The causes of MHC-I-opathies in cellular stress

主要组织相容性复合体(MHC)I类分子(在人类中称为人类白细胞抗原(HLAI))是对细胞内病原体和肿瘤产生细胞毒性适应性反应所必需的。过继反应的特异性依赖于来自非自身(例如，病毒或肿瘤)蛋白的多肽片段的准确和有效的呈现，来自每个个体的两个等量表达的等位基因的六个潜在不同的HLAI分子中的一个。自我与非我的区别通过消除自身反应性T细胞得到保障。然而，一组自身反应性疾病(如强直性脊柱炎和其他脊柱关节病、Behçet病、银屑病、鸟弹头脉络膜视网膜病)显示出与个体HLAI等位基因的强烈遗传联系。过去40年来积累的大量遗传数据最近导致了将这些自身反应性疾病归类为MHC-I-opathies。有趣的是，在疾病个体中，还没有检测到与疾病相关的CD8+T细胞对特定的多肽-HLAI复合体的反应。这表明存在其他免疫机制(例如，NK细胞对人类白细胞抗原-I的天然反应；细胞应激)，不依赖于所提的多肽。我们以前对大量HLAI分子的研究支持这样的观点，即某些HLAI同种异型在生物化学上是不稳定的，低蛋白质稳定性会导致错误折叠的HLAI蛋白在细胞内积累。在这种情况下，HLAI在细胞表面的抗原提呈减少，积累的HLAI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相关的每个单独的HLAI蛋白的稳定性，评估它们与细胞应激的联系，并确定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，以提高它们的稳定性，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.