FcγRIIB: a modulator of cell activation and humoral tolerance.
ABSTRACT An immune response needs to be tightly regulated to prevent excessive inflammation, which may result in the destruction of healthy tissues. At the molecular level, the strength of an immune response is determined by the integration of a multitude of positive and negative signals. This review will focus on IgG-dependent immune responses and discuss how the inhibitory receptor FcγRIIB may be involved in regulating both the afferent and efferent phases of such a response. Furthermore, we will discuss recent evidence suggesting that FcγRIIB may have important functions beyond the negative regulation of signals transduced by the B-cell receptor or activating FcγRs and could be responsible for the activity of agonistic antibodies in vivo.
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ABSTRACT: The phase III RV144 HIV-1 vaccine trial estimated vaccine efficacy (VE) to be 31.2%. This trial demonstrated that the presence of HIV-1-specific IgG-binding Abs to envelope (Env) V1V2 inversely correlated with infection risk, while the presence of Env-specific plasma IgA Abs directly correlated with risk of HIV-1 infection. Moreover, Ab-dependent cellular cytotoxicity responses inversely correlated with risk of infection in vaccine recipients with low IgA; therefore, we hypothesized that vaccine-induced Fc receptor-mediated (FcR-mediated) Ab function is indicative of vaccine protection. We sequenced exons and surrounding areas of FcR-encoding genes and found one FCGR2C tag SNP (rs114945036) that associated with VE against HIV-1 subtype CRF01_AE, with lysine at position 169 (169K) in the V2 loop (CRF01_AE 169K). Individuals carrying CC in this SNP had an estimated VE of 15%, while individuals carrying CT or TT exhibited a VE of 91%. Furthermore, the rs114945036 SNP was highly associated with 3 other FCGR2C SNPs (rs138747765, rs78603008, and rs373013207). Env-specific IgG and IgG3 Abs, IgG avidity, and neutralizing Abs inversely correlated with CRF01_AE 169K HIV-1 infection risk in the CT- or TT-carrying vaccine recipients only. These data suggest a potent role of Fc-gamma receptors and Fc-mediated Ab function in conferring protection from transmission risk in the RV144 VE trial.The Journal of clinical investigation 08/2014; · 15.39 Impact Factor
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ABSTRACT: The importance of immunoglobulin G (IgG) molecules for providing long-term sterile immunity as well as their major contribution to tissue inflammation during autoimmune diseases is generally accepted. In a similar manner, studies over the last years have elucidated many details of the molecular and cellular pathways underlying this protective activity in vivo, emphasizing the role of cellular recognizing the constant antibody fragment. In contrast, the active anti-inflammatory activity of IgG, despite being known and actually identified in human autoimmune patients more than 30 years ago, is much less defined. Recent evidence from several independent model systems suggests that IgG glycosylation is critical for the immunomodulatory activity of IgG and that both monomeric IgG as well as IgG immune complexes can diminish Fc receptor and complement dependent inflammatory processes. Moreover, there is increasing evidence that IgG molecules also modulate B and T cell responses, which may suggest that IgG is centrally involved in the establishment and maintenance of immune homeostasis.Current topics in microbiology and immunology 01/2014; 382:393-417. · 3.47 Impact Factor
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ABSTRACT: Adenomatous colorectal polyps are the precursors of the majority of colorectal cancers. Investigation into the gene expression changes in the progression of colorectal adenoma may offer potential targets for the development of novel diagnostic strategies. Previous gene expression studies have generally been based on a limited number of cases or only focused on a single or a few genes. The present study aimed to identify molecular characteristics of colorectal adenoma through analysis of pathways and gene ontology. The study identified 808 upregulated and 857 downregulated genes. Among the 40 pathways enriched with differentially-expressed genes, the Staphylococcus aureus infection pathway and the intestinal immune network for immunoglobulin A production pathway were identified as the most statistically noteworthy pathways at the early stage for colorectal tumorigenesis (P<0.05). These results provide new understanding of colorectal adenoma pathogenesis, with the hope of offering theoretical support for future therapeutic studies.Oncology letters 11/2014; 8(5):2081-2085. · 0.99 Impact Factor