Background Rheumatoid arthritis preferentially affects women. RA has its peak over 50 years coincidencing with the decrease in sex hormones in menopause. Recently, the transition from asymptomatic autoimmunity to RA has been shown to essentially depend on the glycosylation status of antibodies affecting the binding affinity to Fc gamma receptors¹. Hence a decrease in the sialylation of antibodies resulting from a decrease in the activity of the sialylation enzyme β-galactoside α2,6-sialylltransferase (St6Gal1) was shown to trigger the onset of RA.

Objectives To test whether estrogen influences the glycosylation status of antibodies and St6Gal1 expression explaining why postmenopausal women are particularly prone to develop RA

Methods In the experimental part we tested the influence of estrogen on antibody glycosylation and St6Gal1 expression. Ovariectomized mice, which were either left without estrogen supplementation or were supplemented with estrogen (hormone replacement), were immunized with ovalbumin (OVA) to induce antibody production. Immunoglobulin G (IgG) levels were analyzed by ELISA and the glycosylation of the Fc-part of total and OVA-specific IgG was determined by lectin ELISA and MALDI-TOF, respectively. St6Gal1 expression in plasma cells was determined by RT-PCR and FACS. Inhuman part we measured the effects of estrogen treatment on autoantibody levels and IgG glycosylation in a cohort of postmenopausal RA patients over 2 years².

Results Ovariectomy and loss of estrogens was associated with a lower sialylation of OVA-specific IgG. Conversely estrogen treatment significantly increased the sialylation level of newly formed OVA-specific and totals IgG as well as enhanced the expression of St6Gal1 enzyme in plasma cells suggesting a shift towards an anti-inflammatory pattern of IgG. These results were confirmed with estrogen treated postmenopausal RA patients showing that hormone replacement therapy significantly increased antibody glycosylation, while in a control RA population not exposed to estrogens no such increase in sialylation of IgG was found. Estrogens however, did not influence the CCP autoantibody levels.

Conclusions These findings indicate that estrogen regulates St6Ga1 and increases the glycosylation of IgG. Lack of estrogen decreases IgG glycosylation and results in pro-inflammatory properties of IgG which may explain the increase prevalence of RA in postmenopausal women.

References

1. Pfeifle et al. Regulation of autoantibody activity by the IL-23-T_H17 axis determines the onset of autoimmune disease. Nat Immunol. 2017 Jan;18(1):104–113.

2. D'Elia HF, et al. Influence of hormone replacement therapy on disease progression and bone mineral density in rheumatoid arthritis. J Rheumatol. 2003 Jul;30(7):1456–63.

References

Disclosure of Interest None declared