Fc(gamma)RIIB regulates T-cell autoreactivity, ANCA production, and neutrophil activation to suppress anti-myeloperoxidase glomerulonephritis

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis involves innate and adaptive immune cells in the induction of autoimmunity and in autoimmune effector responses. Most Fcgamma receptors (FcgammaRs) activate immune cells, but FcgammaRIIB, found in humans and mice on B cells and innate cells, is an inhibitory receptor. Here we tested whether endogenous FcgammaRIIB negatively regulates autoreactivity and effector responses in experimental anti-myeloperoxidase (MPO) glomerulonephritis, using wild-type and FcgammaRIIB(-/-) mice. After MPO immunization, FcgammaRIIB(-/-) mice developed higher MPO-ANCA titers and increased anti-MPO T-cell responses. Transfer of FcgammaRIIB-deficient dendritic cells loaded with a nephritogenic MPO peptide (MPO409-428) into wild-type mice induced stronger autoimmunity than dendritic cells derived from wild-type mice. Transferring anti-MPO antibodies into lipopolysaccharide-primed mice resulted in increased glomerular neutrophil accumulation and injury in FcgammaRIIB(-/-) mice, showing a role for FcgammaRIIB in suppressing neutrophil activation. Inducing active autoimmunity to MPO followed by triggering T cell-mediated glomerular injury by transfer of sub-nephritogenic doses of lipopolysaccharide and anti-MPO antibodies resulted in more disease in FcgammaRIIB(-/-) mice. Thus, endogenous FcgammaRIIB negatively regulates anti-MPO autoimmunity and glomerulonephritis by dendritic cells, B cells, and neutrophils to limit MPO-ANCA production, T-cell responses, and neutrophil activation.
Original languageEnglish
Pages (from-to)1140 - 1149
Number of pages10
JournalKidney International
Volume86
Issue number6
DOIs
Publication statusPublished - 2014

Cite this

@article{c1d630e8db0e4c7e846136589081ef36,
title = "Fc(gamma)RIIB regulates T-cell autoreactivity, ANCA production, and neutrophil activation to suppress anti-myeloperoxidase glomerulonephritis",
abstract = "Anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis involves innate and adaptive immune cells in the induction of autoimmunity and in autoimmune effector responses. Most Fcgamma receptors (FcgammaRs) activate immune cells, but FcgammaRIIB, found in humans and mice on B cells and innate cells, is an inhibitory receptor. Here we tested whether endogenous FcgammaRIIB negatively regulates autoreactivity and effector responses in experimental anti-myeloperoxidase (MPO) glomerulonephritis, using wild-type and FcgammaRIIB(-/-) mice. After MPO immunization, FcgammaRIIB(-/-) mice developed higher MPO-ANCA titers and increased anti-MPO T-cell responses. Transfer of FcgammaRIIB-deficient dendritic cells loaded with a nephritogenic MPO peptide (MPO409-428) into wild-type mice induced stronger autoimmunity than dendritic cells derived from wild-type mice. Transferring anti-MPO antibodies into lipopolysaccharide-primed mice resulted in increased glomerular neutrophil accumulation and injury in FcgammaRIIB(-/-) mice, showing a role for FcgammaRIIB in suppressing neutrophil activation. Inducing active autoimmunity to MPO followed by triggering T cell-mediated glomerular injury by transfer of sub-nephritogenic doses of lipopolysaccharide and anti-MPO antibodies resulted in more disease in FcgammaRIIB(-/-) mice. Thus, endogenous FcgammaRIIB negatively regulates anti-MPO autoimmunity and glomerulonephritis by dendritic cells, B cells, and neutrophils to limit MPO-ANCA production, T-cell responses, and neutrophil activation.",
author = "Joshua Ooi and Gan, {Poh Yi} and Tong Chen and Eggenhuizen, {Peter James} and Janet Chang and Maliha Alikhan and Dragana Odobasic and Holdsworth, {Stephen Roger} and Kitching, {Arthur Richard}",
year = "2014",
doi = "10.1038/ki.2014.189",
language = "English",
volume = "86",
pages = "1140 -- 1149",
journal = "Kidney International",
issn = "0085-2538",
publisher = "Elsevier",
number = "6",

