Zhang Chi, Wang Jia, Dang Pengtao, Wei Yuhui, Wang Xiao, Brothwell Julie, Sun Yifan, Zhu Haiqi, So Kaman, Liu Jing, Wang Yijie, Lu Xiongbin, Spinola Stanley, Zhang Xinna, Cao Sha
Indiana University School of Medicine.
Indiana University.
Res Sq. 2025 Jan 17:rs.3.rs-5629379. doi: 10.21203/rs.3.rs-5629379/v1.
Antigen processing and presentation via major histocompatibility complex (MHC) molecules are central to immune surveillance. Yet, quantifying the dynamic activity of MHC class I and II antigen presentation remains a critical challenge, particularly in diseases like cancer, infection and autoimmunity where these pathways are often disrupted. Current methods fall short in providing precise, sample-specific insights into antigen presentation, limiting our understanding of immune evasion and therapeutic responses. Here, we present PSAA (PINN-empowered Systems Biology Analysis of Antigen Presentation Activity), which is designed to estimate sample-wise MHC class I and class II antigen presentation activity using bulk, single-cell, and spatially resolved transcriptomics or proteomics data. By reconstructing MHC pathways and employing pathway flux estimation, PSAA offers a detailed, stepwise quantification of MHC pathway activity, enabling predictions of gene-specific impacts and their downstream effects on immune interactions. Benchmarked across diverse omics datasets and experimental validations, PSAA demonstrates a robust prediction accuracy and utility across various disease contexts. In conclusion, PSAA and its downstream functions provide a comprehensive framework for analyzing the dynamics of MHC antigen presentation using omics data. By linking antigen presentation to immune cell activity and clinical outcomes, PSAA both elucidates key mechanisms driving disease progression and uncovers potential therapeutic targets.
通过主要组织相容性复合体（MHC）分子进行的抗原加工和呈递是免疫监视的核心。然而，量化MHC I类和II类抗原呈递的动态活性仍然是一项严峻挑战，尤其是在癌症、感染和自身免疫性疾病等这些途径经常被破坏的疾病中。目前的方法在提供对抗原呈递的精确、样本特异性见解方面存在不足，限制了我们对免疫逃逸和治疗反应的理解。在此，我们介绍PSAA（基于物理学神经网络增强的抗原呈递活性系统生物学分析），其旨在使用批量、单细胞和空间分辨转录组学或蛋白质组学数据来估计样本特异性的MHC I类和II类抗原呈递活性。通过重建MHC途径并采用途径通量估计，PSAA提供了对MHC途径活性的详细、逐步量化，能够预测基因特异性影响及其对免疫相互作用的下游效应。在各种组学数据集和实验验证中进行基准测试，PSAA在各种疾病背景下都表现出强大的预测准确性和实用性。总之，PSAA及其下游功能提供了一个使用组学数据分析MHC抗原呈递动态的综合框架。通过将抗原呈递与免疫细胞活性和临床结果联系起来，PSAA既阐明了驱动疾病进展的关键机制，又揭示了潜在的治疗靶点。
