Fc Gamma Receptors and Complement Component 3 Facilitate Anti-fVIII Antibody Formation.
Fc gamma receptors
alloimmunization
complement component 3
hemophilia
humoral immunity
inhibitors
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2020
2020
Historique:
received:
17
01
2020
accepted:
20
04
2020
entrez:
26
6
2020
pubmed:
26
6
2020
medline:
7
4
2021
Statut:
epublish
Résumé
Anti-factor VIII (fVIII) alloantibodies, which can develop in patients with hemophilia A, limit the therapeutic options and increase morbidity and mortality of these patients. However, the factors that influence anti-fVIII antibody development remain incompletely understood. Recent studies suggest that Fc gamma receptors (FcγRs) may facilitate recognition and uptake of fVIII by recently developed or pre-existing naturally occurring anti-fVIII antibodies, providing a mechanism whereby the immune system may recognize fVIII following infusion. However, the role of FcγRs in anti-fVIII antibody formation remains unknown. In order to define the influence of FcγRs on the development of anti-fVIII antibodies, fVIII was injected into WT or FcγR knockout recipients, followed by evaluation of anti-fVIII antibodies. Anti-fVIII antibodies were readily observed following fVIII injection into FcγR knockouts, with similar anti-fVIII antibody levels occurring in FcγR knockouts as detected in WT mice injected in parallel. As antibodies can also fix complement, providing a potential mechanism whereby anti-fVIII antibodies may influence anti-fVIII antibody formation independent of FcγRs, fVIII was also injected into complement component 3 (C3) knockout recipients in parallel. Similar to FcγR knockouts, C3 knockout recipients developed a robust response to fVIII, which was likewise similar to that observed in WT recipients. As FcγRs or C3 may compensate for each other in recipients only deficient in FcγRs or C3 alone, we generated mice deficient in both FcγRs and C3 to test for potential antibody effector redundancy in anti-fVIII antibody formation. Infusion of fVIII into FcγRs and C3 (FcγR × C3) double knockouts likewise induced anti-fVIII antibodies. However, unlike individual knockouts, anti-fVIII antibodies in FcγRs × C3 knockouts were initially lower than WT recipients, although anti-fVIII antibodies increased to WT levels following additional fVIII exposure. In contrast, infusion of RBCs expressing distinct alloantigens into FcγRs, C3 or FcγR × C3 knockout recipients either failed to change anti-RBC levels when compared to WT recipients or actually increased antibody responses, depending on the target antigen. Taken together, these results suggest FcγRs and C3 can differentially impact antibody formation following exposure to distinct alloantigens and that FcγRs and C3 work in concert to facilitate early anti-fVIII antibody formation.
Identifiants
pubmed: 32582142
doi: 10.3389/fimmu.2020.00905
pmc: PMC7295897
doi:
Substances chimiques
C3 protein, mouse
0
Complement C3
0
Isoantibodies
0
Isoantigens
0
Receptors, IgG
0
F8 protein, human
839MOZ74GK
Factor VIII
9001-27-8
Types de publication
Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
905Subventions
Organisme : NIGMS NIH HHS
ID : T32 GM008169
Pays : United States
Organisme : NHLBI NIH HHS
ID : U54 HL141981
Pays : United States
Organisme : NHLBI NIH HHS
ID : P01 HL132819
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL135575
Pays : United States
Organisme : NIH HHS
ID : DP5 OD019892
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL069769
Pays : United States
Organisme : NICHD NIH HHS
ID : K12 HD072245
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL141335
Pays : United States
Informations de copyright
Copyright © 2020 Zerra, Arthur, Chonat, Maier, Mener, Shin, Allen, Baldwin, Cox, Verkerke, Jajosky, Tormey, Meeks and Stowell.
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