Opposite Regulation of Type II and III Receptors for Immunoglobulin G in Mouse Glomerular Mesangial Cells and in the Induction of Anti-glomerular Basement Membrane (GBM) Nephritis

Radeke, Heinfried H.; Janssen-Graalfs, Iska; Sowa, Eveline; Chouchakova, Nelli; Skokowa, Julia; Löscher, Fabian; Schmidt, Reinhold; Heeringa, Peter; Gessner, J. Engelbert

doi:10.1074/jbc.m200419200

Cited by 81 publications

(88 citation statements)

References 58 publications

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“…In addition, enhanced development of IC inflammation was seen in mice lacking the inhibitory FcgRII ( [37]; Fig. 7B), and similar results were now obtained with the FcgRII-specific blocking Ab, Ly17.2 [35], supporting the current view that the balance of activating FcgRIII and inhibitory FcgRII signals is of prime importance in IC disease [37][38][39][40]. Importantly, however, the Arthus reaction was fully prevented not only in FcgRIII KO mice but also in B6 mice treated with the 9E9 FcgRIV-blocking Ab (Fig.…”

Section: Discussionsupporting

confidence: 70%

Both FcγRIV and FcγRIII are essential receptors mediating type II and type III autoimmune responses via FcRγ‐LAT‐dependent generation of C5a

et al. 2009

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FcγRIV is a relatively new IgG Fc receptor (FcγR) that is reported to contribute to the pathogenesis of autoimmune diseases, although its specific role in relation to FcγRIII, complement and IgG2 subclasses remains uncertain. Here we define FcγRIV on macrophages as a receptor for soluble IgG2a/b complexes but not for cellular bound IgG2a and show that simultaneous activation of FcγRIV and FcγRIII is critical to mediate certain type II/III autoimmune responses. FcγRIII‐deficient mice display compensatory enhanced FcγRIV expression, are protected from lung inflammation after deposition of IgG complexes, and show reduced sensitivity to IgG2a/b‐mediated hemolytic anemia, indicating that increased FcγRIV alone is not sufficient to trigger these diseases in the absence of FcγRIII. Importantly, however, blockade of FcγRIV is also effective in inhibiting phagocytosis and cytokine production in IgG2b‐induced anemia and acute lung injury, processes that display a further dependence on C5a anaphylatoxin receptor. Using gene deletion and functional inhibition studies, we found that FcγRIII and FcγRIV are each essential to trigger an FcRγ‐linker for activation of T‐cell‐dependent signal that drives C5a production in the Arthus reaction. Together, the results demonstrate a combined requirement for FcγRIII and FcγRIV in autoimmune injury, and identify the linker for activation of T cells adaptor as an integral component of linked FcγR and C5a anaphylatoxin receptor activation to generate inflammation.

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Section: Discussionsupporting

confidence: 70%

Both FcγRIV and FcγRIII are essential receptors mediating type II and type III autoimmune responses via FcRγ‐LAT‐dependent generation of C5a

et al. 2009

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“…1B). However, expression of FcgRIIb on intrinsic renal cells has previously been reported (11), and an FcgRIIb on intrinsic renal cells was suggested by experiments in which a blocking anti-FcgRIIb Ab was injected under the kidney capsule (17). We therefore sought to determine whether there was a contribution of disease susceptibility from intrinsic renal cells to explain the slightly increased susceptibility to disease in the full FcgRIIb 2/2 mice compared with FcgRIIb fl/fl /CEBPaCre + mice.…”

Section: Role Of Fcgriib In Intrinsic Renal Cellsmentioning

confidence: 99%

“…This could be due to increased Ab production by FcgRIIb-deficient B cell lineages or, alternatively, due to increased myeloid cell activation. Mesangial cells have also been shown to express FcgRIIb (11,12), adding another possible checkpoint in the prevention of severe Abmediated glomerulonephritis.…”

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confidence: 99%

FcγRIIb on Myeloid Cells and Intrinsic Renal Cells Rather than B Cells Protects from Nephrotoxic Nephritis

