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A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo
P R Taylor1, A Carugati, V A Fadok
1Rheumatology Section, Imperial College School of Medicine, Hammersmith Hospital, London W12 0NN, United Kingdom.
Insights
Deficiencies in complement proteins, crucial for clearing apoptotic cells, are linked to systemic lupus erythematosus (SLE). Impaired clearance by macrophages in vivo explains this connection, highlighting complement
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- Systemic lupus erythematosus (SLE) susceptibility is strongly linked to genetic defects in classical pathway complement proteins.
- A hierarchy of disease severity exists, with C1q deficiency correlating with the most severe SLE.
- Apoptotic cells are implicated as a source of autoantigens in SLE.
Purpose of the Study:
- To investigate the in vivo role of classical pathway complement proteins in the clearance of apoptotic cells.
- To establish a mammalian model demonstrating impaired phagocytosis of apoptotic cells.
- To elucidate the mechanism linking complement deficiency to SLE pathogenesis.
Main Methods:
- Utilized novel in vivo models of sterile peritonitis to study apoptotic cell clearance.
- Assessed the function of classical pathway complement proteins in macrophage-mediated phagocytosis.
- Analyzed the hierarchical impact of complement protein deficiencies on apoptotic cell clearance.
Main Results:
- Demonstrated a hierarchical role for classical pathway complement proteins in vivo during apoptotic cell clearance by macrophages.
- Provided the first in vivo evidence in a mammalian system of impaired phagocytosis of apoptotic cells.
- Confirmed that complement protein deficiencies impact the clearance of apoptotic cells.
Conclusions:
- Impaired clearance of apoptotic cells by macrophages due to complement deficiencies contributes to SLE development.
- The findings establish a direct link between hereditary complement deficiencies and the pathogenesis of SLE.
- This study offers novel insights into the immunological mechanisms underlying SLE.
Abstract:
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.