Article

Low-affinity Fcgamma receptors, autoimmunity and infection.

Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, CB2 0XY, UK.
Expert Reviews in Molecular Medicine (impact factor: 7.14). 02/2009; 11:e24. DOI:10.1017/S1462399409001161 pp.e24
Source: PubMed

ABSTRACT Low-affinity Fcgamma receptors (FcgammaRs) mediate the effects of immunoglobulin G (IgG) antibodies on leukocytes, including recruitment to inflammatory lesions, phagocytosis, antibody-dependent cellular cytotoxicity, release of inflammatory mediators and regulation of B cell activation. These functions are an important part of the mammalian response to infection, but if deployed inappropriately can cause autoimmune disease. Although most FcgammaRs are activatory, there is also an inhibitory FcgammaR that, when bound to IgG immune complexes, is able to downregulate the effects of both the activatory FcgammaRs and the B cell receptor. This review discusses the role of the low-affinity FcgammaRs in a balanced immune response and how perturbations in FcgammaR function result in susceptibility to infection or autoimmunity.

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    Article: Copy number, linkage disequilibrium and disease association in the FCGR locus.
    Heather A Niederer, Lisa C Willcocks, Tim F Rayner, Wanling Yang, Yu Lung Lau, Thomas N Williams, J Anthony G Scott, Britta C Urban, Norbert Peshu, Sarah J Dunstan, Tran Tinh Hien, Nguyen Hoan Phu, Leonid Padyukov, Iva Gunnarsson, Elisabet Svenungsson, Caroline O Savage, Richard A Watts, Paul A Lyons, David G Clayton, Kenneth G C Smith
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    ABSTRACT: The response of a leukocyte to immune complexes (ICs) is modulated by receptors for the Fc region of IgG (FcgammaRs), and alterations in their affinity or function have been associated with risk of autoimmune diseases, including systemic lupus erythematosus (SLE). The low-affinity FcgammaR genomic locus is complex, containing regions of copy number variation (CNV) which can alter receptor expression and leukocyte responses to IgG. Combined paralogue ratio tests (PRTs) were used to distinguish three intervals within the FCGR locus which undergo CNV, and to determine FCGR gene copy number (CN). There were significant differences in FCGR3B and FCGR3A CNV profiles between Caucasian, East Asian and Kenyan populations. A previously noted association of low FCGR3B CN with SLE in Caucasians was supported [OR = 1.57 (1.08-2.27), P = 0.018], and replicated in Chinese [OR = 1.65 (1.25-2.18), P = 4 x 10(-4)]. There was no association of FCGR3B CNV with vasculitis, nor with malarial or bacterial infection. Linkage disequilibrium (LD) between multi-allelic FCGR3B CNV and SLE-associated SNPs in the FCGR locus was defined for the first time. Despite LD between FCGR3B CNV and a variant in FcgammaRIIB (I232T) which abolishes inhibitory function, both reduced CN of FCGR3B and homozygosity of the FcgammaRIIB-232T allele were individually strongly associated with SLE risk. Thus CN of FCGR3B, which controls IC responses and uptake by neutrophils, and variations in FCGR2B, which controls factors such as antibody production and macrophage activation, are important in SLE pathogenesis. Further interpretations of contributions to pathogenesis by FcgammaRs must be made in the context of LD involving CNV regions.
    Human Molecular Genetics 08/2010; 19(16):3282-94. · 7.64 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

able
 
activatory FcgammaRs
 
antibody-dependent cellular cytotoxicity
 
B cell activation
 
B cell receptor
 
balanced immune response
 
downregulate
 
FcgammaR function result
 
FcgammaRs
 
IgG immune complexes
 
immunoglobulin G
 
inappropriately
 
inflammatory lesions
 
inflammatory mediators
 
inhibitory FcgammaR
 
Low-affinity Fcgamma receptors
 
low-affinity FcgammaRs
 
mammalian response
 
review discusses
 
susceptibility
 

Lisa C Willcocks