The functional variant of the inhibitory Fcγ receptor IIb (CD32B) is associated with the rate of radiologic joint damage and dendritic cell function in rheumatoid arthritis

Radstake, Timothy R. D. J.; Franke, Barbara; Wenink, Mark H.; Nabbe, Karin C.; Coenen, Marieke J. H.; Welsing, Paco M J; Bonvini, Ezio; Koenig, Scott; Berg, Wim B. van den; Barrera, Pilar; Riel, P.L.C.M. van

doi:10.1002/art.22275

Cited by 55 publications

(52 citation statements)

References 48 publications

(69 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Genetic variants of CD32B gene are reported to affect the expression and function of this receptor and be associated with select autoimmune conditions in both mice and humans (40)(41)(42). We cannot completely exclude the possibility that specific CD32B polymorphisms, known to affect CD32B expression, partially account for our observations in RA; however, the extremely low prevalence of these polymorphisms limits their potential influence on our findings (41,42).…”

Section: Discussionmentioning

confidence: 73%

See 1 more Smart Citation

CD40 Mediates Downregulation of CD32B on Specific Memory B Cell Populations in Rheumatoid Arthritis

Zhang

Burch

Cai

et al. 2013

The Journal of Immunology

View full text Add to dashboard Cite

Altered B cell function is important in the pathogenesis of rheumatoid arthritis (RA). In this report, we show that patients with active RA have an increased frequency of CD32B low/neg cells in the CD27+IgD− memory B cell subset and that these changes are associated with phenotypic and functional B cell activation. Studies using PBMCs from healthy donors revealed that downregulation of CD32B on B cells is mediated by CD40–CD40L interactions and is potentiated by IL-4 and inhibited by both IL-10 and IL-21. These findings appear physiologically relevant because CD4 T cell expression of CD40L correlated with the frequency of CD32B low/neg cells in the CD27+IgD− memory B subset in patients with RA. Our data support a model in which high levels of CD40L, present on circulating T cells in patients with RA, causes B cell activation and CD32B downregulation, resulting in secondary protection of memory B cells from CD32B-mediated cell death.

show abstract

Section: Discussionmentioning

confidence: 73%

“…We cannot completely exclude the possibility that specific CD32B polymorphisms, known to affect CD32B expression, partially account for our observations in RA; however, the extremely low prevalence of these polymorphisms limits their potential influence on our findings (41,42).…”

Section: Discussionmentioning

confidence: 79%

CD40 Mediates Downregulation of CD32B on Specific Memory B Cell Populations in Rheumatoid Arthritis

Zhang

Burch

Cai

et al. 2013

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Treatment in vitro of both healthy donor and patient monocytes with IL-4 plus IL-10 led to increases in Fc␥RIIb expression and decreases in IgG-mediated cytokine production (45). It has also been shown that a Fc␥RIIb polymorphism that was less inhibitory could serve as a strong predictor of joint damage in rheumatoid arthritis patients (60).…”

Section: Discussionmentioning

confidence: 99%

Toll-like Receptor 4 Ligands Down-regulate Fcγ Receptor IIb (FcγRIIb) via MARCH3 Protein-mediated Ubiquitination

