Uncoupling complement C1s activation from C1q binding in apoptotic cell phagocytosis and immunosuppressive capacity

Area of Science:

• Immunology
• Cell Biology

Background:

• Complement activation plays a dual role in inflammation and the clearance of apoptotic cells (AC).
• Dissecting the specific roles of complement components in AC phagocytosis is challenging using traditional methods.
• The classical complement pathway and its components, like C1q and C1s, are involved in AC clearance and immune regulation.

Purpose of the Study:

• To differentiate the roles of C1s enzymatic activity from C1q opsonization in the phagocytosis and immunosuppressive effects of AC.
• To evaluate the therapeutic potential of inhibiting C1s using TNT003 in human in vitro systems.

Main Methods:

• Utilized human in vitro systems to study AC phagocytosis and immunosuppression.
• Employed the novel antibody complement C1s inhibitor TNT003.
• Differentiated the effects of C1s inhibition from C1q's opsonizing function.

Main Results:

• C1s inhibition had a minor effect on the clearance of early AC.
• The immunosuppressive properties of early AC remained unaffected by C1s inhibition.
• C1s inhibition significantly impaired the phagocytosis of late apoptotic/secondary necrotic cells.

Conclusions:

• C1s inhibition selectively targets late apoptotic cell clearance, sparing early AC clearance and their immunosuppressive functions.
• Targeting C1s may be a viable therapeutic approach to manage classical complement pathway activation in diseases.
• This strategy could control inflammation without causing substantial AC accumulation, particularly in conditions without inherent phagocytosis defects.