Interleukin 4-driven reversal of self-reactive B cell anergy contributes to the pathogenesis of systemic lupus erythematosus

Yaoyang Liu; Zhiguo Zhang; Zijian Kang; Xu-Jie Zhou; Shujun Liu; Shicheng Guo; Qianmei Jin; Ting Li; Ling Zhou; Xin Wu; Yan-Na Wang; Liangjing Lu; Yanran He; Fubin Li; Hong Zhang; Yuncai Liu; Huji Xu

doi:10.1136/ard-2023-224453

Interleukin 4-driven reversal of self-reactive B cell anergy contributes to the pathogenesis of systemic lupus erythematosus

Ann Rheum Dis. 2023 Nov;82(11):1444-1454. doi: 10.1136/ard-2023-224453. Epub 2023 Aug 11.

Authors

Yaoyang Liu^#¹, Zhiguo Zhang^#¹, Zijian Kang^#¹, Xu-Jie Zhou², Shujun Liu³, Shicheng Guo^{4

5}, Qianmei Jin¹, Ting Li¹, Ling Zhou¹, Xin Wu¹, Yan-Na Wang², Liangjing Lu⁶, Yanran He⁷, Fubin Li³, Hong Zhang², Yuncai Liu^{8

9}, Huji Xu^{10

8

9}

Affiliations

¹ Department of Rheumatology and Immunology, Changzheng Hospital, Naval Medical University, Shanghai, China.
² Renal Division, Department of Medicine, Peking University First Hospital; Peking University Institute of Nephrology; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University) Ministry of Education, Beijing, China.
³ Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁴ Department of Medical Genetics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
⁵ Computation and Informatics in Biology and Medicine, University of Wisconsin-Madison, Madison, WI, USA.
⁶ Department of Rheumatology and Immunology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁷ Committee on Cancer Biology, The University of Chicago, Chicago, IL, USA.
⁸ Peking-Tsinghua Center for Life Sciences, Tsinghua University, Beijing, China.
⁹ School of Medicine, Tsinghua University, Beijing, China.
¹⁰ Department of Rheumatology and Immunology, Changzheng Hospital, Naval Medical University, Shanghai, China huji_xu@tsinghua.edu.cn.

^# Contributed equally.

PMID: 37567607
DOI: 10.1136/ard-2023-224453

Abstract

Objectives: Reactivation of anergic autoreactive B cells (B_ND cells) is a key aetiological process in systemic lupus erythematosus (SLE), yet the underlying mechanism remains largely elusive. This study aimed to investigate how B_ND cells participate in the pathogenesis of SLE and the underlying mechanism.

Methods: A combination of phenotypical, large-scale transcriptome and B cell receptor (BCR) repertoire profiling were employed at molecular and single cell level on samples from healthy donors and patients with SLE. Isolated naïve B cells from human periphery blood were treated with anti-CD79b mAb in vitro to induce anergy. IgM internalisation was tracked by confocal microscopy and was qualified by flow cytometer.

Results: We characterised the decrease and disruption of B_ND cells in SLE patients and demonstrated IL-4 as an important cytokine to drive such pathological changes. We then elucidated that IL-4 reversed B cell anergy by promoting BCR recycling to the cell surface via STAT6 signalling.

Conclusions: We demonstrated the significance of IL-4 in reversing B cell anergy and established the scientific rationale to treat SLE via blocking IL-4 signalling, also providing diagnostic and prognostic biomarkers to identify patients who are most likely going to benefit from such treatments.

Keywords: Immune System Diseases; Rheumatoid Factor; Systemic Lupus Erythematosus.