The causes of MHC-I-opathies in cellular stress

主要组织相容性复合体（MHC）I类分子（称为人类白细胞抗原（HLA I））对于针对细胞内病原体和肿瘤的细胞毒性适应性应答是必不可少的。过继应答的特异性依赖于来自非自身（例如，病毒或肿瘤性）蛋白质，每六种潜在不同的HLA I分子之一，来自每个个体中HLA-A、HLA-B和HLA-C基因座的两个等显性表达等位基因。自我与非自我的区分是通过消除自身反应性T细胞来保证的。然而，一组自身反应性疾病（例如强直性脊柱炎和其他脊柱关节病、白塞氏病、银屑病、鸟射性脉络膜视网膜病变）显示出与个体HLA I等位基因的强烈遗传联系。在过去的四十年中积累了大量的遗传数据，最近导致将这些自身反应性疾病分类为MHC-I-病。有趣的是，在患病个体中，尚未检测到与疾病相关的CD 8 + T细胞对特定肽-HLA I复合物的反应。这表明存在独立于呈递肽的额外免疫机制（例如来自NK细胞的针对HLA-I的先天应答;细胞应激）。我们以前对许多HLA I分子的研究支持了这样的观点，即某些HLA I同种异型可能是生化不稳定的，并且低蛋白稳定性可能导致错误折叠的HLA I蛋白的细胞内重复。在这种情况下，HLA I的抗原呈递在细胞表面减少，积累的HLA I可以刺激细胞应激途径，如未折叠蛋白反应（UPR）。在这项工作中，我们将确定与MHC-I-opathies相关的每个个体HLA I蛋白的稳定性，评估它们与细胞应激的联系，并定义它们之间的共同结构特征。最后，根据我们的专业知识，我们将使用小分子进行筛选，以提高其稳定性并防止细胞模型中的病理表型。

Major histocompatibility complex (MHC) class I molecules (termed human leukocyte antigen (HLA I in human) are essential for mounting a cytotoxic adaptive response to intracellular pathogens and tumors. The specificity of the adoptive response relies on the accurate and efficient presentation of peptide fragments from non-self (e.g., viral or neoplastic) proteins by one of each six potentially dif-ferent HLA I molecules from two equidominantly expressed alleles of HLA-A, HLA-B and HLA-C loci in each individual. Discrimination of self from non-self is safeguarded by the elimination of auto-reactive T cells. Nevertheless, a group of autoreactive diseases (e.g. ankylosing spondylitis and oth-er spondyloarthropathies, Behçet’s disease, psoriasis, birdshot chorioretinopathy) display a strong genetic link to individual HLA I alleles. Accumulation of vast genetic data over the last four decades has recently lead to classification of those autoreactive diseases as MHC-I-opathies. Interestingly, in diseased individuals, disease-related CD8+ T cell responses to specific peptide-HLA I complexes have not been detected. This suggests that there are additional immune mechanisms (e.g innate response from NK cells directed towards HLA-I; cellular stress), independent of the presented peptides. Our previous work on numerous HLA I molecules supports the idea that certain HLA I allo-types can be biochemically unstable, and that low protein stability can result in intracellular accumu-lation of misfolded HLA I proteins. In such cases, antigen presentation by HLA I is diminished at the cell surface, and accumulated HLA I can stimulate cellular stress pathways such as unfolded protein response (UPR). In this work, we will determine the stability of each individual HLA I protein associated with MHC-I-opathies, assess their link to cellular stress, and define common structural features among them. Finally, according to our expertise, we will perform screens with small molecules to improve their stability and prevent pathological phenotypes in cellular models.