Two distinct regions of FC gamma RI initiate separate signalling pathways involved in endocytosis and phagocytosis.

Davis, William C.; Harrison, Patrick T.; Hutchinson, Michael J.; Allen, Janet M.

doi:10.1002/j.1460-2075.1995.tb07019.x

Cited by 94 publications

(86 citation statements)

References 24 publications

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“…The ␥-chain cytoplasmic domain contains immunoreceptor tyrosine-based activation motifs (ITAMs) and the ␥-chain cytoplasmic domain is both necessary and sufficient for Fc␥RI␣-induced functions (33,34). Biochemical studies have shown that both cross-linking of Fc⑀RI␣-␥-chain complex and the Fc␥RI␣-␥-chain complex result in activation of Src family kinases and the tyrosine kinase p72 Syk (4,(35)(36)(37)(38).…”

Section: Discussionmentioning

confidence: 99%

A Comparison of Mediators Released or Generated by IFN-γ-Treated Human Mast Cells Following Aggregation of FcγRI or FcεRI

Okayama

Hagaman

Metcalfe

2001

The Journal of Immunology

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The high affinity receptor for IgG (FcγRI, CD64) is expressed on human mast cells, where it is up-regulated by IFN-γ and, thus, may allow mast cells to be recruited through IgG-dependent mechanisms in IFN-γ-rich tissue inflammation. However, the mediators produced by human mast cells after aggregation of FcγRI are incompletely described, and it is unknown whether these mediators are distinct from those produced after activation of human mast cells via FcεRI. Thus, we investigated the release of histamine and arachidonic acid metabolites and examined the chemokine and cytokine mRNA profiles of IFN-γ-treated cultured human mast cells after FcγRI or FcεRI aggregation. Aggregation of FcγRI resulted in histamine release and PGD2 and LTC4 generation. These responses were qualitatively indistinguishable from responses stimulated via FcεRI. Aggregation of FcεRI or FcγRI led to an induction or accumulation of 22 cytokine and chemokine mRNAs. Among them, seven cytokines (TNF-α, IL-1β, IL-5, IL-6, IL-13, IL-1R antagonist, and GM-CSF) were significantly up-regulated via aggregation of FcγRI compared with FcεRI. TNF-α mRNA data were confirmed by quantitative RT-PCR and ELISA. Furthermore, we confirmed histamine and TNF-α data using IFN-γ-treated purified human lung mast cells. Thus, aggregation of FcγRI on mast cells led to up-regulation and/or release of three important classes of mediators: biogenic amines, lipid mediators, and cytokines. Some cytokines, such as TNF-α, were released and generated to a greater degree after FcγRI aggregation, suggesting that selected biologic responses of mast cells may be preferentially generated through FcγRI in an IFN-γ-rich environment.

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Section: Discussionmentioning

confidence: 99%

A Comparison of Mediators Released or Generated by IFN-γ-Treated Human Mast Cells Following Aggregation of FcγRI or FcεRI

Okayama

Hagaman

Metcalfe

2001

The Journal of Immunology

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“…Despite the capacity of monocytes and macrophages to internalize IgG-opsonized substrates (23)(24)(25), the mechanism of antigenic modulation promoted by monocytes has been generally presumed to be due to internalization of IgG Ab/target Ag immune complexes by the cancer cells, rather than by monocytes.…”

Section: T Argeting Of Ags On Cancer Cells By Mabs Has Been a Key Strmentioning

confidence: 99%

“…8A) (47). Phagocytosis is characterized by sequential phosphorylation of cellular proteins mediated by Src and Syk kinases (66), whereas simple endocytosis of small Ab-Ag complexes does not require tyrosine kinase action (23). Based on these considerations, we propose the following mechanism for shaving.…”

Section: Role Of Fc␥r In the Mechanism Of Shavingmentioning

confidence: 99%

“…It is likely that shaving is mediated by cellular Fc␥RI (53), which, despite the level of competing monomeric IgG in the circulation, can interact effectively with opsonized B cells containing large amounts of bound RTX. These effector cells may include both fixed cells, such as Kupffer cells and liver endothelial cells, as well as circulating monocytes (23,24,79).…”

Section: Relevance Of Shaving To Rtx Therapy For Cllmentioning

confidence: 99%

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The Shaving Reaction: Rituximab/CD20 Complexes Are Removed from Mantle Cell Lymphoma and Chronic Lymphocytic Leukemia Cells by THP-1 Monocytes

