Molecular mechanisms used by Fc-gamma receptors to trigger physiological responses.
Receptors for the constant region (Fc) of immunoglobulins play a pivotal role linking the humoral and cellular arms of the immune system. On leukocytes, aggregation of receptors (FcgRs) for immunoglobulin G (IgG) leads to a number of cellular responses including the internalisation of immune complexes (endocytosis), and/or of opsonised large particles/cells (phagocytosis). IgG –triggered Endocytosis or phagocytosis, stimulate a number of down-stream events including cytokine and matrix-protease release, activation of the NADPH oxidative burst, the production of eicosanoids (leukotriens and prostaglandins) and cellular migration. It also results in antigen presentation in association with either MHC Class I or II, resulting in CD8+ or CD4+ T cell activation respectively. In contrast, internalisation of apoptotic cells results in either no antigen presentation (degradation) or to presentation in the absence of activating co-receptors which induces T cell anergy and self tolerance. Fc g receptors specific for IgG (FcgRs) have been implicated in the pathogenesis of several diseases, in particular in inflammatory autoimmune diseases such as, systemic lupus erythromatous and rheumatoid arthritis. These Fc receptors, therefore, play critical roles in host defense mechanisms against invading pathogens, in auto-immune diseases and in cancer surveillance.
To mediate cell activation, the Fc-receptor initiates intracellular signalling cascades through the recruitment and activation of non-receptor tyrosine kinases. The cytoplasmic tail of the high affinity receptor for IgG, FcgRI, contains no recognised motif capable of activating tyrosine kinases. This receptor must recruit an accessory molecule to initiate signal transduction through the recruitment of non-receptor tyrosine kinases and the g chain has been shown to fulfil this role. The g chain exists as a homodimer being a small 7kDa membrane anchored protein that contains an immunoreceptor tyrosine activation motif (ITAM). It acts as the accessory molecule for signal transduction for a number of receptor including FcgRI, FceRI, FcaRI and FcgRIII. We have recently reported that, in interferon-g (IFNg) primed U937 cells, the g chain functionally couples FcgRI to a novel signalling pathway that involves the sequential activation of PI3-kinases, phosphatidyl choline phospholipase D (PLD) and sphingosine kinase.This pathway is necessary for efficient intracellular trafficking of FcgRI-internalised immune complexes to lysosomes for degradation the release of calcium from intracellular stores and the activation of the NADPH oxidase.
Our aim is to further investigate the molecular mechanisms that control FcgR-triggered physiological responses, including the release of enzymes from internal stores (degranulation), matrix metalloproteinase (MMP) release, cytokine release, the generation of leukotriens and prostaglandins (eicosanoids), internalisation, and antigen presentation, in inflammatory models, in order to identify key signalling molecules as target for novel therapeutic to treat inflammatory and autoimmune conditions.