Complement Plays a Critical Role in Inflammation-Induced Immunoprophylaxis Failure in Mice

Area of Science:

• Immunology
• Transfusion Medicine
• Complement System

Background:

• Complement significantly influences both innate and adaptive immunity.
• Immunoprophylaxis using anti-KEL immunoglobulin (KELIg) prevents alloimmunization to transfused red blood cells (RBCs) in healthy recipients.
• Immunoprophylaxis efficacy is compromised in the presence of inflammatory stimuli.

Purpose of the Study:

• To investigate the role of complement in the failure of KELIg immunoprophylaxis during a viral-like inflammatory stimulus.
• To elucidate the mechanisms by which complement and inflammation interact to reduce immunoprophylaxis effectiveness.

Main Methods:

• Utilized a murine model expressing human KEL glycoprotein on RBCs.
• Administered KELIg and KEL RBCs to wild-type and complement-deficient (C3-/-, C1q-/-, CR1/2-/-) mice under baseline and viral-like stimulus conditions.
• Assessed anti-KEL IgG alloantibody generation, RBC uptake by monocytes, and B-cell binding to opsonized RBCs in vitro.

Main Results:

• Recipient C3 and C1q are essential for KELIg failure during viral-like inflammation; no alloantibodies were generated in C3-/- or C1q-/- mice.
• Mice lacking C3 exhibited reduced inflammatory monocyte-mediated RBC clearance.
• Mice lacking complement receptors (CR1/2-/-) showed no alloantibody production, implicating cells expressing these receptors in immunoprophylaxis failure.
• In vitro studies indicated reduced binding of complement-opsonized RBCs to B-cells from CR1/2-/- mice compared to wild-type.

Conclusions:

• A two-hit model is proposed for inflammation-induced immunoprophylaxis failure: inflammation (hit 1) and complement activation/sensing (hit 2).
• Complement receptor-expressing cells, particularly B-cells, may play a key role in overcoming immunoprophylaxis during inflammation.
• These findings have potential translational implications for understanding antigen-antibody interactions in human transfusion medicine.