Human IgA Fc Receptor FcαRI (CD89) Triggers Different Forms of Neutrophil Death Depending on the Inflammatory Microenvironment

Wehrli, Marc; Cortinas-Elizondo, Fabiola; Hlushchuk, Ruslan; Daudel, Fritz; Villiger, Peter M.; Miescher, Sylvia; Zuercher, Adrian W.; Djonov, Valentin; Simon, Hans‐Uwe; Gunten, Stephan von

doi:10.4049/jimmunol.1400028

Cited by 33 publications

(50 citation statements)

References 56 publications

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“…mIgA also induces death in activated neutrophils (14) and inhibits complement deposition mediated by anti-ganglioside antibodies (15). The anti-inflammatory effects of mIgA have been explored in various experimental models (10–13, 16).…”

Section: Introductionmentioning

confidence: 99%

Monomeric Immunoglobulin A from Plasma Inhibits Human Th17 Responses In Vitro Independent of FcαRI and DC-SIGN

et al. 2017

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Circulating immunoglobulins including immunoglobulin G (IgG) and IgM play a critical role in the immune homeostasis by modulating functions of immune cells. These functions are mediated in part by natural antibodies. However, despite being second most abundant antibody in the circulation, the immunoregulatory function of IgA is relatively unexplored. As Th17 cells are the key mediators of a variety of autoimmune, inflammatory, and allergic diseases, we investigated the ability of monomeric IgA (mIgA) isolated from pooled plasma of healthy donors to modulate human Th17 cells. We show that mIgA inhibits differentiation and amplification of human Th17 cells and the production of their effector cytokine IL-17A. mIgA also suppresses IFN-γ responses under these experimental conditions. Suppressive effect of mIgA on Th17 responses is associated with reciprocal expansion of FoxP3-positive regulatory T cells. The effect of mIgA on Th17 cells is dependent on F(ab′)2 fragments and independent of FcαRI (CD89) and DC-SIGN. Mechanistically, the modulatory effect of mIgA on Th17 cells implicates suppression of phosphorylation of signal transducer and activator of transcription 3. Furthermore, mIgA binds to CD4+ T cells and recognizes in a dose-dependent manner the receptors for cytokines (IL-6Rα and IL-1RI) that mediate Th17 responses. Our findings thus reveal novel anti-inflammatory functions of IgA and suggest potential therapeutic utility of mIgA in autoimmune and inflammatory diseases that implicate Th17 cells.

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Section: Introductionmentioning

confidence: 99%

Monomeric Immunoglobulin A from Plasma Inhibits Human Th17 Responses In Vitro Independent of FcαRI and DC-SIGN

et al. 2017

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“…Human neutrophils were isolated from peripheral blood of healthy donors by density gradient centrifugation, as previously described 73 . Briefly, granulocytes and erythrocytes were separated from peripheral blood mononuclear cells (PBMCs) by density gradient using Pancoll (Pan-Biotech, Aidenbach, Germany).…”

Section: Methodsmentioning

confidence: 99%

“…Cell death was assessed by uptake of 1 μM ethidium bromide (Invitrogen, Lucerne, Switzerland) and subsequent flow cytometric analysis (FACSVerse; Becton Dickinson Biosciences) as previously described 73 . Redistribution of phosphatidylserine (PS) in presence of propidium iodide (PI; Sigma-Aldrich, Buchs, Switzerland) and DNA fragmentation were assessed by flow cytometry as previously described 73 .…”

Section: Methodsmentioning

confidence: 99%

“…Redistribution of phosphatidylserine (PS) in presence of propidium iodide (PI; Sigma-Aldrich, Buchs, Switzerland) and DNA fragmentation were assessed by flow cytometry as previously described 73 . Recombinant His6-tagged annexin V-FITC, Fas-Ligand (FasL, at 100 ng/ml) and FasL cross-linker (anti-FLAG at 2 μg/ml) were from Alexis (Enzo) and Sigma, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…Anti-Siglec-9 (Becton Dickinson Bioscience, Allschwil, Switzerland) was used at 35 μg/ml in combination with 20 μg/ml unlabeled F(ab’) 2 fragments of secondary GaM Ab (Jackson ImmunoResearch Laboratories, Baltimore, US). Specific cell death was calculated as previously described 73 : …”

Section: Methodsmentioning

confidence: 99%

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IVIG regulates the survival of human but not mouse neutrophils

Schneider

Wicki

Graeter

et al. 2017

Sci Rep

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Intravenous immunoglobulin (IVIG) are purified IgG preparations made from the pooled plasma from thousands of healthy donors and are being tested in preclinical mouse models. Inherent challenges, however, are the pluripotency of IVIG and its xenogeneicity in animals. IVIG can alter the viability of human neutrophils via agonistic antibodies to Fas and Siglec-9. In this study, we compared the effects of IVIG on human and mouse neutrophils using different death assays. Different commercial IVIG preparations similarly induced cytokine-dependent death in human neutrophils, whereas they had no effects on the survival of either peripheral blood or bone marrow neutrophils from C57BL/6 or BALB/c mice. F(ab’)2 but not Fc fragments of IVIG induced death of human neutrophils, whereas neither of these IVIG fragments, nor agonistic monoclonal antibodies to human Fas or Siglec-9 affected the viability of mouse neutrophils. Pooled mouse IgG, which exhibited a different immunoprofile compared to IVIG, also had no effect on mouse cells. Together, these observations demonstrate that effects of IVIG on neutrophil survival are not adequately reflected in current mouse models, despite the key role of these cells in human inflammatory and autoimmune diseases.

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Impact of IgA isoforms on their ability to activate dendritic cells and to prime T cells

et al. 2020

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Human IgA could be from different isotypes (IgA1/IgA2) and/or isoforms (monomeric, dimeric, or secretory). Monomeric IgA mainly IgA1 are considered as an anti‐inflammatory isotype whereas dimeric/secretory IgA have clearly dual pro‐ and anti‐inflammatory effects. Here, we show that IgA isotypes and isoforms display different binding abilities to FcαRI, Dectin‐1, DC‐SIGN, and CD71 on monocyte‐derived dendritic cells (moDC). We describe that IgA regulate the expression of their own receptors and trigger modulation of moDC maturation. We also demonstrate that dimeric IgA2 and IgA1 induce different inflammatory responses leading to cytotoxic CD8+ T cells activation. moDC stimulation by dimeric IgA2 was followed by a strong pro‐inflammatory effect. Our study highlights differences regarding IgA isotypes and isoforms in the context of DC conditioning. Further investigations are needed on the activation of adaptive immunity by IgA in the context of microbiota/IgA complexes during antibody‐mediated immune selection.

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Human IgA Fc Receptor FcαRI (CD89) Triggers Different Forms of Neutrophil Death Depending on the Inflammatory Microenvironment

Cited by 33 publications

References 56 publications

Monomeric Immunoglobulin A from Plasma Inhibits Human Th17 Responses In Vitro Independent of FcαRI and DC-SIGN

Monomeric Immunoglobulin A from Plasma Inhibits Human Th17 Responses In Vitro Independent of FcαRI and DC-SIGN

IVIG regulates the survival of human but not mouse neutrophils

Impact of IgA isoforms on their ability to activate dendritic cells and to prime T cells

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