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Inhibitory Fc? receptor is required for the maintenance of tolerance through distinct mechanisms.

ABSTRACT: The inhibitory Fc?R Fc?RIIB is widely expressed on B cells, dendritic cells (DCs), and myeloid effector cells and modulates a variety of Ab-driven in vivo functions. Although it has been established that Fc?RIIB plays an important role in the maintenance of peripheral tolerance, the responsible cell-specific Fc?RIIB expression remains to be determined. In this study, we generated mice with selective deletion of Fc?RIIB in B cells, DCs, and myeloid effector cells and evaluated these novel strains in models of tolerance and autoimmune diseases. Our results demonstrate that mice with selective deletion of Fc?RIIB expression in B cells and DCs have increased Ab and T cell responses, respectively, and display enhanced susceptibility to disease in distinct models, suggesting that Fc?RIIB expression in distinct cellular populations contributes to the maintenance of peripheral tolerance through different mechanisms.

SUBMITTER: Li F

PROVIDER: S-EPMC3967505 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Inhibitory Fcγ receptor is required for the maintenance of tolerance through distinct mechanisms.

Li Fubin F Smith Patrick P Ravetch Jeffrey V JV

Journal of immunology (Baltimore, Md. : 1950) 20140221 7

The inhibitory FcγR FcγRIIB is widely expressed on B cells, dendritic cells (DCs), and myeloid effector cells and modulates a variety of Ab-driven in vivo functions. Although it has been established that FcγRIIB plays an important role in the maintenance of peripheral tolerance, the responsible cell-specific FcγRIIB expression remains to be determined. In this study, we generated mice with selective deletion of FcγRIIB in B cells, DCs, and myeloid effector cells and evaluated these novel strains ...[more]

PMID: 24563255

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Project description:BackgroundTumor necrosis factor (TNF) is an important cytokine in the pathogenesis of inflammatory bowel disease (IBD). Anti-TNF antibodies have been successfully implemented in IBD therapy, however their efficacies differ among IBD patients. Here we investigate the influence of CD64 Fc receptor on the inhibitory activity of anti-TNFs in cells of intestinal wall.MethodsIntestinal cell lines, monocytes/macrophages and peripheral blood mononuclear cells (PBMCs) were used as models. The efficacies of adalimumab, infliximab and certolizumab-pegol were assessed by RT-PCR for target genes. Protein levels and localizations were examined by Western blotting and immunofluorescence. Antibody fragments were obtained by proteolytic digestion, immunoprecipitation and protein chip analysis. Knock-down of specific gene expression was performed using siRNAs.ResultsInfliximab had limited efficacy towards soluble TNF in cell types expressing Fc gamma receptor CD64. Both adalimumab and infliximab had lower efficacies in PBMCs of IBD patients, which express elevated levels of CD64. Infliximab-TNF complexes were more potent in activating CD64 in THP-1 cells than adalimumab, which was accompanied by distinct phospho-tyrosine signals. Blocking Fc parts and isolation of Fab fragments of infliximab improved its efficacy. IFN-?-induced expression of CD64 correlated with a loss of efficacy of infliximab, whereas reduction of CD64 expression by either siRNA or PMA treatment improved inhibitory activity of this drug. Colonic mRNA expression levels of CD64 and other Fc gamma receptors were significantly increased in the inflamed tissues of infliximab non-responders.ConclusionsCD64 modulates the efficacy of infliximab both in vitro and ex vivo, whereas the presence of this receptor has no impact on the inhibitory activity of certolizumab-pegol, which lacks Fc fragment. These data could be helpful in both predicting and evaluating the outcome of anti-TNF therapy in IBD patients with elevated systemic and local levels of Fc receptors.

Dataset Information

Inhibitory Fc? receptor is required for the maintenance of tolerance through distinct mechanisms.

Publications

Inhibitory Fcγ receptor is required for the maintenance of tolerance through distinct mechanisms.

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