IgG hexamers initiate 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. 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.
| Errataetall: | |
|---|---|
| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
|---|---|
| Enthalten in: |
bioRxiv : the preprint server for biology - (2024) vom: 27. Jan. |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Cleary, Simon J [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
|---|
| Anmerkungen: |
Date Revised 08.04.2024 published: Electronic UpdateIn: J Clin Invest. 2024 Mar 26;:. - PMID 38530369 Citation Status PubMed-not-MEDLINE |
|---|
| doi: |
10.1101/2024.01.24.577129 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM368172767 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM368172767 | ||
| 003 | DE-627 | ||
| 005 | 20240408232331.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240208s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1101/2024.01.24.577129 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1369.xml |
| 035 | |a (DE-627)NLM368172767 | ||
| 035 | |a (NLM)38328049 | ||
| 035 | |a (PII)2024.01.24.577129 | ||
| 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 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: Electronic | ||
| 500 | |a UpdateIn: J Clin Invest. 2024 Mar 26;:. - PMID 38530369 | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 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. 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 | ||
| 650 | 4 | |a Preprint | |
| 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 bioRxiv : the preprint server for biology |d 2020 |g (2024) vom: 27. Jan. |w (DE-627)NLM31090014X |7 nnns |
| 773 | 1 | 8 | |g year:2024 |g day:27 |g month:01 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1101/2024.01.24.577129 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |j 2024 |b 27 |c 01 | ||