Susceptibility for Lupus Nephritis by Low Copy Number of the FCGR3B Gene Is Linked to Increased Levels of Pathogenic Autoantibodies.

Johannes C Nossent,Sue Lester,Maureen Rischmueller,Andrea Becker-Merok

doi:10.1155/2013/750814

Abstract

Low copy number (CN) of the FCGR3B gene reduces FCGR3B membrane expression on neutrophils and results in clearance of a smaller amount of immune complex. We investigated FCGR3B CN in relation to the clinical phenotype in a Caucasian SLE cohort (n = 107). FCGR3B CN was determined by three different qPCR parameter estimations (Ct−, Cy0, and cpD1) and confirmed by the FCGR2C/FCGR2A paralog ratio test. Clinical and serological data were then analyzed for their association with FCGR3B CN. Low FCGR3B CN (<2) was more frequent in SLE patients than in healthy controls (n = 162) (20% versus 6%, OR 4.15, P = 0.003) and associated with higher disease activity scores (SLEDAI 10.4 versus 6.1, P = 0.03), lupus nephritis (LN) (25 versus 5%, P = 0.03), and increased levels of antibodies against dsDNA (81 versus 37 IU, P = 0.03), C1q (22 versus 6 IU, P = 0.003), and ribosomal P (10 versus 5 IU, P = 0.01). No such associations were seen with antibodies against extractable nuclear antigens or high FCGR3B CN (>2). In multivariate analyses, LN was independently associated with anti-C1q-Ab levels (P = 0.03) and low FCGR3B CN (P = 0.09). We conclude that the susceptibility for LN in patients with low FCGR3B CN is linked to increased levels of pathogenic autoantibodies.

Highlights

Systemic lupus erythematosus (SLE) is a severe autoimmune disease that causes a wide spectrum of clinical and serological abnormalities [1]
We investigated FCGR3B copy number (CN) in relation to the clinical phenotype in a Caucasian SLE cohort (n = 107)
We conclude that the susceptibility for lupus nephritis (LN) in patients with low FCGR3B CN is linked to increased levels of pathogenic autoantibodies

Summary

Introduction

Systemic lupus erythematosus (SLE) is a severe autoimmune disease that causes a wide spectrum of clinical and serological abnormalities [1]. Immune complexes containing autoantibodies and nuclear antigens (IC) play a central role in renal inflammation, and depending on their interaction with activating and/or inhibitory FCgR can lead to complement activation, cytokine release, and attraction of neutrophils in Lupus Nephritis (LN), similar to findings in anti-GBM disease [4,5,6]. FCGR3B is an activating membrane glycoprotein expressed by human neutrophils (and stimulated eosinophils) and preferentially interacts with complexed IgG [12]. Despite the role of FCGR3B in clearance of immune complexes, none of these studies have been able to demonstrate the presumed link between low FCGR3B CN and pathogenic IgG autoantibodies. Given the limited data available, we investigated the potential association between FCGR3B CNV and relevant disease manifestations in SLE

Methods

Results

Conclusion