Müller-Hilke Brigitte, Mitchison N Avrion
Institute of Immunology, Medical Faculty, Schillingallee 70, 18055 Rostock, Germany.
Curr Pharm Des. 2006;12(29):3743-52. doi: 10.2174/138161206778559759.
Population studies reveal HLA class I and class II gene polymorphisms associated with all the common chronic autoimmune diseases, notably spondylarthropathies, rheumatoid arthritis, multiple sclerosis and type I diabetes. We here discuss the exceptionally high levels of nucleotide diversity in the MHC region likely to reflect not only balancing selection acting on the epitope binding sites but also natural selection operating on the promoter region. The latter possibility is supported by functional studies with promoters, higher levels of diversity in the promoters of class II than class I genes and the relatively high frequency of single nucleotide polymorphisms around transcription factor binding sites. This, we argue, reflects the need for an appropriate level of signalling at the immunological synapse. We here summarise our knowledge of HLA promoter polymorphisms and how these translate into differential expression, T cell polarisation and inflammation. We discuss current strategies for pharmaceutical intervention in HLA expression.
人群研究揭示了与所有常见慢性自身免疫性疾病相关的HLA I类和II类基因多态性，尤其是脊柱关节病、类风湿性关节炎、多发性硬化症和I型糖尿病。我们在此讨论MHC区域中异常高水平的核苷酸多样性，这可能不仅反映了作用于表位结合位点的平衡选择，还反映了作用于启动子区域的自然选择。后一种可能性得到了启动子功能研究、II类基因启动子中比I类基因更高的多样性水平以及转录因子结合位点周围单核苷酸多态性相对高频率的支持。我们认为，这反映了在免疫突触处需要适当水平的信号传导。我们在此总结我们对HLA启动子多态性的认识，以及这些多态性如何转化为差异表达、T细胞极化和炎症。我们讨论了目前针对HLA表达进行药物干预的策略。
