Complement activation by human IgG antibodies to galactose-α-1,3-galactose

Area of Science:

• Immunology
• Microbiology
• Complement System

Background:

• Human antibodies can paradoxically inhibit complement activation, enhancing pathogen survival.
• IgG antibodies targeting terminal galactose-α-1,3-galactose (IgG anti-αGal) were previously claimed to inhibit complement.
• These IgG anti-αGal antibodies are naturally occurring and abundant, targeting various pathogens.

Purpose of the Study:

• To reinvestigate the effects of IgG anti-αGal on complement activation.
• To determine if IgG anti-αGal activates or inhibits complement pathways.
• To clarify the role of IgG anti-αGal in host defense against pathogens.

Main Methods:

• Isolated IgG anti-αGal from human serum.
• Used flow cytometry to assess antibody binding and complement deposition on pig erythrocytes, Escherichia coli O86, and Streptococcus pneumoniae 9V.
• Employed specific nanobodies to block complement factors and identify involved pathways.

Main Results:

• IgG anti-αGal activated the classical complement pathway on all tested target cells.
• Complement activation degree correlated with antibody density, with variations between cell types.
• The alternative pathway amplified complement deposition, and C3 fragment deposition obscured IgG anti-αGal detection.

Conclusions:

• IgG anti-αGal possesses inherent complement-activating properties, similar to normal human IgG.
• Previously reported complement inhibition by IgG anti-αGal likely resulted from suboptimal assay configurations.
• This study demonstrates the complement-activating capacity of IgG anti-αGal, challenging prior assumptions.