Markedly Different Pathogenicity of Four Immunoglobulin G Isotype-Switch Variants of an Antierythrocyte Autoantibody Is Based on Their Capacity to Interact in Vivo with the Low-Affinity Fcγ Receptor III

Fossati-Jimack, Liliane; Ioan-Facsinay, A.; Reininger, Luc; Chicheportiche, Yves; Watanabe, Norihiko; Saito, Takashi; Hofhuis, F. M. A.; Gessner, J. Engelbert; Schiller, C.; Schmidt, Reinhold; Honjo, Tasuku; Verbeek, J. Sjef; Izui, Shozo

doi:10.1084/jem.191.8.1293

Cited by 163 publications

(166 citation statements)

References 56 publications

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“…For example, anti-CD20 mouse IgG1 mAb depletes mouse B cells predominantly through interactions with FcgRIII [29] and a similar finding has been reported in an anaphylaxis model [30]. Additionally, in the model of autoimmune hemolytic anemia in which Ab-mediated erythrophagocytosis is a major pathogenic mechanism, ADCP of mouse IgG1-coated erythrocytes depends on FcgRIII and the IgG1 Ab fails to trigger autoimmune hemolytic anemia in FcgRIII-deficient mice [30][31][32]. These reports and our findings suggest that mouse and rat IgG1 share common effector functions in mice despite the different target cells.…”

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confidence: 63%

In vivo depletion of CD4⁺FOXP3⁺ Treg cells by the PC61 anti‐CD25 monoclonal antibody is mediated by FcγRIII⁺ phagocytes

Setiady¹,

Coccia²,

Park³

2010

Eur J Immunol

198

180

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Depletion of CD4 1 CD25 1 FoxP3 1 Treg using PC61 mAb (anti-murine CD25 rat IgG1) is widely used to characterize Treg function in vivo. However, the mechanism of Treg depletion remains largely unknown. Herein, we report the PC61 mAb's mechanism of action. In peripheral blood, a single injection of PC61 mAb eliminated $70% of CD4 1 FoxP3 1 cells with the remaining Treg expressing low or no CD25. Functional blockade of Fcc receptors with 2.4G2 mAb significantly inhibited PC61 mAb activity. Furthermore, Fcc receptor (FccR)III À/À mice were resistant to Treg depletion. FccRIII is expressed on immune cells including NK cells and macrophages that are the major effector cells for Ab-dependentcellular-cytotoxicity and Ab-dependent-cellular-phagocytosis, respectively. Depletion of NK cells had no effect, whereas depletion of phagocytes, including macrophages, by clodronate liposome significantly inhibited Treg depletion. Furthermore, in vitro, PC61 mAb can mediate Ab-dependent-cellular-phagocytosis of CD25 1 cells by WT or FccRIIB À/À , but not FccRIII À/À , macrophages. Altogether these data demonstrate the critical role of FccRIII 1 phagocytes in mediating Treg depletion by PC61 mAb. This finding may be useful in guiding the development of human Treg targeting therapy.Key words: CD25 . Fcc receptor . PC61 Ab . Phagocytes . Treg Supporting Information available online IntroductionNaturally occurring Treg play a critical role in the maintenance of peripheral tolerance. They can suppress not only CD4 1 and CD8 1 T cells, but also NK cells, macrophages and dendritic cells [1]. Treg are marked by expression of FoxP3 1 transcription factor (Foxp3), which confers the Treg's regulatory activity. Induction of Foxp3 expression in naïve T cells can convert them into Treg [2,3]. Before the discovery of Foxp3, Treg were identified by expression of CD25, an IL-2 receptor a subunit. Initially, CD25 was simply considered a Treg marker that was not associated with Treg function because of its expression on activated T cells without suppressive activity. More recently, however, it became clear that CD25, thus also IL-2, is essential for the generation, peripheral expansion and maintenance of Treg. CD25-deficient mice and mice lacking IL-2 or Foxp3 have a reduced Treg number and spontaneously develop a fatal lymphoproliferative autoimmune syndrome that can be rescued by adoptive transfer of Treg from WT mice [1]. Temporary neutralization of IL-2 using anti-IL-2 mAb also reduces Treg number, induces autoimmune gastritis in BALB/c mice and accelerates autoimmune diabetes in NOD mice [4]. Additionally, ectopic expression of IL-2 receptor b in the thymus increases Treg production [5]. A recent study using transgenic mice expressing GFP-linked Foxp3 shows that the peripheral expansion of CD25 À Treg is significantly reduced compared with that of CD25 Results and discussion Treg depletion by PC61 mAbWe first tested the extent of Treg depletion after CD25 mAb injection in C57BL/6 mice. In naïve mice (Fig. 1A left panel), around 70% of CD4 1 Fo...

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confidence: 63%

In vivo depletion of CD4⁺FOXP3⁺ Treg cells by the PC61 anti‐CD25 monoclonal antibody is mediated by FcγRIII⁺ phagocytes

Setiady¹,

Coccia²,

Park³

2010

Eur J Immunol

198

180

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“…This elevated IgG2a in the PD-L2 -/-mice may contribute to the exacerbated disease observed in these mice. Interestingly, IgG2a has been reported to have the highest binding affinity to macrophages and FccR, while IgG1 has been reported to be a poor interactor [23,24]. The increased Leishmania-specific IgG2a in PD-L2 -/-mice may lead to increased binding of opsonized parasites to FccR and suppress protective immune responses.…”

