Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, Maryland 20892, USA.
J Transl Med. 2011 Oct 12;9:174. doi: 10.1186/1479-5876-9-174.
In humans, the role and relationship between molecular pathways that lead to tissue destruction during acute allograft rejection are not fully understood. Based on studies conducted in humans, we recently hypothesized that different immune-mediated tissue destruction processes (i.e. cancer, infection, autoimmunity) share common convergent final mechanisms. We called this phenomenon the "Immunologic Constant of Rejection (ICR)." The elements of the ICR include molecular pathways that are consistently described through different immune-mediated tissue destruction processes and demonstrate the activation of interferon-stimulated genes (ISGs), the recruitment of cytotoxic immune cells (primarily through CXCR3/CCR5 ligand pathways), and the activation of immune effector function genes (IEF genes; granzymes A/B, perforin, etc.). Here, we challenge the ICR hypothesis by using a meta-analytical approach and systematically reviewing microarray studies evaluating gene expression on tissue biopsies during acute allograft rejection. We found the pillars of the ICR consistently present among the studies reviewed, despite implicit heterogeneity. Additionally, we provide a descriptive mechanistic overview of acute allograft rejection by describing those molecular pathways most frequently encountered and thereby thought to be most significant. The biological role of the following molecular pathways is described: IFN-γ, CXCR3/CCR5 ligand, IEF genes, TNF-α, IL-10, IRF-1/STAT-1, and complement pathways. The role of NK cell, B cell and T-regulatory cell signatures are also addressed.
在人类中，导致急性移植物排斥反应期间组织破坏的分子途径的作用和关系尚未完全了解。基于在人类中进行的研究，我们最近假设不同的免疫介导的组织破坏过程（即癌症、感染、自身免疫）共享共同的趋同最终机制。我们将这种现象称为“免疫排斥常数（ICR）”。ICR 的要素包括通过不同的免疫介导的组织破坏过程一致描述的分子途径，并显示干扰素刺激基因（ISGs）的激活、细胞毒性免疫细胞的募集（主要通过 CXCR3/CCR5 配体途径），以及免疫效应功能基因（IEF 基因；颗粒酶 A/B、穿孔素等）的激活。在这里，我们通过使用荟萃分析方法和系统地审查评估急性移植物排斥反应期间组织活检中基因表达的微阵列研究来挑战 ICR 假设。尽管存在隐含的异质性，但我们发现 ICR 的支柱在审查的研究中始终存在。此外，我们通过描述最常遇到的分子途径来提供对急性移植物排斥反应的描述性机制概述，从而认为这些分子途径最为重要。描述了以下分子途径的生物学作用：IFN-γ、CXCR3/CCR5 配体、IEF 基因、TNF-α、IL-10、IRF-1/STAT-1 和补体途径。还讨论了 NK 细胞、B 细胞和 T 调节细胞特征的作用。
