Copy number of FCGR3B, which is associated with systemic lupus erythematosus, correlates with protein expression and immune complex uptake.
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). FcgammaRIIIb 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 FcgammaRIIIb-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 FcgammaRIIIb. Reduced FcgammaRIIIb 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.
Willcocks
Lisa C
LC
Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, CB2 0XY, England, UK.
Lyons
Paul A
PA
Clatworthy
Menna R
MR
Robinson
James I
JI
Yang
Wanling
W
Newland
Stephen A
SA
Plagnol
Vincent
V
McGovern
Naomi N
NN
Condliffe
Alison M
AM
Chilvers
Edwin R
ER
Adu
Dwomoa
D
Jolly
Elaine C
EC
Watts
Richard
R
Lau
Yu Lung
YL
Morgan
Ann W
AW
Nash
Gerard
G
Smith
Kenneth G C
KG
D019268:Antibodies, Antineutrophil Cytoplasmic / Q000276:immunology; D000936:Antigen-Antibody Complex / Q000235:genetics* / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics; D005260:Female; D058851:GPI-Linked Proteins; D018628:Gene Dosage / Q000235:genetics* / Q000276:immunology; D005786:Gene Expression Regulation / Q000235:genetics* / Q000276:immunology; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000276:immunology; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology*; D008297:Male; D009504:Neutrophils / Q000276:immunology; D017452:Receptors, IgG / Q000235:genetics* / Q000276:immunology; D014657:Vasculitis / Q000235:genetics / Q000276:immunology; D044465:White People
D019268:Antibodies, Antineutrophil Cytoplasmic; D000936:Antigen-Antibody Complex; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D017452:Receptors, IgG