Document Detail


The inhibiting Fc receptor for IgG, FcγRIIB, is a modifier of autoimmune susceptibility.
MedLine Citation:
PMID:  21724994     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
FcγRIIB-deficient mice generated in 129 background (FcγRIIB(129)(-/-)) if back-crossed into C57BL/6 background exhibit a hyperactive phenotype and develop lethal lupus. Both in mice and humans, the Fcγr2b gene is located within a genomic interval on chromosome 1 associated with lupus susceptibility. In mice, the 129-derived haplotype of this interval, named Sle16, causes loss of self-tolerance in the context of the B6 genome, hampering the analysis of the specific contribution of FcγRIIB deficiency to the development of lupus in FcγRIIB(129)(-/-) mice. Moreover, in humans genetic linkage studies revealed contradictory results regarding the association of "loss of function" mutations in the Fcγr2b gene and susceptibility to systemic lupus erythematosis. In this study, we demonstrate that FcγRIIB(-/-) mice generated by gene targeting in B6-derived ES cells (FcγRIIB(B6)(-/-)), lacking the 129-derived flanking Sle16 region, exhibit a hyperactive phenotype but fail to develop lupus indicating that in FcγRIIB(129)(-/-) mice, not FcγRIIB deficiency but epistatic interactions between the C57BL/6 genome and the 129-derived Fcγr2b flanking region cause loss of tolerance. The contribution to the development of autoimmune disease by the resulting autoreactive B cells is amplified by the absence of FcγRIIB, culminating in lethal lupus. In the presence of the Yaa lupus-susceptibility locus, FcγRIIB(B6)(-/-) mice do develop lethal lupus, confirming that FcγRIIB deficiency only amplifies spontaneous autoimmunity determined by other loci.
Authors:
Peter Boross; Victoria L Arandhara; Javier Martin-Ramirez; Marie-Laure Santiago-Raber; Francesco Carlucci; Roelof Flierman; Jos van der Kaa; Cor Breukel; Jill W C Claassens; Marcel Camps; Erik Lubberts; Daniela Salvatori; Maria Pia Rastaldi; Ferry Ossendorp; Mohamed R Daha; H Terence Cook; Shozo Izui; Marina Botto; J Sjef Verbeek
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-07-01
Journal Detail:
Title:  Journal of immunology (Baltimore, Md. : 1950)     Volume:  187     ISSN:  1550-6606     ISO Abbreviation:  J. Immunol.     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-07-20     Completed Date:  2011-10-24     Revised Date:  2011-12-27    
Medline Journal Info:
Nlm Unique ID:  2985117R     Medline TA:  J Immunol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1304-13     Citation Subset:  AIM; IM    
Affiliation:
Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cells, Cultured
Crosses, Genetic
Disease Models, Animal
Embryonic Stem Cells / immunology,  metabolism
Female
Gene Targeting
Genetic Predisposition to Disease / prevention & control*
Humans
Immunoglobulin G / metabolism*
Immunophenotyping
Lupus Nephritis / genetics*,  immunology*,  prevention & control
Male
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Receptors, IgG / deficiency,  genetics,  physiology*
Chemical
Reg. No./Substance:
0/Fc gamma receptor IIB; 0/Immunoglobulin G; 0/Receptors, IgG
Comments/Corrections
Comment In:
J Immunol. 2011 Dec 1;187(11):5473; author reply 5473-4   [PMID:  22102729 ]
J Immunol. 2011 Oct 15;187(8):3909; author reply 3909-10   [PMID:  21969314 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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