Sialylation of IgG antibodies inhibits IgG-mediated allergic reactions

Epp, Alexandra; Hobusch, Juliane; Bartsch, Yannic C.; Petry, Janina; Lilienthal, Gina-Maria; Koeleman, Carolien A. M.; Eschweiler, Simon; Möbs, Christian; Hall, Ashley; Morris, Suzanne C.; Braumann, Dominique; Engellenner, Christine; Bitterling, Josephine; Rahmöller, Johann; Leliavski, Alexei; Thurmann, Robina; Collin, Mattias; Moremen, Kelley W.; Strait, Richard T.; Blanchard, Véronique; Petersen, Arnd; Gemoll, Timo; Habermann, Jens K.; Petersen, Frank; Nandy, Andreas; Kahlert, Helga; Hertl, Michael; Wuhrer, Manfred; Pfützner, Wolfgang; Jappe, Uta; Finkelman, Fred D.; Ehlers, Marc

doi:10.1016/j.jaci.2017.06.021

Cited by 32 publications

(48 citation statements)

References 51 publications

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“…For IgG, it has been shown that the composition of these sugars greatly affects IgG effector functions 29 . Mouse and in vitro experiments indicate that for example the presence of terminal galactose or sialic acid plays an important role in the decision if IgG acts pro-or anti-inflammatory [30][31][32] . While IgG contains only one conserved N-glycosylation site, IgA1 holds two and IgA2 even four conserved sites for N-glycosylation 33 (Fig.…”

Section: Resultsmentioning

confidence: 99%

IgA subclasses have different effector functions associated with distinct glycosylation profiles

et al. 2020

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Monomeric serum immunoglobulin A (IgA) can contribute to the development of various autoimmune diseases, but the regulation of serum IgA effector functions is not well defined. Here, we show that the two IgA subclasses (IgA1 and IgA2) differ in their effect on immune cells due to distinct binding and signaling properties. Whereas IgA2 acts pro-inflammatory on neutrophils and macrophages, IgA1 does not have pronounced effects. Moreover, IgA1 and IgA2 have different glycosylation profiles, with IgA1 possessing more sialic acid than IgA2. Removal of sialic acid increases the pro-inflammatory capacity of IgA1, making it comparable to IgA2. Of note, disease-specific autoantibodies in patients with rheumatoid arthritis display a shift toward the pro-inflammatory IgA2 subclass, which is associated with higher disease activity. Taken together, these data demonstrate that IgA effector functions depend on subclass and glycosylation, and that disturbances in subclass balance are associated with autoimmune disease.

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Section: Resultsmentioning

confidence: 99%

IgA subclasses have different effector functions associated with distinct glycosylation profiles

et al. 2020

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“…To investigate antigen-dependent interference between non-C1q-binding murine IgG1 and C1q-binding IgG2a, IgG2b, and IgG3 subclasses for C1q binding, we used TNP-specific murine monoclonal IgG1 (clone H5), IgG3 (clone 9A6), and IgG1, IgG2a, and IgG2b class-switch variant (sv; with identical VDJ sequences) Abs ( 10 , 19 , 33 , 34 , 36 , 37 ). Incubation of plate-bound TNP-Ficoll with different concentrations of single TNP-specific IgG subclasses and serum as a source of C1q showed preferential binding of C1q to IgG2a (sv), but also to IgG2b (sv) and IgG3 (9A6).…”

Section: Resultsmentioning

confidence: 99%

“…The TNP-specific monoclonal hybridoma IgG1 (clone H5) ( 10 , 11 , 19 , 33 , 34 ) and IgG1, IgG2a, and IgG2b class-switch variant (sv; with identical VDJ sequences) ( 19 ) Abs as well as the ovalbumin (OVA)-specific IgG1 (clone 4C9) ( 10 ) Abs were produced, purified and verified as described ( 19 ).…”

