Genome-wide association studies (GWAS) involve analysis of dozens of thousands of samples. It is not surprising that the polymorphisms of the IL2RA gene are associated with the development of a number of autoimmune diseases such as type I diabetes (Lowe et al., 2007), multiple sclerosis (Hafler et al., 2007), Gravis disease (Brand et al., 2007), systemic lupus (Harley et al., 2008) and rheumatoid arthritis (Stahl et al., 2010). It was found that daclizumab inhibited formation of lymphoid tissue inducer (LTi) cells, which play a role in chronic inflammation, and stimulated production of immunoregulatory CD56 bright natural killer cells (Perry et al., 2012). Meanwhile, daclizumab, a specific IL-2 blocker based on anti-IL2Rα antibody, was effective in treatment of multiple sclerosis (Wynn et al., 2010). On the other hand, without IL-2 regulatory T-cells do not develop at all, which strongly promotes the progression of autoimmune diseases (Fehervari et al., 2006). On the one hand, it was shown that in the absence of IL-2 the effector T-cells proliferate slower leading to delayed development of autoimmune reaction. These two groups of cells play opposite roles in development of autoimmune diseases which in turn suggests a contradictory role of the receptor for IL-2. The binding of interleukin-2 (IL-2) to its receptor activates effector T-cells enhancing autoimmunity processes and regulatory T-cells involved in attenuating and terminating inflammatory reactions. However, rare variants of several SNPs (rs139767239, rs115133228, rs12722502, rs12722635) genetically linked to either rs706778 and/or rs706779 significantly influenced the activity of E1, E3 and E5 enhancers, presumably by disrupting EBF1, GABPA and ELF1 binding sites. Neither rs706778 nor rs706779 SNPs, both associated with a number of autoimmune diseases, had any effect on the activity of the enhancer E2. The E4 enhancer with minor T variant of rs61839660 SNP demonstrated reduced activity due to disrupted binding of MEF2A/C transcription factors (TFs). We described five enhancers containing the selected SNPs that stimulated activity of the IL2RA promoter in a cell-type specific manner, and tested the effect of specific SNP alleles on activity of the respective enhancers (E1 to E5, labeled according to the distance to the promoter). With bioinformatics analysis we the dissected the first intron of the IL2RA gene and selected several single nucleotide polymorphisms (SNPs) that may influence the regulation of the IL2RA gene in cell types relevant to autoimmune pathology.
A large number of polymorphic alleles of the IL2RA locus are associated with the development of various autoimmune diseases.
Annual Review of Immunology Annual Reviews IL2RA gene encodes the alpha subunit of a high-affinity receptor for interleukin-2 which is expressed by several distinct populations of lymphocytes involved in autoimmune processes. My current scientific challenge is exploring the hypothesis of whether all major medical needs can be approached via cytokine blockade. This success was made possible by enthusiastic support from many laboratory and clinical colleagues and taught us that cytokines are important rate-limiting steps and hence good therapeutic targets. These experiments defined the concept of a TNF-dependent cytokine cascade driving the manifestations of RA, which led to successful clinical trials of anti-TNF monoclonal antibody in RA patients, heralding a major change in medical practice. Linking upregulated antigen presentation to autoimmunity led to an investigation of the role of cytokines in rheumatoid arthritis (RA), in collaboration with Ravinder Maini.
After my initial studies on immune cell culture and immune regulation, I returned to an analysis of the pathogenesis of human autoimmunity in London. Translating Molecular Insights in Autoimmunity into Effective Therapy Translating Molecular Insights in Autoimmunity into Effective TherapyĪutoimmunity and the pathogenesis of autoimmune diseases were a major focus of the Walter and Eliza Hall Institute, where I started my research career.
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