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Arthritis Res Ther. 2018 May 2;20(1):84. doi: 10.1186/s13075-018-1586-z.

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.

Author information

1
Department of Internal Medicine 3, Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich Alexander University Erlangen-Nürnberg, Erlangen, Germany. cecilia.engdahl@gu.se.
2
Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden. cecilia.engdahl@gu.se.
3
Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden. cecilia.engdahl@gu.se.
4
Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
5
Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands.
6
Department of Internal Medicine 3, Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich Alexander University Erlangen-Nürnberg, Erlangen, Germany.
7
Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
8
Institute of Genetics at the Department of Biology, FAU Erlangen-Nuremberg, Erlangen, Germany.
9
Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
10
Department of Internal Medicine 3, Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich Alexander University Erlangen-Nürnberg, Erlangen, Germany. georg.schett@uk-erlangen.de.

Abstract

BACKGROUND:

Rheumatoid 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.

METHODS:

Postmenopausal (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.

RESULTS:

E2 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.

CONCLUSIONS:

E2 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.

KEYWORDS:

Antibody sialylation; Estrogen; Female sex; Rheumatoid arthritis

PMID:
29720252
PMCID:
PMC5932893
DOI:
10.1186/s13075-018-1586-z
[Indexed for MEDLINE]
Free PMC Article

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