The placental regulatory factor involved in the asymmetric IgG antibody synthesis responds to IL-6 features

Gutiérrez, Gabriela; Borel, Ileana Malán; Margni, Ricardo A.

doi:10.1016/s0165-0378(00)00074-7

Cited by 33 publications

(38 citation statements)

References 14 publications

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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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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

View full text Add to dashboard Cite

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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 studies showed that IL-6 and progesterone (P4) modulate the asymmetric glycosylation of Fabs [17][18][19]. The progesterone-induced blocking factor (PIBF) was discovered as a progesterone-induced protein secreted by human pregnancy lymphocytes [20].…”

Section: Introductionmentioning

confidence: 99%