Fatehchand

Elavazhagan

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Monocytes and macrophages are critical for the effectiveness of monoclonal antibody therapy. Responses to antibody-coated tumor cells are largely mediated by Fc␥ receptors (Fc␥Rs), which become activated upon binding to immune complexes. Fc␥RIIb is an inhibitory Fc␥R that negatively regulates these responses, and it is expressed on monocytes and macrophages. Therefore, deletion or down-regulation of this receptor may substantially enhance therapeutic outcomes. Here we screened a panel of Toll-like receptor (TLR) agonists and found that those selective for TLR4 and TLR8 could significantly down-regulate the expression of Fc␥RIIb. Upon further examination, we found that treatment of monocytes with TLR4 agonists could lead to the ubiquitination of Fc␥RIIb protein. A search of our earlier microarray database of monocytes activated with the TLR7/8 agonist R-848 (in which Fc␥RIIb was down-regulated) revealed an up-regulation of membrane-associated ring finger (C3HC4) 3 (MARCH3), an E3 ubiquitin ligase. Therefore, we tested whether LPS treatment could up-regulate MARCH3 in monocytes and whether this E3 ligase was involved with LPS-mediated Fc␥RIIb down-regulation. The results showed that LPS activation of TLR4 significantly increased MARCH3 expression and that siRNA against MARCH3 prevented the decrease in Fc␥RIIb following LPS treatment. These data suggest that activation of TLR4 on monocytes can induce a rapid down-regulation of Fc␥RIIb protein and that this involves ubiquitination.Monocytes and macrophages play an important role in the innate immune response by phagocytosing IgG-opsonized infectious particles (1) and are major mediators in the destruction of tumor cells (2-5). Indeed, the importance of monocytes in clearing antibody-targeted tumor cells following the administration of therapeutic mAbs used in oncology indications has been well established (6 -8). However, despite showing statistically significant effects, the low rates of complete remission combined with the relatively high relapse rate suggest strongly that there is much room for improvement (9 -11). Therapeutic mAbs themselves are being improved, with the goal of increasing affinity toward Fc␥ receptors in some cases (12, 13). Along with this, immune modulators such as interferons (14, 15), interleukins (16 -20), synthetic compounds (21-23), and CpG oligonucleotides (16) are being explored as potential enhancers of antibody therapy.Antibody-dependent destruction of target cells is largely mediated by Fc␥ receptors (Fc␥Rs) 4 (5, 24, 25). Human monocytes and macrophages express at least four different functional Fc␥Rs: Fc␥RI, Fc␥RIIa, Fc␥RIIb, and Fc␥RIIIa (26). Of these, Fc␥RI, Fc␥RIIa, and Fc␥RIIIa are activating receptors that drive cellular responses to antibodies. These receptors either contain, within their cytoplasmic tails, an immune receptor tyrosine-based activation motif (ITAM), as in the case of Fc␥RIIa (27), or are associated with the ␥-chain homodimer that has an ITAM (28). The association of the ␥-chain is critical not only for surfa...

show abstract

“…The Fc RIIIa variant is less effective in IC binding, implicating impaired clearance of ICs might play a role in the pathogenesis of RA, similar to SLE [71]. A functional variant of the inhibitory Fc RIIb is associated with disease severity rather than susceptibility [72]. APCs from patients with this variant fail to develop an inhibitory phenotype upon IC binding, thereby stimulating pro-inflammatory immune responses and subsequent joint damage.…”

Section: Rheumatoid Arthritismentioning

confidence: 99%

Antigen-Presenting Cells and their Fcγ and Toll-Like Receptors: Leading Suspects in Autoimmunity

Santegoets¹,

Bon²,

Wenink³

et al. 2010

Open Arth J

Self Cite

View full text Add to dashboard Cite

Antigen-presenting cells (APCs) play an important role in the development of autoimmune diseases. These cells recognize pathogen associated molecular patterns but also endogenously produced ligands through toll-like receptors (TLRs). Aberrant activation of these receptors and the following intracellular signaling pathways can induce the deleterious production of pro-inflammatory cytokines. In genetically predisposed individuals this might lead to a breach in tolerance and eventually autoimmunity. IgG and IgG immune complexes (ICs), which are abundantly present in autoimmune diseases like systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and systemic sclerosis (SSc) are recognized by APCs via Fc gamma receptors (Fc Rs) and can also modulate their activation state. Upon their uptake specific antigens present in ICs are capable of stimulating APCs via their intracellular TLRs, increasing their capability to induce (autoreactive) T and B cell responses. This underscores their likely role in the generation and maintenance of autoimmunity. By focusing on three autoimmune diseases, SLE, RA and SSc, we will illustrate the importance of TLRs and Fc Rs in the pathogenesis of autoimmune diseases.

show abstract

The functional variant of the inhibitory Fcγ receptor IIb (CD32B) is associated with the rate of radiologic joint damage and dendritic cell function in rheumatoid arthritis

Cited by 55 publications

References 48 publications

CD40 Mediates Downregulation of CD32B on Specific Memory B Cell Populations in Rheumatoid Arthritis

CD40 Mediates Downregulation of CD32B on Specific Memory B Cell Populations in Rheumatoid Arthritis

Toll-like Receptor 4 Ligands Down-regulate Fcγ Receptor IIb (FcγRIIb) via MARCH3 Protein-mediated Ubiquitination

Antigen-Presenting Cells and their Fcγ and Toll-Like Receptors: Leading Suspects in Autoimmunity

Contact Info

Product

Resources

About