Advertisement
ResearchIn-Press PreviewPulmonologyTransplantation Open Access | 10.1172/JCI178351
1Department of Medicine, UCSF, San Francisco, United States of America
2Department of Biochemistry and Biophysics, UCSF, San Francisco, United States of America
3Department of Experimental Immunohematology, Sanquin Research, Amsterdam, Netherlands
4Infectious and Immune Diseases, Research Center of the University Hospital of Quebec - Laval University, Quebec, Canada
5Research, CSL Behring Biologics Research Center, Bern, Switzerland
6Department of Pathology, University of Virginia School of Medicine, Charlottesville, United States of America
Find articles by Cleary, S. in: JCI | PubMed | Google Scholar |
1Department of Medicine, UCSF, San Francisco, United States of America
2Department of Biochemistry and Biophysics, UCSF, San Francisco, United States of America
3Department of Experimental Immunohematology, Sanquin Research, Amsterdam, Netherlands
4Infectious and Immune Diseases, Research Center of the University Hospital of Quebec - Laval University, Quebec, Canada
5Research, CSL Behring Biologics Research Center, Bern, Switzerland
6Department of Pathology, University of Virginia School of Medicine, Charlottesville, United States of America
Find articles by Seo, Y. in: JCI | PubMed | Google Scholar
1Department of Medicine, UCSF, San Francisco, United States of America
2Department of Biochemistry and Biophysics, UCSF, San Francisco, United States of America
3Department of Experimental Immunohematology, Sanquin Research, Amsterdam, Netherlands
4Infectious and Immune Diseases, Research Center of the University Hospital of Quebec - Laval University, Quebec, Canada
5Research, CSL Behring Biologics Research Center, Bern, Switzerland
6Department of Pathology, University of Virginia School of Medicine, Charlottesville, United States of America
Find articles by Tian, J. in: JCI | PubMed | Google Scholar |
1Department of Medicine, UCSF, San Francisco, United States of America
2Department of Biochemistry and Biophysics, UCSF, San Francisco, United States of America
3Department of Experimental Immunohematology, Sanquin Research, Amsterdam, Netherlands
4Infectious and Immune Diseases, Research Center of the University Hospital of Quebec - Laval University, Quebec, Canada
5Research, CSL Behring Biologics Research Center, Bern, Switzerland
6Department of Pathology, University of Virginia School of Medicine, Charlottesville, United States of America
Find articles by Kwaan, N. in: JCI | PubMed | Google Scholar |
1Department of Medicine, UCSF, San Francisco, United States of America
2Department of Biochemistry and Biophysics, UCSF, San Francisco, United States of America
3Department of Experimental Immunohematology, Sanquin Research, Amsterdam, Netherlands
4Infectious and Immune Diseases, Research Center of the University Hospital of Quebec - Laval University, Quebec, Canada
5Research, CSL Behring Biologics Research Center, Bern, Switzerland
6Department of Pathology, University of Virginia School of Medicine, Charlottesville, United States of America
Find articles by Bulkley, D. in: JCI | PubMed | Google Scholar
1Department of Medicine, UCSF, San Francisco, United States of America
2Department of Biochemistry and Biophysics, UCSF, San Francisco, United States of America
3Department of Experimental Immunohematology, Sanquin Research, Amsterdam, Netherlands
4Infectious and Immune Diseases, Research Center of the University Hospital of Quebec - Laval University, Quebec, Canada
5Research, CSL Behring Biologics Research Center, Bern, Switzerland
6Department of Pathology, University of Virginia School of Medicine, Charlottesville, United States of America
Find articles by Bentlage, A. in: JCI | PubMed | Google Scholar |
1Department of Medicine, UCSF, San Francisco, United States of America
2Department of Biochemistry and Biophysics, UCSF, San Francisco, United States of America
3Department of Experimental Immunohematology, Sanquin Research, Amsterdam, Netherlands
4Infectious and Immune Diseases, Research Center of the University Hospital of Quebec - Laval University, Quebec, Canada
5Research, CSL Behring Biologics Research Center, Bern, Switzerland
6Department of Pathology, University of Virginia School of Medicine, Charlottesville, United States of America
Find articles by Vidarsson, G. in: JCI | PubMed | Google Scholar |
1Department of Medicine, UCSF, San Francisco, United States of America
2Department of Biochemistry and Biophysics, UCSF, San Francisco, United States of America
3Department of Experimental Immunohematology, Sanquin Research, Amsterdam, Netherlands
4Infectious and Immune Diseases, Research Center of the University Hospital of Quebec - Laval University, Quebec, Canada
5Research, CSL Behring Biologics Research Center, Bern, Switzerland
6Department of Pathology, University of Virginia School of Medicine, Charlottesville, United States of America
Find articles by Boilard, É. in: JCI | PubMed | Google Scholar |
1Department of Medicine, UCSF, San Francisco, United States of America
2Department of Biochemistry and Biophysics, UCSF, San Francisco, United States of America
3Department of Experimental Immunohematology, Sanquin Research, Amsterdam, Netherlands
4Infectious and Immune Diseases, Research Center of the University Hospital of Quebec - Laval University, Quebec, Canada
5Research, CSL Behring Biologics Research Center, Bern, Switzerland
6Department of Pathology, University of Virginia School of Medicine, Charlottesville, United States of America
Find articles by Spirig, R. in: JCI | PubMed | Google Scholar
1Department of Medicine, UCSF, San Francisco, United States of America
2Department of Biochemistry and Biophysics, UCSF, San Francisco, United States of America
3Department of Experimental Immunohematology, Sanquin Research, Amsterdam, Netherlands
4Infectious and Immune Diseases, Research Center of the University Hospital of Quebec - Laval University, Quebec, Canada
5Research, CSL Behring Biologics Research Center, Bern, Switzerland
6Department of Pathology, University of Virginia School of Medicine, Charlottesville, United States of America
Find articles by Zimring, J. in: JCI | PubMed | Google Scholar
1Department of Medicine, UCSF, San Francisco, United States of America
2Department of Biochemistry and Biophysics, UCSF, San Francisco, United States of America
3Department of Experimental Immunohematology, Sanquin Research, Amsterdam, Netherlands
4Infectious and Immune Diseases, Research Center of the University Hospital of Quebec - Laval University, Quebec, Canada
5Research, CSL Behring Biologics Research Center, Bern, Switzerland
6Department of Pathology, University of Virginia School of Medicine, Charlottesville, United States of America
Find articles by Looney, M. in: JCI | PubMed | Google Scholar |
Published March 26, 2024 - More info
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.