自身免疫性糖尿病和人白细胞抗原B3906高度关联的分子机制研究

1型糖尿病（T1DM）是由于CD8+T细胞破坏胰岛β细胞，影响患者胰岛素分泌和血糖控制，进而引发的慢性自身免疫性疾病。自身免疫反应由胰岛β细胞中的MHC I分子的抗原呈递引起。假设MHC I的构象变化或错误折叠决定了T1DM的易感性。我们从细胞系、体外和计算机模拟三方面比较三种相关的MHC I亚型：包括两种T1DM易感型（高易感性HLA-B*39:06和低易感性HLA-B*39:01）和一种T1DM保护型（HLA-B*38:01）。通过模拟B*39:06的结构，解析B*39:01和B*38:01结合胰岛素肽的复合物晶体结构，比较其抗原肽结合模式，研究MHC I结合抗原肽的分子动力学，明确T1DM易感的条件。阐明与T1DM密切相关的HLA-B*39:06分子机制有助于开发结合HLA-B*39:06异常抗原呈递的小分子。如证明有效，则可发展为T1DM患者的治疗新方案。

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease, in which auto-reactive CD8+ T cells destroy pancreatic β cells. This negatively affects insulin production and blood glucose levels, leading to numerous complications. There is no cure for T1DM; patients receive insulin treatment and need to follow a healthy lifestyle. CD8+ T cell auto-reactivity is caused by antigen presentation by certain MHC class I molecules at the pancreatic β islets. Targeting T1DM-associated MHC class I molecules may prevent killing of insulin-producing β cells and be a via-ble treatment option..We hypothesized that conformational changes/misfolding of MHC class I alleles determine susceptibility to T1DM. We are characterizing and comparing three closely-related MHC I al-leles, two predisposing to T1DM (one strongly - HLA-B*39:06 and one weakly - HLA-B*39:01), in cell lines under normal and ER stress conditions, in vitro and in sillico. B*39:06 shows reduced folding efficiency and B*39:01 seems conformationally disordered with a higher flexibility in the middle and C terminal part of the antigen/peptide-binding groove..We are generating crystal structures of B*39 and B*38 alleles with insulin peptides to compare the mode they bind the antigen. We plan to determine the final structure of B*39:06. We will per-form molecular dynamics simulations to study the dynamics of these MHC I alleles with and without peptides to identify the requirements for T1DM susceptibility. Understanding the molecu-lar basis of the strong linkage of B*39:06 with T1DM will allow us to develop small molecules binding to the HLA-B*39:06 peptide-binding groove to block aberrant antigen presentation to CD8+ T lymphocytes. When proven effective in vitro, this approach could be further developed into treatment options for T1DM patients.