Mast cells are known to play an important role in allergic events and in other inflammatory reactions through varied intracellular signaling transduction proteins. RasGRP4 is a mast cell-restricted guanine nucleotide exchange factor (GEF) and diacylglycerol (DAG)/phorbol ester receptor. Interleukin (IL) -13, a critical cytokine for allergic inflammation, exerts its effects through a complex receptor system including IL-4Rα, IL-13Rα1 and IL-13Rα2. IL-13Rα2 has been reported to be a decoy receptor for IL-13. My experiments indicate that the mast cell specific RasGRP4 protein regulates the level of IL 13Rα2 and controls IL-13/ IL 13Rα1-mediated intracellar signaling events in mast cells. Phosphorylation of STAT6 plays an important role in airway hyperresponsiveness and asthma. The development of therapeutics that can regulate RasGRP4 could be used to modulate the IL-13-induced phosphorylation of STAT-6 that may be used as therapy in patients with asthma. SLE is a complex, heterogeneous systemic autoimmune disease characterized by the presence of high levels of autoantibodies. Dysregulation of RasGRP1, a Ras active gene, in mice resulted in a SLE-like disorder. Yasuda and coworkers demonstrated that a defective isoform of RasGRP1 (Δ11) was present in a subset of patients with SLE. My experiments indicate that RasGRP1 upregulates the expression of IL2RG in T cells. In contrast the Δ11 RasGRP1 isoform expressed in a subset of SLE patients leads to defective expression of IL2RG. The IL2RG chain is a common chain which forms part of a number of different receptors eg. IL-2, 4, 7, 9, 15, 21. IL-2 as well as IL-21, which shares sequence homology with IL-2, has been reported to be involved in the generation of regulatory T cells (Tregs). In SLE patients, CD4 + CD25+ Tregs, which play an essential role in controlling immunologic tolerance to self-antigens and preventing autoimmunity, are significantly decreased when compared with healthy controls. The accumulative evidence suggests that the defective isoform of RasGRP1 (Δ11) downregulates expression of IL2RG in SLE patients?? T cells and this could effect the generation of CD4 + CD25+ Tregs. This may be another immunological mechanism in loss of tolerance observed in patient with SLE.
| Identifer | oai:union.ndltd.org:ADTP/232636 |
| Date | January 2009 |
| Creators | Qi, Miao, Clinical School - St George Hospital, Faculty of Medicine, UNSW |
| Publisher | Publisher:University of New South Wales. Clinical School - St George Hospital |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | http://unsworks.unsw.edu.au/copyright, http://unsworks.unsw.edu.au/copyright |
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