PMID- 36189253
OWN - NLM
STAT- MEDLINE
DCOM- 20221004
LR  - 20230608
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 13
DP  - 2022
TI  - FcgammaRIV is required for IgG2c mediated enhancement of RBC alloimmunization.
PG  - 972723
LID - 10.3389/fimmu.2022.972723 [doi]
LID - 972723
AB  - Passive immunization with anti-D can prevent maternal alloimmunization to RhD 
      thereby preventing hemolytic disease of the fetus and newborn. Unexpectedly, 
      anti-D fails in some cases and some monoclonal anti-D preparations paradoxically 
      enhances alloimmunization. The underlying mechanisms modulating humoral 
      alloimmunization by anti-D are unknown. We previously reported that IgG antibody 
      subclasses differentially regulate alloimmunity in response to red blood cell 
      (RBC) transfusions in a mouse model; in particular, IgG2c significantly enhanced 
      RBC alloantibody responses. Initial mechanistic studies revealed that IgG2c:RBC 
      immune complexes were preferentially consumed by the splenic dendritic cell (DC) 
      subsets that play a role in RBC alloimmunization. The deletion of activating 
      Fc-gamma receptors (FcgammaRs) (i.e., FcgammaRI, FcgammaRIII, and FcgammaRIV) on DCs abrogated 
      IgG2c-mediated enhanced alloimmunization. Because DCs express high levels of 
      FcgammaRIV, which has high affinity for the IgG2c subclass, we hypothesized that 
      FcgammaRIV was required for enhanced alloimmunization. To test this hypothesis, 
      knockout mice and blocking antibodies were used to manipulate FcgammaR expression. 
      The data presented herein demonstrate that FcgammaRIV, but not FcgammaRI or FcgammaRIII, is 
      required for IgG2c-mediated enhancement of RBC alloantibody production. 
      Additionally, FcgammaRI is alone sufficient for IgG2c-mediated RBC clearance but not 
      for increased alloimmunization, demonstrating that RBC clearance can occur 
      without inducing alloimmunization. Together, these data, combined with prior 
      observations, support the hypothesis that passive immunization with an 
      RBC-specific IgG2c antibody increases RBC alloantibody production through FcgammaRIV 
      ligation on splenic conventional DCs (cDCs). This raises the question of whether 
      standardizing antibody subclasses in immunoprophylaxis preparations is desirable 
      and suggests which subclasses may be optimal for generating monoclonal anti-D 
      therapeutics.
CI  - Copyright (c) 2022 Qiu, Miller, Zotti, Santhanakrishnan, Hendrickson, Tredicine, 
      Stowell, Luckey, Zimring and Hudson.
FAU - Qiu, Annie
AU  - Qiu A
AD  - Department of Pathology and Cell Biology, Columbia University Irving Medical 
      Center, New York, NY, United States.
FAU - Miller, Anabel
AU  - Miller A
AD  - Department of Pathology and Cell Biology, Columbia University Irving Medical 
      Center, New York, NY, United States.
FAU - Zotti, Flavia Dei
AU  - Zotti FD
AD  - Department of Pathology and Cell Biology, Columbia University Irving Medical 
      Center, New York, NY, United States.
FAU - Santhanakrishnan, Manjula
AU  - Santhanakrishnan M
AD  - Department of Laboratory Medicine, Yale University School of Medicine, New Haven, 
      CT, United States.
FAU - Hendrickson, Jeanne E
AU  - Hendrickson JE
AD  - Department of Laboratory Medicine, Yale University School of Medicine, New Haven, 
      CT, United States.
FAU - Tredicine, Maria
AU  - Tredicine M
AD  - Department of Translational Medicine and Surgery, Section of General Pathology, 
      Universita Cattolica del Sacro Cuore, Rome, Italy.
FAU - Stowell, Sean R
AU  - Stowell SR
AD  - Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 
      Boston, MA, United States.
FAU - Luckey, Chance John
AU  - Luckey CJ
AD  - Department of Pathology, University of Virginia, Charlottesville, VA, United 
      States.
FAU - Zimring, James C
AU  - Zimring JC
AD  - Carter Immunology Center, University of Virginia, Charlottesville, VA, United 
      States.
AD  - Department of Pathology, University of Virginia School of Medicine, 
      Charlottesville, VA, United States.
FAU - Hudson, Krystalyn E
AU  - Hudson KE
AD  - Department of Pathology and Cell Biology, Columbia University Irving Medical 
      Center, New York, NY, United States.
LA  - eng
GR  - R01 HL135248/HL/NHLBI NIH HHS/United States
GR  - P01 HL132819/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20220913
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
RN  - 0 (Antibodies, Blocking)
RN  - 0 (Antigen-Antibody Complex)
RN  - 0 (Immunoglobulin G)
RN  - 0 (Isoantibodies)
SB  - IM
MH  - *Anemia, Hemolytic, Autoimmune
MH  - Animals
MH  - Antibodies, Blocking
MH  - *Antigen-Antibody Complex
MH  - Immunoglobulin G
MH  - Isoantibodies
MH  - Mice
MH  - Mice, Knockout
PMC - PMC9519184
OTO - NOTNLM
OT  - Fc receptor
OT  - alloantibody
OT  - antibody
OT  - antibody mediated enhancement
OT  - red blood cell
COIS- Although unrelated to the contents of this manuscript, KH has a sponsored 
      research agreement with Alpine Immune Sciences. JZ is a consultant for Rubius 
      Therapeutics and is the founder and CSO of Svalinn Therapeutics. The remaining 
      authors declare that the research was conducted in the absence of any commercial 
      or financial relationships that could be construed as a potential conflict of 
      interest.
EDAT- 2022/10/04 06:00
MHDA- 2022/10/05 06:00
PMCR- 2022/01/01
CRDT- 2022/10/03 05:18
PHST- 2022/06/18 00:00 [received]
PHST- 2022/08/18 00:00 [accepted]
PHST- 2022/10/03 05:18 [entrez]
PHST- 2022/10/04 06:00 [pubmed]
PHST- 2022/10/05 06:00 [medline]
PHST- 2022/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2022.972723 [doi]
PST - epublish
SO  - Front Immunol. 2022 Sep 13;13:972723. doi: 10.3389/fimmu.2022.972723. eCollection 
      2022.