<i>In Vitro</i> Modulation of Protective Antibody Responses by Estrogen, Progesterone and Interleukin‐6

Canellada, Andrea; Blois, Sandra M.; Gentile, Teresa; Idehu, Ricardo A Margni

doi:10.1034/j.1600-0897.2002.01141.x

Cited by 60 publications

(50 citation statements)

References 61 publications

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“…[18][19][20] The effects of progesterone in particular include inhibition of natural killer cell cytotoxicity via release of progesterone-induced blocking factor, increased production of IL-10 by dendritic cells, inhibition of Th1 development and induction of a Th2 response and increased antibody production. [21][22][23][24][25] There is also evidence to suggest that progesterone affects macrophage function. For example, it has been demonstrated that treatment of lipopolysaccharide (LPS)/interferon-c (IFN-c)-stimulated RAW 264.7 macrophages with progesterone results in a dose-dependent decrease in nitric oxide (NO) production, which is the result of a reduction in inducible nitric oxide synthase (iNOS) gene promotor activity and iNOS gene expression.…”

Section: Discussionmentioning

confidence: 99%

Toll‐like receptor‐4‐mediated macrophage activation is differentially regulated by progesterone via the glucocorticoid and progesterone receptors

et al. 2008

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Summary Macrophage function has been demonstrated to be subject to modulation by progesterone. However, as this steroid hormone can act through the glucocorticoid receptor as well as the progesterone receptor, the mechanism of action has not been precisely characterized. To determine the mode of action, we compared the ability of progesterone, norgestrel (a synthetic progesterone‐receptor‐specific agonist) and dexamethasone (a synthetic glucocorticoid receptor agonist) to modulate macrophage function following stimulation of the Toll‐like receptor‐4 (TLR‐4) ligand lipopolysaccharide (LPS). The results demonstrate that following stimulation of TLR‐4 with LPS and cotreatment with either progesterone or dexamethasone, but not norgestrel, there is a significant reduction in nitric oxide (NO) production, indicating that this progesterone‐mediated effect is through ligation of the glucocorticoid receptor. In contrast, LPS‐induced interleukin‐12 (IL‐12) production could be downregulated by all three steroids, indicating that ligation by progesterone of either the glucocorticoid or the progesterone receptors or both could mediate this effect. While progesterone downmodulated NO‐mediated killing of Leishmania donovani by activated macrophages in vitro, most probably via the glucocorticoid receptor, it had little effect on Toxoplasma gondii growth in these cells. This would suggest that progesterone‐mediated increased susceptibility to T. gondii during pregnancy is more likely to be related to the ability of the hormone to downregulate IL‐12 production and a type‐1 response utilizing the progesterone as well as the glucocorticoid receptors.

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Section: Discussionmentioning

confidence: 99%

Toll‐like receptor‐4‐mediated macrophage activation is differentially regulated by progesterone via the glucocorticoid and progesterone receptors

et al. 2008

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“…Furthermore, Fab glycosylation may be regulated by the mode of B cell activation. For instance, IL-6 and progesterone can enhance the expression of oligosaccharyltransferase, which catalyzes attachment of the N-linked glycan precursor to the polypeptide chain in the lumen of the endoplasmic reticulum, resulting in increased IgG Fab glycosylation with a proportional increase in high-mannose structures up to 30% (28)(29)(30). T cell signaling, known to influence the structure of Fc glycans (31), may also affect Fab glycosylation, but this has not been studied.…”

Section: Structural Features Of Igg Fab Glycosylationmentioning

confidence: 99%

The Emerging Importance of IgG Fab Glycosylation in Immunity

Bovenkamp

Hafkenscheid

Rispens

et al. 2016

The Journal of Immunology

255

216

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Human IgG is the most abundant glycoprotein in serum and is crucial for protective immunity. In addition to conserved IgG Fc glycans, ∼15–25% of serum IgG contains glycans within the variable domains. These so-called “Fab glycans” are primarily highly processed complex-type biantennary N-glycans linked to N-glycosylation sites that emerge during somatic hypermutation. Specific patterns of Fab glycosylation are concurrent with physiological and pathological conditions, such as pregnancy and rheumatoid arthritis. With respect to function, Fab glycosylation can significantly affect stability, half-life, and binding characteristics of Abs and BCRs. Moreover, Fab glycans are associated with the anti-inflammatory activity of IVIgs. Consequently, IgG Fab glycosylation appears to be an important, yet poorly understood, process that modulates immunity.

