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Fc receptors (FcR) are the receptors for the Fc regions of immunoglobulins. They belong to several families of molecules. FcRs are defined by their specificity for immunoglobulin isotypes: FcγR bind IgG, FcαR bind IgA, FcεR bind IgE, FcμR bind IgM, and FcδR bind IgD.

Functions of FcδR

IgD mainly consists of the transmembrane form (mIgD) and secreted form (sIgD) in humans and mice. Accumulating evidence has shown that mIgD participates in B cell development, anergy, and regulated peripheral B cell immunity and tolerance. IgD exerts biological functions by binding to a specific membrane receptor (FcδR or IgDR). After the discovery of FcδR, further evidence demonstrated that the molecular weight of FcδR is approximately 70 kDa in humans, whereas two components of 78 and 38 kDa are the case for the mouse. In vivo and in vitro studies have suggested that this putative FcδR on T cells might play a role in the regulation of IgD. FcδR is expressed on both CD4+ and CD8+ human T cells and CD4+ murine T cells, and human FcδR can also be induced by IL-2, IL-4, and IFN-γ. FcδR could bind sIgD, mIgD, dimeric and polymeric or complexed IgD. Unlike most FcRs which belong to the Ig family, human FcδR has been reported as a lectin with binding affinity for the O-glycans of IgD, which also bind carbohydrate moieties of IgD. In addition, when T cells are induced to express FcδR, which can be attached to mIgD on B cells to promote the interaction of each homologous cell, enhanced antigen T cell and B cell responses are yielded. Meanwhile, as previously reported, enhancement of antibody production is observed in mice after injection of oligomeric IgD and is mediated by these FcδR+ T cells, while injection of monomeric IgD inhibits both FcδR+ upregulation and augmentation of antibody responses induced by simultaneous injection of oligomeric IgD.

Signaling Pathways of FcδR

Earlier mouse studies have shown that inhibitors of protein tyrosine kinase (PTK) completely prevented upregulation of FcδR in response to oligomeric IgD, suggesting that cross-linking of FcδR may induce signal transduction and functional consequences through one or more PTK activation pathways. Accumulating evidence suggests that p56 Lck following FcδR cross-linking plays an important role in the activation of downstream events. In mice, phosphorylation of Lck and total protein expression of FcδR were shown to be enhanced by IgD in mouse T cells in vitro. Scientists further reported that IgD was shown to bind to FcδR on human CD4+ T cells in a concentration-dependent manner and stimulate the activation and proliferation of these cells by enhancing phosphorylation of the activating tyrosine residue (Tyr 394) of Lck. Furthermore, FcδR cross-linking also resulted in tyrosine phosphorylation of PLC-γ. PLC-γ activation leads to PKC activation and release of the transcription factor, NFκB, calcium mobilization, as well as activation of ras and MAP kinase family members. This indicates that FcδR activation is closely related to T cell activation.

Schematic diagram of the FcδR signaling pathway. Fig.1 Schematic diagram of the FcδR signaling pathway. (Wu, 2021)

FcδR in Rheumatoid Arthritis (RA) Pathogenesis and Targeting Therapy

The previous studies have shown the abnormal expression of sIgD and mIgD in patients with RA. In addition, the expression of FcδR in RA patients is higher on T and B cells. Human in vitro studies has confirmed that IgD-FcδR crosslinking may be involved in enhancing the proliferation of PBMCs, inducing activation and FcδR expression of CD4+ T cells, indicating that the assumptive target of IgD is FcδR on T cells in RA. Accumulating reports have demonstrated the contribution of FcδR in RA progression. The IgD-Fc-Ig fusion protein is recommended to be administered during the early stage of RA to effectively block excessive IgD-FcδR crosslinking in RA.

FcRs involved in RA progression. Fig.2 FcRs involved in RA progression. (Wu, 2021)

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  1. Wu, Y.; et al. The prospects for targeting FcR as a novel therapeutic strategy in rheumatoid arthritis. Biochem Pharmacol. 2021 Jan;183:114360.

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