Copy number of FCGR3B, which is associated with systemic lupus erythematosus, correlates with protein expression and immune complex uptake

Research output: Contribution to journalArticle

Authors

  • LC Willcocks
  • PA Lyons
  • MR Clatworthy
  • JI Robinson
  • W Yang
  • SA Newland
  • V Plagnol
  • NN McGovern
  • AM Condliffe
  • ER Chilvers
  • Dwomoa Adu
  • EC Jolly
  • R Watts
  • YL Lau
  • AW Morgan
  • KGC Smith

Colleges, School and Institutes

Abstract

Copy number (CN) variation (CNV) has been shown to be common in regions of the genome coding for immune-related genes, and thus impacts upon polygenic autoimmunity. Low CN of FCGR3B has recently been associated with systemic lupus erythematosus (SLE). Fc gamma RIIIb is a glycosylphosphatidylinositol-linked, low affinity receptor for IgG found predominantly on human neutrophils. We present novel data demonstrating that both in a family with Fc gamma RIIIb-deficiency and in the normal population, FCGR3B CNV correlates with protein expression, with neutrophil uptake of and adherence to immune complexes, and with soluble serum Fc gamma RIIIb. Reduced Fc gamma RIIIb expression is thus likely to contribute to the impaired clearance of immune complexes, which is a feature of SLE, explaining the association between low FCGR3B CNV and SLE that we have confirmed in a Caucasian population. In contrast, antineutrophil cytoplasmic antibody-associated systemic vasculitis (AASV), a disease not associated with immune complex deposition, is associated with high FCGR3B CN. Thus, we define a role for FCGR3B CNV in immune complex clearance, a function that may explain why low FCGR3B CNV is associated with SLE, but not AASV. This is the first report of an association between disease-related gene CNV and variation in protein expression and function that may contribute to autoimmune disease susceptibility.

Details

Original languageEnglish
Pages (from-to)1573-1582
Number of pages10
JournalThe Journal of Experimental Medicine
Volume205
Issue number7
Publication statusPublished - 1 Jul 2008