IgG hexamers initiate complement-dependent acute lung injury.

Area of Science:

• Immunology
• Pathology
• Biochemistry

Background:

• Antibodies can cause lung injury in various conditions like autoimmunity and transplantation.
• The precise mechanisms by which antibodies induce injury in vivo remain incompletely understood.
• Complement activation is frequently observed with pathogenic antibodies, suggesting a key role.

Purpose of the Study:

• To investigate the role of IgG hexamer formation in initiating antibody- and complement-mediated acute lung injury.
• To evaluate the therapeutic potential of targeting IgG hexamerization.

Main Methods:

• Utilized a mouse model of alloantibody- and complement-mediated acute lung injury.
• Employed three distinct strategies to inhibit alloantibody hexamerization: antibody carbamylation, K439E Fc mutation, and staphylococcal protein A domain B treatment.
• Assessed the impact of Fc mutations that either promote or inhibit spontaneous hexamerization.
• Tested a recombinant Fc hexamer "decoy" therapeutic in injury models, including one with human FCGR2A expression.

Main Results:

• All three methods to block alloantibody hexamerization significantly reduced acute lung injury.
• Fc mutations promoting hexamerization increased the pathogenicity of a harmful alloantibody and rendered a non-pathogenic one harmful.
• The Fc hexamer decoy therapeutic successfully protected mice from lung injury.

Conclusions:

• IgG hexamerization plays a critical role in initiating acute lung injury in vivo.
• Targeting IgG hexamerization, either by inhibition or mimicry, represents a potential therapeutic strategy for antibody-mediated diseases.