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“…9,10 The amount of "asymmetric" IgG was found to increase during pregnancy, as well as after the treatment of antibody-producing cells with hormones and cytokines. 11,12 Fab-linked glycans from human serum IgG exhibit primarily complex-type bi-antennary N-glycans with high contents of core fucose (80%), bisecting GlcNAc (50%), and sialic acid (80%). 9 Depending on their structures and locations, the Fab glycans may influence IgG effector functions by increasing or decreasing the affinity for the antigen.…”

Section: 2mentioning

confidence: 99%

Processing of complex N-glycans in IgG Fc-region is affected by core fucosylation

Castilho

Gruber

Thader

et al. 2015

mAbs

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(2015) Processing of complex N-glycans in IgG Fc-region is affected by core fucosylation, mAbs, 7:5, 863-870, DOI: 10.1080DOI: 10. /19420862.2015 To link to this article: https://doi.org/10. 1080/19420862.2015 Keywords: core fucosylation, sialylation, Nicotiana benthamiana, bisected glycans, glycan modelling, IgG, cetuximab Abbreviations: 3-FucT, Zea maize core a1,3-fucosyltransferase;3-FucT GnTIV, human a1,3-mannosyl-b1,4-N-acetyL-glucosaminyltransferase fused to the CTS region of the Arabidopsis thaliana core a1,3-fucosyltransferase (FUT11); 6-FucT, Mus musculus core a1,6-fucosyltransferase; CH2, constant domain of an IgG heavy chain; CTS, cytoplasmic tail, transmembrane domain and stem region; CxMab cetuximab (Erbitux Ò ); Fab, fragment, antigen-binding; Fc, Fragment crystallizable region of immunoglobulin G; GlcNAc, N-acetylglucosamine; IgG1, Immunoglobulin G subclass 1; LC-ESI-MS, Liquid chromatography-electrospray ionisationmass spectrometry; mAb, monoclonal antibody; SDS-PAGE, Sodium dodecyl sulfate polyacrylamide gel electrophoresis; ST GalT, b1,4-galactosyltransferase fused to the CTS region of the rat a2,6-sialyltransferase; 6-SiaT, a2,6-sialyltransferase;ST GnT-III, b1,4-mannosyl-b1,4-N-acetylglucosaminyltransferase fused to the CTS region of the rat a2,6-sialyltransferase; DXT/FT, Nicotiana benthamiana glycosylation mutants lacking plant specific core b1,2-xylose and a1,3-fucose residuesWe investigated N-glycan processing of immunoglobulin G1 using the monoclonal antibody cetuximab (CxMab), which has a glycosite in the Fab domain in addition to the conserved Fc glycosylation, as a reporter. Three GlcNAc (Gn) terminating bi-antennary glycoforms of CxMab differing in core fucosylation (a1,3-and a1,6-linkage) were generated in a plant-based expression platform. These GnGn, GnGnF 3 , and GnGnF 6 CxMab variants were subjected in vivo to further processing toward sialylation and GlcNAc diversification (bisected and branching structures). Mass spectrometry-based glycan analyses revealed efficient processing of Fab glycans toward envisaged structures. By contrast, Fc glycan processing largely depend on the presence of core fucose. A particularly strong support of glycan processing in the presence of plant-specific core a1,3-fucose was observed. Consistently, molecular modeling suggests changes in the interactions of the Fc carbohydrate chain depending on the presence of core fucose, possibly changing the accessibility. Here, we provide data that reveal molecular mechanisms of glycan processing of IgG antibodies, which may have implications for the generation of glycan-engineered therapeutic antibodies with improved efficacies.

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In Vitro Modulation of Protective Antibody Responses by Estrogen, Progesterone and Interleukin‐6

Cited by 60 publications

References 61 publications

Toll‐like receptor‐4‐mediated macrophage activation is differentially regulated by progesterone via the glucocorticoid and progesterone receptors

Toll‐like receptor‐4‐mediated macrophage activation is differentially regulated by progesterone via the glucocorticoid and progesterone receptors

The Emerging Importance of IgG Fab Glycosylation in Immunity

Processing of complex N-glycans in IgG Fc-region is affected by core fucosylation

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