FcyRllb: signalling aspects and implications for autoimmune disease

Brown, Kirsty Stevenson (2001) FcyRllb: signalling aspects and implications for autoimmune disease. PhD thesis, University of Glasgow.

Abstract

Fc receptors (FcRs) provide a critical link between the humoral and cellular arms of the immune system through the targeting of antigen-antibody complexes to effector cells and modulation of an immune response. B cells express a low affinity IgG Fc receptor, FcgammaRIIb, which negatively regulates antigen receptor-mediated proliferative signalling through the binding of IgG- containing immune complexes. Co-ligation of the B cell antigen receptor (BCR) complex with FcyRIIb promotes the induction of B cell growth arrest in the G1 phase of the cell cycle and this ultimately results in commitment to apoptosis. Furthermore, FcgammaRIIb co-ligation also acts as an important negative feedback mechanism to switch off ongoing B cell responses once the pathogen has been cleared. Thus, on resting B cells, FcgammaRIIb acts to prevent aberrant B cell activation by immune complexes and suppresses the potential induction of autoimmunity. It was therefore the aim of this study to identify and characterise the key signalling pathways responsible for FcgammaRIIb-mediated negative regulation of BCR-mediated proliferation. During the course of this study, it emerged that in normal splenic B cells, FcgammaRIIb signalling appears to act by modulating the BCR signalling threshold, via the rapid recruitment and phosphorylation of a variety of phosphatases that ultimately result in the uncoupling of the BCR from MAPKinase activation. We have corroborated these published findings that the tyrosine kinases SHP-1 and SHP-2 and the inositol 5'-phosphatase, SHIP-1, are recruited during FcgammaRIIb signalling and we have extended these studies in that we have generated novel data regarding their mechanism of action. We now also show that FcgammaRIIb co-ligation, in addition to preventing the initiation of MAPKinase signalling, induces the rapid recruitment and activation of the MAPKinase phosphatase, Pac-1, resulting in the abrogation of ongoing ErkMAPK signalling. Furthermore, we show for the first time that FcgammaRIIb coligation results in the activation of the inositol 3'-phosphatase, PTEN, with kinetics which suggest that recruitment of this tumour suppressor element antagonises BCR-coupiing to the PI-3-K/Akt pathway and hence abrogates pro survival mechanisms in B cells. Taken together, this dual pronged mechanism of FcgammaRIIb-mediated abrogation of the ErkMAPKinase and Akt pathways provides a molecular rationale for the biological consequences of BCR-FcgammaRIIb co-ligation, namely commitment to growth arrest and apoptosis. Finally, analysis of potential downstream molecular targets of ErkMAPKinase and Akt revealed that FcgammaRIIb-signalling not only inhibits the phosphorylation and activation of the tumour suppressor protein, retinoblastoma (Rb), but also induces the phosphorylation and activation of the pro-apoptotic tumour suppressor protein, p53 and disruption of mitochondrial potential. Inhibition of Rb activation and consequent induction of genes required for the transition to S phase, is consistent with the observed FcgammaRIIb-mediated arrest in the G1 phase of the cell cycle. Similarly induction of p53 and collapse of mitochondrial integrity provide insight into the effector mechanisms underlying FcgammaRIIb-driven commitment to B cell apoptosis.To maintain homeostasis and tolerance to self-antigens, B cells require a balance of signals via activatory and inhibitory co-receptors. Thus, aberrant signalling through FcgammaRIIb during B cell development could lead to the induction of autoimmunity and/or promote the progression of certain autoimmune diseases. Consistent with this, recently published studies in FcgammaRIIb-deficient mice suggested that this lesion could result in collagen-induced arthritis (CIA) in normally resistant strains of mice. (Abstract shortened by ProQuest.).

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Immunology, Fc receptors .
• Subjects: Q Science > QR Microbiology > QR180 Immunology
• Colleges/Schools: College of Medical Veterinary and Life Sciences
• Supervisor's Name: Harnet, Dr. Maggie
• Date of Award: 2001
• Depositing User: Enlighten Team
• Unique ID: glathesis:2001-72685
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 11 Jun 2019 11:06
• Last Modified: 13 Jul 2022 14:11
• Thesis DOI: 10.5525/gla.thesis.72685
• URI: https://theses.gla.ac.uk/id/eprint/72685