A Hierarchical Role for Classical Pathway Complement Proteins in the Clearance of Apoptotic Cells in Vivo

By Philip R. Taylor, A. Carugati, Valerie Fadok, H. Cook, M. Andrews, Michael C. Carroll, J. Savill, Peter M. Henson, Marina Botto, Mark J. Walport. Journal of Experimental Medicine, 2000

797 citations recorded by the source corpus.

The strongest susceptibility genes for the development of systemic lupus erythematosus (SLE) in humans are null mutants of classical pathway complement proteins. There is a hierarchy of disease susceptibility and severity according to the position of the missing protein in the activation pathway, with the severest disease associated with C1q deficiency. Here we demonstrate, using novel in vivo models of apoptotic cell clearance during sterile peritonitis, a similar hierarchical role for classical pathway complement proteins in vivo in the clearance of apoptotic cells by macrophages. Our results constitute the first demonstration of an impairment in the phagocytosis of apoptotic cells by macrophages in vivo in a mammalian system. Apoptotic cells are thought to be a major source of the autoantigens of SLE, and impairment of their removal by complement may explain the link between hereditary complement deficiency and the development of SLE.

Subfields: Immunology, Nephrology

View Paper: https://www.semanticscholar.org/paper/329787d6a0b8f70f16b8a5bb26f74fc6ef7a3c2e

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. C. Serhan
2. P. Henson
3. S. Gordon
4. Valerie Fadok
5. H. Hemmi
6. J. Savill
7. M. O’Banion
8. T. Wyss‐Coray

Citations in the corpus

• Inflammatory processes in Alzheimer's disease. (2007, background): “Studies of mutant mice lacking complement proteins suggest that impaired phagocytosis can result in immunemediated tissue damage and inflammation (Botto, 1998; Taylor et al., 2000).”
• Corpse clearance defines the meaning of cell death (2000, background): “These include C1q, the first component of complement, for which a bridging role in vivo has been confirmed by elegant studies demonstrating the defective clearance of apoptotic cells in deletion-mutant mic”
• From T to B and back again: positive feedback in systemic autoimmune disease (2001, background): “In addition, defects in mechanisms of clearing apoptotic cells or immune complexes, such as complement, Fc receptor or phagocytic defects, serve to elevate the absolute concentration of available auto-antige”
• A blast from the past: clearance of apoptotic cells regulates immune responses (2002, background): “Indeed, the defective clearance of apoptotic cells has been linked closely to autoimmune and persistent inflammatory disease”
• Dendritic cells: translating innate to adaptive immunity. (2006, background): “Some receptors that have been implicated in uptake include scavenger receptors [106], the phosphatidyl serine receptor [107], certain integrins [108, 109], CD91/calreticulin [110], CD14 [111], C1qR [112], CD93 or C1qRp [113], and CD36 [114].”
• The role of complement in inflammatory diseases from behind the scenes into the spotlight. (2007, result): “For example, gene polymorphisms associated with lower levels of MBL are found in higher frequencies in patients with SLE, and, conversely, polymorphisms that result in high levels of MBL expression are underrepresented in patients with SLE.63 Although homozygous complement deficiencies are extremely”
• Phagocytosis: An Immunobiologic Process. (2016, background): “Deficient clearance of apoptotic cells by C1q receptors contributes to autoimmune diseases (Taylor et al., 2000) and possibly systemic lupus erythematosus.”
• The complement system: an unexpected role in synaptic pruning during development and disease. (2012, background): “Binding of C1q to any of these molecules can initiate the complement cascade, leading to either lysis or phagocytosis , because C1q has recently been identified as crucial for promoting phagocytosis of apoptotic cells in vivo (Taylor et al. 2000, Nauta et al. 2003).”
• Resolution of inflammation: the beginning programs the end (2005, positive): “Although much new information has been obtained over the past few years, many issues still require detailed characterization, including why defective macrophage clearance of apoptotic cells may sometimes be associated with inflammatory diseas”
• C1q and Mannose Binding Lectin Engagement of Cell Surface Calreticulin and Cd91 Initiates Macropinocytosis and Uptake of Apoptotic Cells (2001, background): “Abnormal clearance of apoptotic cells with inappropriate levels of apoptotic nuclei have been suggested to contribute to SLE (14) and the knockout mice also show a defect in clearance of apoptotic cells in vivo (15).”