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

Cecilia Engdahl,Inga-Lill Mårtensson,René Pfeifle,Ulrike Harre,Hans U Scherer,Alessandro Camponeschi,Michaela Seeling,Helena Forsblad-D’Elia,Manfred Wuhrer,Gerhard Krönke,Falk Nimmerjahn,Georg Schett,Albert Bondt,Jasmin Raufer

doi:10.1186/s13075-018-1586-z

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.

Highlights

Rheumatoid arthritis (RA) preferentially affects women, with the peak incidence coinciding with estrogen decrease in menopause
We show that estrogen influences the presence of sialic acid on the Fc glycan of immunoglobulin G (IgG), both in postmenopausal mice challenged by immunization and in postmenopausal women with rheumatoid arthritis (RA)
No difference was found in OVA-depleted IgG2, indicating that estrogen determines the sialylation of newly formed antigen-specific antibodies

Summary

Introduction

Rheumatoid arthritis (RA) preferentially affects women, with the peak incidence coinciding with estrogen decrease in menopause. A person’s gender plays a major role in the development of rheumatoid arthritis (RA). The reason for the gender imbalance is unclear, but sex hormones are considered to be of pivotal importance. The decrease of estrogen in menopause coincides with an increased risk of developing RA [1]. Despite this remarkable association, studies addressing the role of estrogen in the development of RA are scarce [2], and mechanistic studies are virtually absent. The reason for the preponderance of RA in postmenopausal women remains unclear to date

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