IgG hexamers initiate complement-dependent acute lung injury
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.
| Errataetall: | |
|---|---|
| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
|---|---|
| Enthalten in: |
The Journal of clinical investigation - (2024) vom: 26. März |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Cleary, Simon J [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Antigen |
|---|
| Anmerkungen: |
Date Revised 08.04.2024 published: Print-Electronic UpdateOf: bioRxiv. 2024 Jan 27;:. - PMID 38328049 Citation Status Publisher |
|---|
| doi: |
10.1172/JCI178351 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM370199316 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM370199316 | ||
| 003 | DE-627 | ||
| 005 | 20240408232841.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240328s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1172/JCI178351 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1369.xml |
| 035 | |a (DE-627)NLM370199316 | ||
| 035 | |a (NLM)38530369 | ||
| 035 | |a (PII)e178351 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Cleary, Simon J |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a IgG hexamers initiate complement-dependent acute lung injury |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Revised 08.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a UpdateOf: bioRxiv. 2024 Jan 27;:. - PMID 38328049 | ||
| 500 | |a Citation Status Publisher | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Antigen | |
| 650 | 4 | |a Immunoglobulins | |
| 650 | 4 | |a Innate immunity | |
| 650 | 4 | |a Pulmonology | |
| 650 | 4 | |a Transplantation | |
| 700 | 1 | |a Seo, Yurim |e verfasserin |4 aut | |
| 700 | 1 | |a Tian, Jennifer J |e verfasserin |4 aut | |
| 700 | 1 | |a Kwaan, Nicholas |e verfasserin |4 aut | |
| 700 | 1 | |a Bulkley, David P |e verfasserin |4 aut | |
| 700 | 1 | |a Bentlage, Arthur E H |e verfasserin |4 aut | |
| 700 | 1 | |a Vidarsson, Gestur |e verfasserin |4 aut | |
| 700 | 1 | |a Boilard, Éric |e verfasserin |4 aut | |
| 700 | 1 | |a Spirig, Rolf |e verfasserin |4 aut | |
| 700 | 1 | |a Zimring, James C |e verfasserin |4 aut | |
| 700 | 1 | |a Looney, Mark R |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t The Journal of clinical investigation |d 1924 |g (2024) vom: 26. März |w (DE-627)NLM000005487 |x 1558-8238 |7 nnns |
| 773 | 1 | 8 | |g year:2024 |g day:26 |g month:03 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1172/JCI178351 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |j 2024 |b 26 |c 03 | ||