Complement in removal of the dead - balancing inflammation.

Area of Science:

• Immunology
• Cell Biology
• Innate Immunity

Background:

• Efficient clearance of apoptotic and necrotic cells is vital for preventing inflammation and autoimmunity.
• The complement system, a key innate immunity component, mediates this clearance process.
• Dysfunctional clearance is linked to autoimmune diseases like systemic lupus erythematosus.

Purpose of the Study:

• To elucidate the role of the complement system, particularly factor H, in the clearance of dying cells.
• To understand how complement regulators prevent autoimmunity during cell clearance.
• To investigate the link between impaired complement-mediated clearance and autoimmune conditions.

Main Methods:

• Investigated the recognition of dying cells by complement initiators (C1q, MBL, ficolins, properdin).
• Analyzed complement activation, opsonization with C3b fragments, and phagocytosis.
• Studied the function of complement inhibitors (C4b-binding protein, factor H) in regulating inflammation.
• Examined the internalization of factor H by apoptotic cells and its intracellular functions.

Main Results:

• Complement initiators recognize and activate complement on dying cells, leading to C3b opsonization and phagocytosis.
• Complement inhibitors, especially factor H, control inflammation by attenuating complement activation.
• Factor H is internalized by apoptotic cells, catalyzing intracellular C3 cleavage to C3b, further enhancing clearance.
• Internalized factor H binds nucleosomes, directing monocytes to produce anti-inflammatory cytokines.

Conclusions:

• The complement system, regulated by factor H, ensures efficient and safe removal of dying cells, preventing autoimmunity.
• Impaired complement-mediated clearance leads to autoantigen persistence and autoimmune disease development.
• Factor H's dual role in cell surface opsonization and intracellular functions is critical for immune homeostasis.