Section: Methodsmentioning

confidence: 99%

“…Furthermore, the effector function of IgG Abs depends on the type of IgG Fc glycosylation pattern. Non-(a)galactosylated IgG Abs are associated with pro-inflammatory functions, such as IgG autoAbs in rheumatoid arthritis patients, whereas galactosylated and sialylated IgG Abs have reduced inflammatory and even immunosuppressive potential ( 6 – 19 ). IgG Fc sialylation reduces the affinity to the classical FcγRs and, instead, promotes interaction with members of the sugar-binding C-type lectin receptor family ( 6 – 8 , 13 , 14 , 19 ).…”

Section: Introductionmentioning

confidence: 99%

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Potential of Murine IgG1 and Human IgG4 to Inhibit the Classical Complement and Fcγ Receptor Activation Pathways

et al. 2018

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IgG antibodies (Abs) mediate their effector functions through the interaction with Fcγ receptors (FcγRs) and the complement factors. The main IgG-mediated complement activation pathway is induced through the binding of complement C1q to IgG Abs. This interaction is dependent on antigen-dependent hexamer formation of human IgG1 and IgG3 to increase the affinity for the six-headed C1q molecule. By contrast, human IgG4 fails to bind to C1q. Instead, it has been suggested that human IgG4 can block IgG1 and IgG3 hexamerization required for their binding to C1q and activating the complement. Here, we show that murine IgG1, which functionally resembles human IgG4 by not interacting with C1q, inhibits the binding of IgG2a, IgG2b, and IgG3 to C1q in vitro, and suppresses IgG2a-mediated complement activation in a hemolytic assay in an antigen-dependent and IgG subclass-specific manner. From this perspective, we discuss the potential of murine IgG1 and human IgG4 to block the complement activation as well as suppressive effects of sialylated IgG subclass Abs on FcγR-mediated immune cell activation. Accumulating evidence suggests that both mechanisms seem to be responsible for preventing uncontrolled IgG (auto)Ab-induced inflammation in mice and humans. Distinct IgG subclass distributions and functionally opposite IgG Fc glycosylation patterns might explain different outcomes of IgG-mediated immune responses and provide new therapeutic options through the induction, enrichment, or application of antigen-specific sialylated human IgG4 to prevent complement and FcγR activation as well.

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“…In addition, IL-10 produced by T Reg cells orchestrates antibody production in allergies from IgE toward IgG4. IgG4 and IL-10 production is upregulated in a course of allergen-specific immunotherapies and inhibits IgE-mediated anaphylaxis ( Epp et al, 2018 ).…”

Section: Regulatory T Cells (T Reg ) In Health Andmentioning

confidence: 99%

Intrahepatic TH17/TReg Cells in Homeostasis and Disease—It’s All About the Balance

et al. 2020

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Both acute and chronic hepatic inflammation likely result from an imbalance in the T H 1/T H 2 cell response and can lead to liver fibrosis and end-stage liver disease. More recently, a novel CD4+ T helper cell subset was described, characterized by the production of IL-17 and IL-22. These T H 17 cells 50were predominantly implicated in host defense against infections and in autoimmune diseases. Interestingly, studies over the last 10 years revealed that the development of T H 17 cells favors pro-inflammatory responses in almost all tissues and there is a reciprocal relationship between T H 17 and T Reg cells. The balance between T H 17and T Reg cells is critical for immune reactions, especially in injured liver tissue and the return to immune homeostasis. The pathogenic contribution of T H 17 and T Reg cells in autoimmunity, acute infection, and chronic liver injury is diverse and varies among disease etiologies. Understanding the mechanisms underlying T H 17 cell development, recruitment, and maintenance, along with the suppression of T Reg cells, will inform the development of new therapeutic strategies in liver diseases. Active manipulation of the balance between pathogenic and regulatory processes in the liver may assist in the restoration of homeostasis, especially in hepatic inflammation.

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Sialylation of IgG antibodies inhibits IgG-mediated allergic reactions

Cited by 32 publications

References 51 publications

IgA subclasses have different effector functions associated with distinct glycosylation profiles

IgA subclasses have different effector functions associated with distinct glycosylation profiles

Potential of Murine IgG1 and Human IgG4 to Inhibit the Classical Complement and Fcγ Receptor Activation Pathways

Intrahepatic TH17/TReg Cells in Homeostasis and Disease—It’s All About the Balance

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