Section: Pd-l2 -/-But Not Pd-l1 -/-Mice Exhibit Enhanced Levels Of Lmentioning

confidence: 99%

PD‐L1 and PD‐L2 have distinct roles in regulating host immunity to cutaneous leishmaniasis

et al. 2005

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To compare the roles of programmed death 1 ligand 1 (PD‐L1) and PD‐L2 in regulating immunity to infection, we investigated responses of mice lacking PD‐L1 or PD‐L2 to infection with Leishmania mexicana. PD‐L1–/– and PD‐L2–/– mice exhibited distinct disease outcomes following infection with L. mexicana. In comparison to susceptible WT mice, PD‐L1–/– mice showed resistance to L. mexicana, as demonstrated by reduced growth of cutaneous lesions and parasite burden. In contrast, PD‐L2–/– mice developed exacerbated disease with increased parasite burden. Host resistance to L. mexicana is partly associated with the development of a Th1 response and down‐regulation of the Th2 response. Both PD‐L1–/– and PD‐L2–/– mice produced levels of IFN‐γ similar to WT mice. However, the development of IL‐4‐producing cells was reduced in PD‐L1–/– mice, demonstrating a role for PD‐L1 in regulating Th cell differentiation. This inadequate Th2 response may explain the increased resistance of PD‐L1–/– mice. Although no alterations in Th1/Th2 skewing were observed in PD‐L2–/– mice, PD‐L2–/– mice exhibited a marked increase in L. mexicana‐specific antibody production. Increased Leishmania‐specific IgG production may suppress the healing response through FcγR ligation on macrophages. Taken together, our results demonstrate that PD‐L1 and PD‐L2 have distinct roles in regulating the immune response to L. mexicana.

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“…It has been shown that some IgG subclasses are more pathogenic than others (39)(40)(41)(42). We therefore examined glomerular deposition of IgG1, IgG2a, IgG2b, and IgG3 (Fig.…”

Section: Proteinuria Kidney Histopathology and Ic Depositionmentioning

confidence: 99%

Expression of Natural Autoantibodies in MRL-lpr Mice Protects from Lupus Nephritis and Improves Survival

Mannoor

Matejuk

et al. 2012

The Journal of Immunology

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Natural autoantibodies (NAA) and their associated B cells constitute a substantial proportion of the normal Ab and B cell repertoire. They often have weak reactivity toward a variety of self-Ags such as DNA, nucleoproteins, and phospholipids. It remains controversial whether NAA contribute to or protect from autoimmune diseases. Using site-directed transgenic (sd-tg) mice expressing a prototypic NAA, we investigated the effect of NAA and NAA-producing B cells in disease development in the autoimmune-prone MRL/MpJ-Faslpr (MRL-lpr) mice. We found that the expression of NAA in MRL-lpr mice prevented proteinuria and reduced kidney immune complex formation. The mice had significantly improved survival. Administration of the IgM NAA to MRL-lpr mice also delayed the onset of nephritis. The sd-tg MRL-lpr mice had decreased levels of anti-dsDNA Abs, anti-Hep2 nuclear Abs, and anti-Sm/ribonucleoprotein Abs. There is a shift in the IgG subclass profile from IgG2a and IgG3 to IgG1 in the sd-tg MRL-lpr mice. The CD4+ T cells from the sd-tg MRL-lpr mice had increased expression of the negative costimulatory molecule CTLA-4 and increased production of IL-10 as compared with those from the wild-type mice. Furthermore, the NAA B cells produced large amounts of IL-10 upon TLR stimulation. These results indicate that NAA and NAA-producing B cells play an important role in protection from lupus nephritis and suggest that the NAA B cells may have an immune regulatory function via the provision of IL-10.

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Markedly Different Pathogenicity of Four Immunoglobulin G Isotype-Switch Variants of an Antierythrocyte Autoantibody Is Based on Their Capacity to Interact in Vivo with the Low-Affinity Fcγ Receptor III

Cited by 163 publications

References 56 publications

In vivo depletion of CD4⁺FOXP3⁺ Treg cells by the PC61 anti‐CD25 monoclonal antibody is mediated by FcγRIII⁺ phagocytes

In vivo depletion of CD4⁺FOXP3⁺ Treg cells by the PC61 anti‐CD25 monoclonal antibody is mediated by FcγRIII⁺ phagocytes

PD‐L1 and PD‐L2 have distinct roles in regulating host immunity to cutaneous leishmaniasis

Expression of Natural Autoantibodies in MRL-lpr Mice Protects from Lupus Nephritis and Improves Survival

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Markedly Different Pathogenicity of Four Immunoglobulin G Isotype-Switch Variants of an Antierythrocyte Autoantibody Is Based on Their Capacity to Interact in Vivo with the Low-Affinity Fcγ Receptor III

Cited by 163 publications

References 56 publications

In vivo depletion of CD4+FOXP3+ Treg cells by the PC61 anti‐CD25 monoclonal antibody is mediated by FcγRIII+ phagocytes

In vivo depletion of CD4+FOXP3+ Treg cells by the PC61 anti‐CD25 monoclonal antibody is mediated by FcγRIII+ phagocytes

PD‐L1 and PD‐L2 have distinct roles in regulating host immunity to cutaneous leishmaniasis

Expression of Natural Autoantibodies in MRL-lpr Mice Protects from Lupus Nephritis and Improves Survival

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In vivo depletion of CD4⁺FOXP3⁺ Treg cells by the PC61 anti‐CD25 monoclonal antibody is mediated by FcγRIII⁺ phagocytes

In vivo depletion of CD4⁺FOXP3⁺ Treg cells by the PC61 anti‐CD25 monoclonal antibody is mediated by FcγRIII⁺ phagocytes