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. Harmful
antibodies often activate the
complement cascade. A model for how
IgG antibodies trigger complement activation involves interactions between
IgG Fc domains driving assembly of
IgG hexamer structures that activate C1 complexes. The importance of
IgG hexamers in initiating injury responses was unclear, so we tested their relevance in a mouse model of alloantibody and
complement-mediated
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 an 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.