance of apoptotic cells. Phagocytosis of labelled apoptotic Jurkat cells by monocytederived macrophages in the presence of sera from individuals with complement deficiencies was studied, as well as C3 deposition on apoptotic cells using flow cytometry. Sera from individuals deficient in C1q, C4, C2 or C3 all showed decreased phagocytosis. Mannose binding lectin (MBL) and the alternative pathway did not influence phagocytosis. Notably, the components of the complement classical pathway, including C1q, were equally important in clearance of apoptotic cells. This indicates that deposition of C3 fragments is of major significance; we therefore studied C3 deposition on apoptotic cells. Experiments with MBL-deficient serum depleted of C1q or factor D confirmed the predominance of the classical pathway. At low dilution, sera deficient of C1q, C4 or C2 supported C3 fragment deposition demonstrating alternative pathway activation. In conclusion, we have found that complement-mediated opsonization and phagocytosis of apoptotic cells, particularly those undergoing secondary necrosis, are dependent mainly upon an intact classical pathway. The alternative pathway is less important, but may play a role in some conditions. C1q was not more important than other classical pathway components, suggesting a role in additional pathogenetic processes in SLE other than clearance of apoptotic cells.

Increased IgG on cell‐derived plasma microparticles in systemic lupus erythematosus is associated with autoantibodies and complement activation

“…Indeed, in our previous study we found decreased numbers of MPs in SLE patients (20). Also, in the case of dead and dying cells, autoantibodies appear to promote complement-dependent phagocytosis (16,18,47,48). In the present study, we found that the concentration of annexin V-positive MPs was inversely correlated with the IgG MFI, supporting the notion that MP opsonization may enhance MP clearance.…”

Alternative Complement Pathway Activation Products in Urine and Kidneys of Patients with ANCA-Associated GN

“…However, the urinary levels of C1q and MBL in AAV patients in remission stage were still significantly higher than those levels in normal controls, which suggested that activation of the classic and lectin pathways might be not pathogenic in AAV. The complement components in the classic and lectin pathways were found to have functions for clearing apoptotic and necrotic cells (25,26). Both MBL and C1q could bind to apoptotic cells and initiate their uptake into macrophages.…”

The dual role of complement in cancer and its implication in anti-tumor therapy

“…This variation in the macrophage repertoire and function is tumor type and stage specific and is extensively reviewed by Biswas and Mantovani (46). Activated macrophages produce C3 and participate in complement-initiated phagocytosis of intruding entities, while they are also involved in the clearance of apoptotic and necrotic cells (47). Moreover, C5aR signaling in TLRactivated macrophages selectively inhibits the transcription of genes that encode the IL-12 cytokine family, that in turn drive the polarization and recruitment of Th1 cells (48).…”