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Letter to the EditorImmunologyPulmonology
Open Access | 
10.1172/JCI182451
Reply: The importance of disrupting complement activation in acute lung injury
Simon J. Cleary1,2 and Mark R. Looney1
1Department of Medicine, UCSF, San Francisco, USA.
2Institute of Pharmaceutical Sciences, King’s College London, London, United Kingdom.
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1Department of Medicine, UCSF, San Francisco, USA.
2Institute of Pharmaceutical Sciences, King’s College London, London, United Kingdom.
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Published June 17, 2024 - More info
J Clin Invest. 2024;134(12):e182451. https://doi.org/10.1172/JCI182451.
© 2024 Cleary, et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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Abstract
Antibodies can initiate lung injury in a variety of disease states such as autoimmunity, in reactions to transfusions, 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 the assembly of IgG hexamer structures that activate C1 complexes. The importance of IgG hexamers in initiating injury responses was not clear, so we tested their relevance in a mouse model of alloantibody- and complement-mediated acute lung injury. We used 3 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.
Authors
Simon J. Cleary, Yurim Seo, Jennifer J. Tian, Nicholas Kwaan, David P. Bulkley, Arthur E.H. Bentlage, Gestur Vidarsson, Éric Boilard, Rolf Spirig, James C. Zimring, Mark R. Looney
Abstract
Authors
Rick Kapur, John W. Semple, Alexander P.J. Vlaar
The authors reply: We appreciate the letter from Kapur and colleagues and are glad to be in agreement on the importance of the complement cascade in experimental transfusion-related acute lung injury (TRALI) (1). We have also measured increased complement activation in clinical TRALI (2), but as complement deposition and lung injury occur within a few minutes in mouse models of TRALI (2, 3), and various mitigation strategies have been effective in preventing clinical TRALI (4), we struggle to take an optimistic view on therapeutic or prophylactic use of complement inhibitors to ameliorate or prevent TRALI. We are hopeful that recombinant IgG Fc hexamers or complement therapeutics might improve outcomes in patients at high risk of developing antibody-mediated rejection (AbMR) following solid-organ transplantation or in other diseases, such as COVID-19. Recent approvals of therapeutics targeting IgG (imlifidase for desensitization to prevent AbMR, ref. 5) or C1s (sutimlimab for cold agglutinin disease, ref. 6) demonstrate that inhibiting “upstream” antibody effectors is feasible, and these approaches would be expected to preserve some of the immune protection mediated by membrane attack complexes. Determining the importance of IgG Fc-Fc interactions and different complement components in antibody-mediated diseases will help to improve diagnostics and therapeutics.
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ISSN: 0021-9738 (print), 1558-8238 (online)