Antibodies can initiate
lung injury in a variety of disease states such as autoimmunity,
transfusion reactions, or after
organ transplantation, but the key factors determining in vivo pathogenicity of injury-inducing
antibodies are unclear. A previously overlooked step in complement activation by
IgG antibodies has been elucidated involving interactions between
IgG Fc domains that enable assembly of
IgG hexamers, which can optimally activate the
complement cascade. Here, we tested the in vivo relevance of
IgG hexamers in a
complement-dependent alloantibody model of
acute lung injury. We used three approaches to block alloantibody hexamerization (antibody carbamylation, the K439E Fc mutation, or treatment with domain B from
Staphylococcal protein A), all of which reduced
acute lung injury. Conversely, Fc mutations promoting spontaneous hexamerization made a harmful alloantibody into a more potent inducer of
acute lung injury and rendered an innocuous alloantibody pathogenic. Treatment with a recombinant Fc hexamer 'decoy' therapeutic protected mice from
lung injury, including in a model with transgenic human FCGR2A expression that exacerbated pathology. These results indicate a direct in vivo role of
IgG hexamerization in initiating
acute lung injury and the potential for
therapeutics that inhibit or mimic hexamerization to treat antibody-mediated diseases.