Beum

Kennedy

Williams

et al. 2006

The Journal of Immunology

203

226

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Clinical investigations have revealed that infusion of immunotherapeutic mAbs directed to normal or tumor cells can lead to loss of targeted epitopes, a phenomenon called antigenic modulation. Recently, we reported that rituximab treatment of chronic lymphocytic leukemia patients induced substantial loss of CD20 on B cells found in the circulation after rituximab infusion, when rituximab plasma concentrations were high. Such antigenic modulation can severely compromise therapeutic efficacy, and we postulated that B cells had been stripped (shaved) of the rituximab/CD20 complex by monocytes or macrophages in a reaction mediated by FcγR. We developed an in vitro model to replicate this in vivo shaving process, based on reacting rituximab-opsonized CD20+ cells with acceptor THP-1 monocytes. After 45 min at 37°C, rituximab and CD20 are removed from opsonized cells, and both are demonstrable on acceptor THP-1 cells. The reaction occurs equally well in the presence and absence of normal human serum, and monocytes isolated from peripheral blood also promote shaving of CD20 from rituximab-opsonized cells. Tests with inhibitors and use of F(ab′)2 of rituximab indicate transfer of rituximab/CD20 complexes to THP-1 cells is mediated by FcγR. Antigenic modulation described in previous reports may have been mediated by such shaving, and our findings may have profound implications for the use of mAbs in the immunotherapy of cancer.

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“…This association is not a prerequisite for transient receptor expression but is necessary for stable expression (11,12). The ␥-chain cytoplasmic domain contains an immunoreceptor tyrosine activation motif (ITAM) and current data suggest that the ␥-chain cytoplasmic domain is both necessary and sufficient for Fc␥RIa induced functions (13)(14)(15). Biochemical studies have shown that cross-linking of the Fc␥RIa⅐␥-chain complex results in activation of a Src family kinase(s) and the tyrosine kinase p72…”

mentioning

confidence: 99%

The Cytoplasmic Domain of Human FcγRIa Alters the Functional Properties of the FcγRI·γ-Chain Receptor Complex

Edberg¹,

Yee²,

Rakshit³

et al. 1999

Journal of Biological Chemistry

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The ␥/-chain family of proteins mediate cell activation for multiple immunoglobulin receptors. However, the recognition that these receptors may have distinct biologic functions suggests that additional signaling elements may contribute to functional diversity. We hypothesized that the cytoplasmic domain (CY) of the ligand binding ␣-chain alters the biological properties of the receptor complex. Using macrophage Fc␥RIa as a model system, we created stable transfectants expressing a full-length or a CY deletion mutant of human Fc␥RIa. Both receptors functionally associate with the endogenous murine ␥-chain. However, we have established that the CY of Fc␥RIa directly contributes to the functional properties of the receptor complex. Deletion of the Fc␥RIa CY leads to slower kinetics of receptorspecific phagocytosis and endocytosis as well as lower total phagocytosis despite identical levels of receptor expression. Deletion of the CY also converts the phenotype of calcium independent Fc␥RIa-specific phagocytosis to a calcium-dependent phenotype. Finally, deletion of the CY abrogates Fc␥RIa-specific secretion of interleukin-6 but does not affect production of interleukin-1␤. These results demonstrate a functional role for the CY of Fc␥RIa and provide a general model for understanding how multiple receptors that utilize the ␥-chain can generate diversity in function.Fc␥ receptors play a central role in the handling of immune complexes, regulation of inflammatory responses, antibody secretion, and T cell activity (1-4). Common to each of these functions is the initiation of tyrosine phosphorylation following receptor cross-linking (5) and the involvement of the ␥/ subunits leading to the view that Fc receptors subserve redundant signaling functions. However, recent evidence suggests that these receptors are not redundant. For example, Fc␥RIIIa appears necessary for initiating the Arthus inflammatory reaction (6, 7), while Fc␥RIa and Fc␣RI can down-regulate inflammatory responses by initiating the secretion of IL 1 -10 and IL-1ra, respectively (4, 8). The basis for these differences are unknown.Fc␥RI is expressed on the cell surface in association with the ␥-chain (9, 10). This association is not a prerequisite for transient receptor expression but is necessary for stable expression (11, 12). The ␥-chain cytoplasmic domain contains an immunoreceptor tyrosine activation motif (ITAM) and current data suggest that the ␥-chain cytoplasmic domain is both necessary and sufficient for Fc␥RIa induced functions (13-15). Biochemical studies have shown that cross-linking of the Fc␥RIa⅐␥-chain complex results in activation of a Src family kinase(s) and the tyrosine kinase p72Syk (2,5). Activation of these kinases results in tyrosine phosphorylation of the ␥-chain and the initiation of a signaling cascade that can culminate in the induction of degranulation, phagocytosis, an oxidative burst, ADCC activity and the induction of gene transcription. The association between Fc␥RIa and ␥-chain may also be important in the formation of a h...

show abstract

Two distinct regions of FC gamma RI initiate separate signalling pathways involved in endocytosis and phagocytosis.

Cited by 94 publications

References 24 publications

A Comparison of Mediators Released or Generated by IFN-γ-Treated Human Mast Cells Following Aggregation of FcγRI or FcεRI

A Comparison of Mediators Released or Generated by IFN-γ-Treated Human Mast Cells Following Aggregation of FcγRI or FcεRI

The Shaving Reaction: Rituximab/CD20 Complexes Are Removed from Mantle Cell Lymphoma and Chronic Lymphocytic Leukemia Cells by THP-1 Monocytes

The Cytoplasmic Domain of Human FcγRIa Alters the Functional Properties of the FcγRI·γ-Chain Receptor Complex

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