Estrogen induces St6gal1 expression and increases IgG sialylation in mice and patients with rheumatoid arthritis: a potential explanation for the increased risk of rheumatoid arthritis in postmenopausal women

Abstract

BackgroundRheumatoid arthritis (RA) preferentially affects women, with the peak incidence coinciding with estrogen decrease in menopause. Estrogen (E2) may therefore have intrinsic immune-regulatory properties that vanish with menopause. Fc sialylation is a crucial factor determining the inflammatory effector function of antibodies. We therefore analyzed whether E2 affects immunoglobulin G (IgG) sialylation.MethodsPostmenopausal (ovariectomized) mice were immunized with ovalbumin and treated with E2 or vehicle. Total and ovalbumin-specific IgG concentrations, sialylation, and Fcγ receptor expression were analyzed. Postmenopausal women with RA receiving hormone replacement therapy, including E2, or no treatment were analyzed for IgG sialylation. Furthermore, effects of E2 on the expression of the sialylation enzyme β-galactoside α2,6-sialyltransferase 1 (St6Gal1) were studied in mouse and human antibody-producing cells.ResultsE2 treatment significantly increased Fc sialylation of total and ovalbumin-specific IgG in postmenopausal mice. Furthermore, E2 led to increased expression of inhibitory Fcγ receptor IIb on bone marrow leukocytes. Treatment with E2 also increased St6Gal1 expression in mouse and human antibody-producing cells, providing a mechanistic explanation for the increase in IgG-Fc sialylation. In postmenopausal women with RA, treatment with E2 significantly increased the Fc sialylation of IgG.ConclusionsE2 induces anti-inflammatory effector functions in IgG by inducing St6Gal1 expression in antibody-producing cells and by increasing Fc sialylation. These observations provide a mechanistic explanation for the increased risk of RA in conditions with low estrogen levels such as menopause.Electronic supplementary materialThe online version of this article (10.1186/s13075-018-1586-z) contains supplementary material, which is available to authorized users.

Fc-Linked IgG N-Glycosylation in FcγR Knock-Out Mice

“…Despite the aforementioned study analyzing total IgG N-glycome rather than subclass-specific Fc-linked N-glycome, we observed similar trends in wild-type BALB/c and C57BL/6 mice, although the magnitude of these differences in most cases was lower than the differences between the glycoprofiles of the two strains ( Supplementary Figures S3A-C). Currently, it is believed that both galactosylation and sialylation of IgG are influenced by sex hormones, namely, estrogens, which might at least in part explain sex-specific differences (Ercan et al, 2017;Engdahl et al, 2018).…”

ST6GAL1: A key player in cancer (Review)

“…ST6GAL1 has been shown to promote B cell activation. IgG has also been shown to be a direct target for ST6GAL1 sialylation in an estrogen dependant manner in rheumatoid arthritis (103). It is evident that immune signalling is a substrate for regulation by sialylation, however much more needs to be done to characterise the effect of ST6GAL1 on the immune system (104).…”

Hubungan Pemilihan Obat dan Keberhasilan Terapi Pasien Rheumatoid Arthritis

“…3 Hampir 75% penderita RA merupakan wanita berusia 40-60 tahun, hal ini karena prevalensi RA berhubungan dengan penurunan jumlah estrogen, terutama setelah menopause. 2 RA berkaitan dengan jumlah estrogen sebab selain bekerja sebagai hormon, estrogen juga memiliki sifat imunomodulator dengan memengaruhi interleukin-17 dari sel Th dan proses sialilasi antibodi G (IgG). 2,4 Estrogen dapat meningkatkan sel Th17 di nodus limpa dan menurunkan kadar sel Th17 di sendi.…”