Control of lupus activity during pregnancy via the engagement of IgG sialylation: novel crosstalk between IgG sialylation and pDC functions

Abstract

Immunoglobulin (IgG) glycosylation affects the effector functions of IgG in a myriad of biological processes and has been closely associated with numerous autoimmune diseases, including systemic lupus erythematosus (SLE), thus underlining the pathogenic role of glycosylation aberration in autoimmunity. This study aims to explore the relationship between IgG sialylation patterns and lupus pregnancy. Relative to that in serum samples from the control cohort, IgG sialylation level was aberrantly downregulated in serum samples from the SLE cohort at four stages (from preconception to the third trimester of pregnancy) and was significantly associated with lupus activity and fetal loss during lupus pregnancy. The type I interferon signature of pregnant patients with SLE was negatively correlated with the level of IgG sialylation. The lack of sialylation dampened the ability of IgG to suppress the functions of plasmacytoid dendritic cells (pDCs). RNA-seq analysis further revealed that the expression of genes associated with the spleen tyrosine kinase (SYK) signaling pathway significantly differed between IgG- and deSia-IgG-treated pDCs. This finding was confirmed by the attenuation of the ability to phosphorylate SYK and BLNK in deSia-IgG. Finally, the coculture of pDCs isolated from pregnant patients with SLE with IgG/deSia-IgG demonstrated the sialylation-dependent anti-inflammatory function of IgG. Our findings suggested that IgG influences lupus activity through regulating pDCs function via the modulation of the SYK pathway in a sialic acid-dependent manner.

Keywords

pregnancy / IgG glycome / type I interferon / systemic lupus erythematosus

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Acknowledgements

We would like to thank Lei Zhou, PhD and Linlin Sun, PhD for technical support in UPLC analyses, and the patients and healthy volunteers for participation in the study. This work was supported by grants from the National Natural Science Foundation of China (Nos. 82172918, 81901494, 82101768, 82171767, and 81974252), the Science and Technology Commission of Shanghai Municipality (No. 18441904800), the Medical-Engineering Joint Funds of Shanghai Jiao Tong University (No. YG2021GD01), the Shanghai Key Laboratory of Gynecologic Oncology (No. FKZL-2021-02), Shanghai Health Commission (No. 201940284) and the Clinical Scientific Research Innovation Cultivation Fund of Renji Hospital (No. PYI20-03).

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-022-0965-7 and is accessible for authorized users.

Compliance with ethics guidelines

You Wang, Sihan Lin, Jiayue Wu, Meng Jiang, Jianhua Lin, Yu Zhang, Haibo Zhou, Nan Shen and Wen Di declare that they have no conflict of interest. All procedures followed were in accordance with the ethical standards of the responsible committees on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for inclusion in the study. This study was approved by the Ethics Committee of Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine (KY2019-138).

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