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Title: Intracellular signalling pathways activated by FcγRI
Author: Romero, Alirio Jose Melendez
ISNI:       0000 0001 3534 3220
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 1998
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The high affinity receptor for immunoglobulin G, FcgammaRI, plays a central role in host immune defence by linking the cellular and humoral arms of the immune system. However, the signalling pathways initiated by this receptor are poorly understood. In this thesis, the intracellular signalling pathways activated by immune complexes were studied using U937 cells as a model system to investigate the effect of differentiation on these pathways. Previous work has shown that, the nature and duration of the calcium transients initiated by immune complexes in these cells changes, as the cells differentiate into cells of a more macrophage phenotype. This thesis describes the signalling pathways underlying this change. Marked differentiation dependent differences in the signalling pathways activated by immune complexes were found. Thus, in cells differentiated to a more macrophage phenotype with dbcAMP, Fc receptor aggregation resulted in the activation of PLC. In cells primed with IFN-gamma, no activation of PLC could be detected. In contrast, immune complexes in these cells resulted in the activation of PLD. The switch in the activation of intracellular signalling pathways was found to result from a switch in the use of accessory molecules by FcgammaRI. Thus, in IFN-gamma primed cells, FcgammaRI signals through the recruitment of the gamma chain whereas in dbcAMP differentiated cells FcgammaRI appears to recruit FcgammaRIIa. A novel signalling pathway responsible for calcium transients and trafficking of immune complexes to lysosomes was identified. This pathway involved the sequential activation of PLD and sphingosine kinase with the generation of sphingosine-1-phosphate. In these cytokine primed cells, immune complexes also resulted in the activation of PI3-kinase. However, an unusual pattern of PIP3 production was observed. Both forms of Class I PI3-kinase were activated. Thus, the initial peak in PIP3 resulted from the activation of the tyrosine kinase (p85) dependent form of PI3-kinase, whereas the latter, prolonged elevation of PIP3, resulted from the activation of the betagamma dependent form of PI3-kinase. The switch in signalling pathway appears to dictate the isoform of PKC activated by FcgammaRI. Thus, in cytokine primed cells where PLD is activated and the resultant calcium transients are brief, only calcium independent isoforms were activated. In dbcAMP differentiated cells, where PLC activation results in prolonged calcium signals, only the calcium dependent PKC isoforms were activated.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Protein phosphorylation; Fc receptors