RESUMO
Recent large-scale association studies have identified over 100 MS risk loci. One of these MS risk variants is single-nucleotide polymorphism (SNP) rs17066096, located ~14 kb downstream of IL22RA2. IL22RA2 represents a compelling MS candidate gene due to the role of IL-22 in autoimmunity; however, rs17066096 does not map into any known functional element. We assessed whether rs17066096 or a nearby proxy SNP may exert pathogenic effects by affecting microRNA-to-mRNA binding and thus IL22RA2 expression using comprehensive in silico predictions, in vitro reporter assays, and genotyping experiments in 6,722 individuals. In silico screening identified two predicted microRNA binding sites in the 3'UTR of IL22RA2 (for hsa-miR-2278 and hsa-miR-411-5p) encompassing a SNP (rs28366) in moderate linkage disequilibrium with rs17066096 (r (2) = 0.4). The binding of both microRNAs to the IL22RA2 3'UTR was confirmed in vitro, but their binding affinities were not significantly affected by rs28366. Association analyses revealed significant association of rs17066096 and MS risk in our independent German dataset (odds ratio = 1.15, P = 3.48 × 10(-4)), but did not indicate rs28366 to be the cause of this signal. While our study provides independent validation of the association between rs17066096 and MS risk, this signal does not appear to be caused by sequence variants affecting microRNA function.
Assuntos
Regiões 3' não Traduzidas , Regulação da Expressão Gênica , MicroRNAs/metabolismo , Esclerose Múltipla/genética , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina/genética , Sítios de Ligação , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Células HEK293 , Humanos , Masculino , RNA Mensageiro/metabolismo , Fatores de RiscoRESUMO
Intravenous immunoglobulins (IVIg) are used in treatment of a broad spectrum of diseases. Immunoglobulin replacement therapy is the standard treatment for immunodeficiencies with compromised humoural immunity. Use of this method as an immunomodulating therapy ranges from transplantation and treatment of autoimmune-haematological diseases to treatment of various neuroimmunological clinical entities. Limited quantitative availability due to dependence on human donors as a source of IVIg, coupled with high treatment costs, make necessary a highly responsible and evidence-based approach with these agents. Discussion of the indications and currently valid recommendations on use of IVIg in treatment of immunomediated demyelinating diseases of the nervous system is based on existing clinical studies. We describe further neurological indications for use of IVIg as well as mechanisms of action and adverse effects of its use.