Sharp

Martín-Ramírez

Mangsbo

et al. 2013

The Journal of Immunology

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FcγRIIb is the sole inhibitory FcR for IgG in humans and mice, where it is involved in the negative regulation of Ab production and cellular activation. FcγRIIb-deficient mice show exacerbated disease following the induction of nephrotoxic nephritis (NTN). In this study, we determined the cellular origin of the FcγRIIb-knockout phenotype by inducing NTN in mice with a deficiency of FcγRIIb on either B cells alone (FcγRIIBfl/fl/CD19Cre+) or myeloid cells (FcγRIIBfl/fl/CEBPαCre+). Deletion of FcγRIIb from B cells did not increase susceptibility to NTN, compared with wild-type (WT) mice, despite higher Ab titers in the FcγRIIBfl/fl/CD19Cre+ mice compared with the WT littermate controls. In contrast, mice lacking FcγRIIb on myeloid cells had exacerbated disease as measured by increased glomerular thrombosis, glomerular crescents, albuminuria, serum urea, and glomerular neutrophil infiltration when compared with WT littermate controls. The role for FcγRIIb expression on radioresistant intrinsic renal cells in the protection from NTN was then investigated using bone marrow chimeric mice. FcγRIIb−/− mice transplanted with FcγRIIb−/− bone marrow were more susceptible to NTN than WT mice transplanted with FcγRIIb−/− bone marrow, indicating that the presence of WT intrinsic renal cells protects from NTN. These results demonstrate that FcγRIIb on myeloid cells plays a major role in protection from NTN, and therefore, augmentation of FcγRIIb on these cells could be a therapeutic target in human Ab-mediated glomerulonephritis. Where there was a lack of FcγRIIb on circulating myeloid cells, expression of FcγRIIb on intrinsic renal cells provided an additional level of protection from Ab-mediated glomerulonephritis.

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“…Compelling evidence suggests that the ratio of the opposing signaling Fc␥R is critical in setting the cellular thresholds for the pathogenic activity of autoantibodies (reviewed in Refs. 10 -12) and that C5a regulates this ratio, thus amplifying the Fc␥R-mediated inflammatory response in autoimmunity (8,(13)(14)(15).…”

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confidence: 99%

Phosphoinositide 3-Kinases γ and δ, Linkers of Coordinate C5a Receptor-Fcγ Receptor Activation and Immune Complex-induced Inflammation

Konrad¹,

Ali²,

Wiege³

et al. 2008

Journal of Biological Chemistry

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Fc␥ receptors (Fc␥R) and the C5a receptor (C5aR) are key effectors of the acute inflammatory response to IgG immune complexes (IC). Their coordinated activation is critical in ICinduced diseases, although the significance of combined signaling by these two different receptor classes in tissue injury is unclear. Here we used the mouse model of the passive reverse lung Arthus reaction to define their requirements for distinct phosphoinositide 3-kinase (PI3K) activities in vivo. We show that genetic deletion of class IB PI3K␥ abrogates C5aR signaling that is crucial for Fc␥R-mediated activation of lung macrophages. Thus, in PI3K␥ ؊/؊ mice, IgG IC-induced Fc␥R regulation, cytokine release, and neutrophil recruitment were blunted. Notably, however, C5a production occurred normally in PI3K␥ ؊/؊ mice but was impaired in PI3K␦ ؊/؊ mice. Consequently, class IA PI3K␦ deficiency caused resistance to acute IC lung injury. These results demonstrate that PI3K␥ and PI3K␦ coordinate the inflammatory effects of C5aR and Fc␥R and define PI3K␦ as a novel and essential element of Fc␥R signaling in the generation of C5a in IC disease.

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Opposite Regulation of Type II and III Receptors for Immunoglobulin G in Mouse Glomerular Mesangial Cells and in the Induction of Anti-glomerular Basement Membrane (GBM) Nephritis

Cited by 81 publications

References 58 publications

Both FcγRIV and FcγRIII are essential receptors mediating type II and type III autoimmune responses via FcRγ‐LAT‐dependent generation of C5a

Both FcγRIV and FcγRIII are essential receptors mediating type II and type III autoimmune responses via FcRγ‐LAT‐dependent generation of C5a

FcγRIIb on Myeloid Cells and Intrinsic Renal Cells Rather than B Cells Protects from Nephrotoxic Nephritis

Phosphoinositide 3-Kinases γ and δ, Linkers of Coordinate C5a Receptor-Fcγ Receptor Activation and Immune Complex-induced Inflammation

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