Immunoglobulin G-dependent inhibition of inflammatory bone remodeling requires pattern recognition receptor Dectin-1

Seeling, Michaela; Pöhnl, Matthias; Kara, Sibel; Horstmann, Nathalie; Riemer, Carolina; Wöhner, Miriam; Liang, Chunguang; Brückner, Christin; Eiring, Patrick; Werner, Anja; Biburger, Markus; Altmann, Leon; Schneider, Martin; Amon, Lukas; Lehmann, Christian; Lee, Sooyeon; Kunz, Meik; Dudziak, Diana; Schett, Georg; Bäuerle, Tobias; Lux, Anja; Tuckermann, Jan; Vögtle, Timo; Nieswandt, Bernhardt; Sauer, Markus; Böckmann, Rainer A.; Nimmerjahn, Falk

doi:10.1016/j.immuni.2023.02.019

Cited by 13 publications

(8 citation statements)

References 80 publications

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“…More recently, Seeling et al identified a novel role for the C-type lectin Dectin-1 (CLEC7A) in IVIg's ability to ameliorate bone erosion in mouse models of arthritis. Their findings suggest that Dectin-1 on monocytes modulates both FcγRIIb binding and ITIM phosphorylation via promotion of FcγRIIb membrane clustering [49]. Such findings highlight the numerous possible mechanisms by which IgGs can exert their anti-inflammatory activity.…”

Section: Discussionmentioning

confidence: 95%

Inhibitory Fc-Gamma IIb Receptor Signaling Induced by Multivalent IgG-Fc Is Dependent on Sialylation

Beneduce,

Nguyen,

Washburn

et al. 2023

Cells

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Immunoglobulin (IgG) Fc glycosylation has been shown to be important for the biological activity of antibodies. Fc sialylation is important for the anti-inflammatory activity of IgGs. However, evaluating the structure–activity relationship (SAR) of antibody Fc glycosylation has been hindered using simplified in vitro models in which antibodies are often displayed in monomeric forms. Presenting antibodies in monomeric forms may not accurately replicate the natural environment of the antibodies when binding their antigen in vivo. To address these limitations, we used different Fc-containing molecules, displaying their Fc domains in monovalent and multivalent fashion. Given the inhibitory role of Fc gamma receptor IIb (FcγRIIb) in autoimmune and inflammatory diseases, we focused on evaluating the impact of Fc sialylation on the activation of FcγRIIb. We report for the first time that in human cellular systems, sialic acid mediates the induction of FcγRIIb phosphorylation by IgG-Fc when the IgG-Fc is displayed in a multivalent fashion. This effect was observed with different types of therapeutic agents such as sialylated anti-TNFα antibodies, sialylated IVIg and sialylated recombinant multivalent Fc products. These studies represent the first report of the specific effects of Fc sialylation on FcγRIIb signaling on human immune cells and may help in the characterization of the anti-inflammatory activity of Fc-containing therapeutic candidates.

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Section: Discussionmentioning

confidence: 95%

Inhibitory Fc-Gamma IIb Receptor Signaling Induced by Multivalent IgG-Fc Is Dependent on Sialylation

Beneduce,

Nguyen,

Washburn

et al. 2023

Cells

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“…The molecular docking simulations were conducted to analyze the binding mechanisms of BTL-I derivatives against FcγRIIB. , As shown in Figure and Table S5, BTL-I and BTL-MK bound to FcγRIIB in a highly overlapped way, and the interacting residues of the two inhibitors were the same. BTL-I and BTL-MK formed two hydrogen bonds with His85, one hydrogen bond with Glu101, a π–σ interaction with Leu100, and other hydrophobic interactions (alkyl and π-alkyl) with Ile19 as well as Val 170.…”

Section: Results and Discussionmentioning

confidence: 99%

Lead Optimization of Butyrolactone I as an Orally Bioavailable Antiallergic Agent Targeting FcγRIIB

Xie,

Xiao,

Song

et al. 2024

J. Med. Chem.

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Food allergy (FA) poses a growing global food safety concern, yet no effective cure exists in clinics. Previously, we discovered a potent antifood allergy compound, butyrolactone I (BTL-I, 1), from the deep sea. Unfortunately, it has a very low exposure and poor pharmacokinetic (PK) profile in rats. Therefore, a series of structural optimizations toward the metabolic pathways of BTL-I were conducted to provide 18 derives (2−19). Among them, BTL-MK (19) showed superior antiallergic activity and favorable pharmacokinetics compared to BTL-I, being twice as potent with a clearance (CL) rate of only 0.5% that of BTL-I. By oral administration, C max and area under the concentration−time curve (AUC 0−∞ ) were 565 and 204 times higher than those of BTL-I, respectively. These findings suggest that butyrolactone methyl ketone (BTL-BK) could serve as a drug candidate for the treatment of FAs and offer valuable insights into optimizing the druggability of lead compounds.

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“…An increase in individuals with higher baseline inflammatory immune states (e.g., obesity, unhealthy diet, altered metabolome and microbiome), which is characterized by low levels of galactosylation and sialylation, may be responsible for more frequent shifts to allergic inflammatory phenotypes. The level of Fc galactosylation and sialylation of the overall (total) serum IgG acts as a vast immunological buffer system by regulating the expression of activating and inhibitory FcγRs and can be controlled, for example, by pregnancy and IVIg treatment [59,61,63,[84][85][86].…”

Section: The Impact Of Antibody Ig-fc Glycosylation On Allergy Develo...mentioning

confidence: 99%

The B Cell Response and Formation of Allergenic and Anti-Allergenic Antibodies in Food Allergy

Udoye,

Ehlers,

Manz

2023

Biology

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Food allergies are a growing public health concern worldwide, especially in children and young adults. Allergen-specific IgE plays a central role in the pathogenesis of food allergies, but their titers poorly correlate with allergy development. Host immune systems yield allergen-specific immunoglobulin (Ig)A, IgE and IgG subclasses with low or high affinities and differential Fc N-glycosylation patterns that can affect the allergic reaction to food in multiple ways. High-affinity IgE is required to induce strong mast cell activation eventually leading to allergic anaphylaxis, while low-affinity IgE can even inhibit the development of clinically relevant allergic symptoms. IgA and IgG antibodies can inhibit IgE-mediated mast cell activation through various mechanisms, thereby protecting IgE-positive individuals from allergy development. The production of IgE and IgG with differential allergenic potential seems to be affected by the signaling strength of individual B cell receptors, and by cytokines from T cells. This review provides an overview of the diversity of the B cell response and the diverse roles of antibodies in food allergy.

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Immunoglobulin G-dependent inhibition of inflammatory bone remodeling requires pattern recognition receptor Dectin-1

Cited by 13 publications

References 80 publications

Inhibitory Fc-Gamma IIb Receptor Signaling Induced by Multivalent IgG-Fc Is Dependent on Sialylation

Inhibitory Fc-Gamma IIb Receptor Signaling Induced by Multivalent IgG-Fc Is Dependent on Sialylation

Lead Optimization of Butyrolactone I as an Orally Bioavailable Antiallergic Agent Targeting FcγRIIB

The B Cell Response and Formation of Allergenic and Anti-Allergenic Antibodies in Food Allergy

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