固有免疫和适应性的免疫系统调节失控引起的免疫功能紊乱是严重脓毒症发病的主要病理生理机制。HLA 分子参与的抗原呈递是适应性免疫反应的关键环节，其肽结合槽区氨基酸组成和空间结构的差异，决定了不同个体对同一抗原应答能力的差异。近年来相继发现经典HLA I和II类基因变异与个体免疫反应的程度相关，与多种感染性和自身免疫性疾病的易感性相关。HLA基因遗传变异是否与严重脓毒症的发生和发展相关，至今尚未见报告。近期我们利用PCR-SBT技术，对HLA-DR基因进行分型，发现HLA-DR基因变异与严重脓毒症易感性和患者早期的免疫功能状态显著相关。本课题拟利用高通量、先进的二代测序技术，通过对经典HLA I和II类基因多态性进行分型，系统的探讨其基因遗传变异与严重脓毒症易感性、病情程度和预后的相关性；并借助体内外功能研究，探讨HLA 遗传变异对严重脓毒症早期免疫功能状态的影响，为个体化的免疫调理提供参考。

The dysfunction of innate and adaptive immune responses plays an important role in the pathophysiology of severe sepsis. Antigen presentation is a pivotal process in the body's immune system by which macrophages, dendritic cells and other cell types capture antigens and then enable their recognition by T-cells. HLA genes encode molecules that are central to the host immune response and antigen presentation, and variation in peptide-binding grooves of the classical HLA genes likely affects severity and outcome after infection with pathogen. There is a growing consensus that specific HLA alleles and heterozygosity at HLA class I and II loci can exert a strong impact on progression and outcome in inflammatory, autoimmune, and infectious disease. However, until now there was no report to evaluate the association between HLA gene variation and severe sepsis. Recently, we found that HLA-DR gene might be one of the susceptibility genes to severe sepsis by PCR-SBT（Sequencing based typing）methods. Moreover, the most interesting finding was that the HLA-DR gene variation was associated with the HLA-DR expression levels in severe sepsis patients. In the future study, we will perform deep sequencing in the classical HLA I and HLA II genes using Roche-454 GS Flx Platform to explore the association between classical HLA gene variation and susceptibility, severity and outcome of severe sepsis. Finally, we will conduct functional experiments to analysis the influence of the associated variation on immune response in the severe sepsis patients. Our study will guide our understanding of how HLA risk alleles influence the immune repertoire and disease susceptibility; hence give help to develop immune regulation in disease therapy.