Identification of monoclonal antibodies against human renal glomerular endothelial cells in lupus nephritis that induce endothelial interferon-alpha production

Yao-Hsu Yang,Ya-Chiao Hu,Bor-Luen Chiang,Hui-Yao Hsu,I-Jung Tsai

doi:10.1186/s13075-021-02552-5

Abstract

BackgroundThe pathogenesis of lupus nephritis (LN) remains not fully understood. In this study, we aimed to explore the pathogenic roles of autoantibodies against human renal glomerular endothelial cells (HRGEC) in LN patients.MethodsThe serum levels of anti-HRGEC antibodies in systemic lupus erythematosus (SLE) patients without LN and LN patients were determined by cell-based enzyme-linked immunosorbent assay (ELISA). Monoclonal IgG anti-HRGEC antibodies were subsequently generated from LN patients. The binding activities of these monoclonal antibodies to HRGEC, their cross-reactivity with double-stranded DNA (dsDNA), and the ability to activate HRGEC were further evaluated.ResultsLN patients had higher serum levels of IgG anti-HRGEC antibodies than SLE patients without LN and healthy controls. Four monoclonal IgG anti-HRGEC antibodies (LN1–4) were obtained; LN1 and LN2 were IgG3 while LN3 and LN4 were IgG1. Among these monoclonal antibodies, LN1–3 were cross-reactive with dsDNA. The functional assays showed that compared with IgG1/IgG3 isotype controls, LN3 had an effect on HRGEC to enhance interleukin (IL)-6 production, LN4 could enhance IL-8 and monocyte chemoattractant protein (MCP)-1 production, and LN1–3 possessed the ability to induce interferon (IFN)-α production by HRGEC. Moreover, the removal of DNA on the HRGEC surface by DNAse 1 did not interpose the binding of LN1–3 to HRGEC and the effects of LN1–3 on IFN-α induction by HRGEC.ConclusionsSome IgG anti-HRGEC antibodies in LN patients had the ability to enhance endothelial proinflammatory cytokine (IL-6, IL-8, and MCP-1) production, and some could induce the DNA-independent production of IFN-α by HRGEC.

Highlights

The pathogenesis of lupus nephritis (LN) remains not fully understood
Patients and healthy controls Based on the American College of Rheumatology (ACR) and Systemic Lupus International Collaborating Clinics (SLICC) classification criteria for Systemic lupus erythematosus (SLE) [19, 20], 12 SLE patients with LN presented with proteinuria (> 2 g/day), hematuria, and ± cellular casts; 12 SLE patients without renal involvement; and 25 age-matched healthy controls were enrolled in the present study
Characteristics and laboratory data of SLE patients Twenty-four SLE patients enrolled in this study were all positive for both antinuclear antibodies (ANA) and antidsDNA antibodies

Summary

Introduction

We aimed to explore the pathogenic roles of autoantibodies against human renal glomerular endothelial cells (HRGEC) in LN patients. Systemic lupus erythematosus (SLE) is a complex chronic autoimmune disorder, which is most prevalent among females of childbearing age but can occur during childhood and in males [1]. It is characterized by the breakdown of tolerance to self-antigens and the production of many autoantibodies [2]. Such immune dysregulation affects multiple organ systems. Class IV and/or class III LN are the most frequent and severe lesions that may progress to end-stage renal disease even under aggressive treatment [3, 4]

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