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Effects of Estradiol on Immunoglobulin G Glycosylation: Mapping of the Downstream Signaling Mechanism
Ist Teil von
Frontiers in immunology, 2021-05, Vol.12, p.680227
Ort / Verlag
Frontiers Media S.A
Erscheinungsjahr
2021
Link zum Volltext
Quelle
EZB Electronic Journals Library
Beschreibungen/Notizen
Glycans attached to immunoglobulin G (IgG) directly affect this antibody effector functions and regulate inflammation at several levels. The composition of IgG glycome changes significantly with age. In women, the most notable change coincides with the perimenopausal period. Aiming to investigate the effect of estrogen on IgG glycosylation, we analysed IgG and total serum glycomes in 36 healthy premenopausal women enrolled in a randomized controlled trial of the gonadotropin-releasing hormone analogue (GnRH
AG
) leuprolide acetate to lower gonadal steroids to postmenopausal levels and then randomized to transdermal placebo or estradiol (E
2
) patch. The suppression of gonadal hormones induced significant changes in the IgG glycome, while E
2
supplementation was sufficient to prevent changes. The observed glycan changes suggest that depletion of E
2
primarily affects B cell glycosylation, while liver glycosylation stays mostly unchanged. To determine whether previously identified IgG GWAS hits
RUNX1
,
RUNX3
,
SPINK4
, and
ELL2
are involved in downstream signaling mechanisms, linking E
2
with IgG glycosylation, we used the FreeStyle 293-F transient system expressing IgG antibodies with stably integrated CRISPR/dCas9 expression cassettes for gene up- and downregulation.
RUNX3
and
SPINK4
upregulation using dCas9-VPR resulted in a decreased IgG galactosylation and, in the case of
RUNX3
, a concomitant increase in IgG agalactosylation.