}

TY - JOUR

T1 - Fc(gamma)RIIB regulates T-cell autoreactivity, ANCA production, and neutrophil activation to suppress anti-myeloperoxidase glomerulonephritis

AU - Ooi, Joshua

AU - Gan, Poh Yi

AU - Chen, Tong

AU - Eggenhuizen, Peter James

AU - Chang, Janet

AU - Alikhan, Maliha

AU - Odobasic, Dragana

AU - Holdsworth, Stephen Roger

AU - Kitching, Arthur Richard

PY - 2014

Y1 - 2014

N2 - Anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis involves innate and adaptive immune cells in the induction of autoimmunity and in autoimmune effector responses. Most Fcgamma receptors (FcgammaRs) activate immune cells, but FcgammaRIIB, found in humans and mice on B cells and innate cells, is an inhibitory receptor. Here we tested whether endogenous FcgammaRIIB negatively regulates autoreactivity and effector responses in experimental anti-myeloperoxidase (MPO) glomerulonephritis, using wild-type and FcgammaRIIB(-/-) mice. After MPO immunization, FcgammaRIIB(-/-) mice developed higher MPO-ANCA titers and increased anti-MPO T-cell responses. Transfer of FcgammaRIIB-deficient dendritic cells loaded with a nephritogenic MPO peptide (MPO409-428) into wild-type mice induced stronger autoimmunity than dendritic cells derived from wild-type mice. Transferring anti-MPO antibodies into lipopolysaccharide-primed mice resulted in increased glomerular neutrophil accumulation and injury in FcgammaRIIB(-/-) mice, showing a role for FcgammaRIIB in suppressing neutrophil activation. Inducing active autoimmunity to MPO followed by triggering T cell-mediated glomerular injury by transfer of sub-nephritogenic doses of lipopolysaccharide and anti-MPO antibodies resulted in more disease in FcgammaRIIB(-/-) mice. Thus, endogenous FcgammaRIIB negatively regulates anti-MPO autoimmunity and glomerulonephritis by dendritic cells, B cells, and neutrophils to limit MPO-ANCA production, T-cell responses, and neutrophil activation.

AB - Anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis involves innate and adaptive immune cells in the induction of autoimmunity and in autoimmune effector responses. Most Fcgamma receptors (FcgammaRs) activate immune cells, but FcgammaRIIB, found in humans and mice on B cells and innate cells, is an inhibitory receptor. Here we tested whether endogenous FcgammaRIIB negatively regulates autoreactivity and effector responses in experimental anti-myeloperoxidase (MPO) glomerulonephritis, using wild-type and FcgammaRIIB(-/-) mice. After MPO immunization, FcgammaRIIB(-/-) mice developed higher MPO-ANCA titers and increased anti-MPO T-cell responses. Transfer of FcgammaRIIB-deficient dendritic cells loaded with a nephritogenic MPO peptide (MPO409-428) into wild-type mice induced stronger autoimmunity than dendritic cells derived from wild-type mice. Transferring anti-MPO antibodies into lipopolysaccharide-primed mice resulted in increased glomerular neutrophil accumulation and injury in FcgammaRIIB(-/-) mice, showing a role for FcgammaRIIB in suppressing neutrophil activation. Inducing active autoimmunity to MPO followed by triggering T cell-mediated glomerular injury by transfer of sub-nephritogenic doses of lipopolysaccharide and anti-MPO antibodies resulted in more disease in FcgammaRIIB(-/-) mice. Thus, endogenous FcgammaRIIB negatively regulates anti-MPO autoimmunity and glomerulonephritis by dendritic cells, B cells, and neutrophils to limit MPO-ANCA production, T-cell responses, and neutrophil activation.

UR - http://www.nature.com/ki/journal/v86/n6/pdf/ki2014189a.pdf

U2 - 10.1038/ki.2014.189

DO - 10.1038/ki.2014.189

M3 - Article

VL - 86

SP - 1140

EP - 1149

JO - Kidney International

JF - Kidney International

SN - 0085-2538

IS - 6

ER -