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Analysis of microRNAs in normal human peripheral B-cell development and patients with primary antibody deficiencies
Summary
Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia and recurrent infections. Otherwise its clinical presentation is very heterogeneous. Phenotypic and functional analysis revealed a plethora of immunological abnormalities in CVID patients, but the impaired B cell memory and plasma cell differentiation, possibly caused by a failed germinal centre reaction, is common in the majority of patients. Nevertheless, in only up to 10% of CVID patients the pathogenesis can so far be ascribed to specific genetic defects in genes encoding ICOS, TACI, CD19 and BAFF-R. The remaining 90% of CVID cases still lack a defined molecular cause. Recently, microRNAs were described as posttranscriptional regulators of gene expression in mammals. MicroRNAs control a variety of biological processes, including development, differentiation and function of the immune system. Several miRNAs have been shown to be involved in B-cell development and differentiation. In particular, the knockout of miR-155 in mice resulted in impaired germinal centre formation, impaired production of isotype-switched high affinity antibodies, low IgG levels and impaired memory responses. These findings motivated us to investigate the possible involvement of microRNAs in the pathogenesis of CVID. We therefore aim to: i.) Investigate the expression profiles of microRNAs in sorted B cells and B-cell subsets in healthy donors and selected CVID patients and correlate the miRNA expression profiles with clinical and immunological phenotypes in CVID patient subgroups; Methods used will be miRNA expression microarrays and real-time PCR using stem-loop primers; ii.) Analyze genomic DNA from CVID patients for mutations/polymorphisms (SNPs) in immune-related microRNA genes and their corresponding target mRNAs using a high-throughput 454 based sequencing approach; microRNAs and target genes of interest will be selected based on data mining using information from publications, public databases on microRNAs/mRNA targets and own experimental data; iii.) Perform functional studies of miRNAs in B cells from CVID patients and healthy donors using overexpression of miRNAs or knock-down of miRNAs with specific antagonists. Our goals in this project are to explore the role of miRNA in CVID disease pathogenesis and to evaluate the diagnostic and therapeutic potential of miRNA in CVID.
Cooperation Partners
- Taro Fukao, Max Planck Institut für Immunbiologie, Freiburg
- Klaus Warnatz, Abteilung für Rheumatologie und klinische Immunologie, CCI Universitätsklinikum Freiburg
Funding
SFB 620, TPC7, Deutsche Forschungsgemeinschaft "Analysis of microRNAs in normal human peripheral B-cell development and patients with primary antibody deficiencies"
