Selective blockade of the inhibitory Fcγ receptor (FcγRIIB) in human dendritic cells and monocytes induces a type I interferon response program

Dhodapkar, Kavita M.; Banerjee, Devi; Connolly, John E.; Kukreja, Anjli; Matayeva, Elyana; Verı̀, Maria Concetta; Ravetch, Jeffrey V.; Steinman, Ralph M.; Dhodapkar, Madhav V.

doi:10.1084/jem.20062545

Cited by 128 publications

(87 citation statements)

References 38 publications

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“…In B cells, FcγRIIB functions as a regulator of activating signals transmitted by the B cell receptor (BCR) 3 . In DC, the balance between activating and inhibitory FcγR activity influences their relative activation status 7 . In addition to hematopoietic cells, FcγR are expressed by follicular DCs, endothelial cells, microglial cells, osteoclasts and mesangial cells 3 .…”

Section: Fcγ Receptor Subtypes and Functionsmentioning

confidence: 99%

Fcγ Receptors and Ligands and Cardiovascular Disease

Tanigaki

Sundgren

Khera

et al. 2015

Circulation Research

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Fcγ receptors (FcγR) classically modulate intracellular signaling upon binding of the Fc region of IgG in immune response cells. How FcγR and their ligands impact cardiovascular health and disease has recently been interrogated in both preclinical and clinical studies. The stimulation of activating FcγR in endothelial cells, vascular smooth muscle cells and monocytes/macrophages causes a variety of cellular responses that may contribute to vascular disease pathogenesis. Stimulation of the lone inhibitory FγcR, FcγRIIB, also has adverse consequences in endothelial cells, antagonizing NO production and reparative mechanisms. In preclinical disease models, activating FcγR promote atherosclerosis whereas FcγRIIB is protective, and activating FcγR also enhance thrombotic and non-thrombotic vascular occlusion. The FcγR ligand C-reactive protein (CRP) has undergone intense study. Although in rodents CRP does not impact atherosclerosis, it causes hypertension and insulin resistance and worsens myocardial infarction. Massive data has accumulated indicating an association between increases in circulating CRP and coronary heart disease in humans. However, Mendelian randomization studies reveal that CRP is not likely a disease mediator. CRP genetics and hypertension warrants further investigation. Studies to date of genetic variants of activating FcγR are insufficient to implicate the receptors in coronary heart disease pathogenesis in humans. However, a link between FcγRIIB and human hypertension may be emerging. Further knowledge of the vascular biology of FcγR and their ligands will potentially enhance our understanding of cardiovascular disorders, particularly in patients whose greater predisposition for disease is not explained by traditional risk factors, such as individuals with autoimmune disorders.

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Section: Fcγ Receptor Subtypes and Functionsmentioning

confidence: 99%

Fcγ Receptors and Ligands and Cardiovascular Disease

Tanigaki

Sundgren

Khera

et al. 2015

Circulation Research

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“…However, activation of various receptor-mediated pathways, such as downregulation of intracellular innate and adaptive antiviral mechanisms, could also contribute to enhanced dengue pathogenesis3. Activating FcγRs are known to signal through phosphorylation of immunoreceptor tyrosine-based activation motif (ITAM) and spleen tyrosine kinase (Syk)4. Activated Syk controls a number of pathways, including actin remodelling necessary for phagocytosis5 and STAT-1-dependent interferon-stimulated gene (ISG) induction independent of interferon receptor signaling4.…”

mentioning

confidence: 99%

Dengue virus compartmentalization during antibody-enhanced infection

Ong

Zhang

Tan

et al. 2017

Sci Rep

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Secondary infection with a heterologous dengue virus (DENV) serotype increases the risk of severe dengue, through a process termed antibody-dependent enhancement (ADE). During ADE, DENV is opsonized with non- or sub-neutralizing antibody levels that augment entry into monocytes and dendritic cells through Fc-gamma receptors (FcγRs). We previously reported that co-ligation of leukocyte immunoglobulin-like receptor-B1 (LILRB1) by antibody-opsonized DENV led to recruitment of SH2 domain-containing phosphatase-1 (SHP-1) to dephosphorylate spleen tyrosine kinase (Syk) and reduce interferon stimulated gene induction. Here, we show that LILRB1 also signals through SHP-1 to attenuate the otherwise rapid acidification for lysosomal enzyme activation following FcγR-mediated uptake of DENV. Reduced or slower trafficking of antibody-opsonized DENV to lytic phagolysosomal compartments, demonstrates how co-ligation of LILRB1 also permits DENV to overcome a cell-autonomous immune response, enhancing intracellular survival of DENV. Our findings provide insights on how antiviral drugs that modify phagosome acidification should be used for viruses such as DENV.

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“…The importance of the inhibitory FcγRIIB in regulating many IgG-mediated responses in different leukocytes was made evident in FcγRIIB-deficient mice, which showed enhanced activity of many IgG-mediated cell responses including: phagocytosis, immune complex-mediated inflammation, IgG- mediated passive and active anaphylaxis, and IgE-mediated anaphylaxis [42,43]. They also showed enhanced dendritic cell maturation, and antigen presentation [44][45][46]. These results thus confirmed that FcγRIIB regulates initiation of cell functions by generating, together with activating Fcγ receptors, a threshold for cell activation [31,47].…”

Section: Coexpression Of Fcγ Receptors and Threshold For Cell Activationmentioning

confidence: 95%

Fc receptors: Cell activators of antibody functions

Rosales¹,

Uribe‐Querol²

2013

ABB

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At the onset of an infection early defense systems, such as complement, get into action. Specialized leukocytes (white blood cells) of the innate immune system, including monocytes, macrophages, and neutrophils also participate as a first line of defense against infections. These early responses are rapid but not very specific and are usually not enough to clear completely many infections. The adaptive immune system is also needed to finish the job against many microorganisms. Antibody molecules, produced during the adaptive immune response, are crucial for preventing recurrent infections. Although, IgG antibodies are essential for controlling infections, these molecules do not directly damage the microorganisms they recognize. Today, it is established that leukocytes of the innate immune system are responsible for the protective effects of these antibodies. IgG molecules bind to their cognate antigens and are in turn recognized by specific receptors (Fcγ receptors) on the membrane of leukocytes. Crosslinking these receptors on the surface of leukocytes leads to activation of several effector cell functions. These effector functions are geared toward the destruction of microbial pathogens and the induction of an inflammatory state that is beneficial during infections. However, in autoimmune diseases, antibodies can direct these effector functions against normal tissues and cause severe tissue damage. In recent years, several factors that can modulate the IgG-FcγR interaction have been elucidated. In this review, we describe the main types of Fcγ receptors, and our current view of how antibody variants interact with these receptors to initiate different cell responses. In addition, new findings on the signaling role of individual Fcγ receptors are also discussed.

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Selective blockade of the inhibitory Fcγ receptor (FcγRIIB) in human dendritic cells and monocytes induces a type I interferon response program

Cited by 128 publications

References 38 publications

Fcγ Receptors and Ligands and Cardiovascular Disease

Fcγ Receptors and Ligands and Cardiovascular Disease

Dengue virus compartmentalization during antibody-enhanced infection

Fc receptors: Cell activators of antibody functions

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