Activation of target-tissue immune-recognition molecules by double-stranded polynucleotides
Activation of target-tissue immune-recognition molecules by double-stranded polynucleotides
复制标题
DOI：
10.1073/pnas.96.5.2285
复制
发表时间：
1999-03-02
影响因子：
11.1
通讯作者：
Kohn, LD
中科院分区：
文献类型：
--
作者：
Suzuki, K;Mori, A;Kohn, LD
各种组织中主要组织相容性复合体（MHC）I类和II类的异常表达与自身免疫性疾病有关。自身免疫反应可由病毒感染或组织损伤引发。我们表明，病毒或组织损伤增加MHC基因表达的能力是通过引入非免疫细胞的细胞质中的任何双链（ds）DNA或dsRNA片段复制的。激活是不依赖于序列的，由长度小至25 bp的ds多核苷酸诱导，并且不被单链多核苷酸复制。除了引起异常MHC表达外，ds核酸还增加抗原加工和呈递所必需的基因的表达：蛋白酶体蛋白（例如，LMP 2）、抗原肽转运蛋白;不变链、HLA-DM和共刺激分子B7.1。该机制不同于γ-干扰素（γ IFN），并且是γ-干扰素（γ IFN）的补充，即，ds多核苷酸增加I类比II类多得多，而γ IFN增加II类比I类多。与γ IFN不同，ds核酸还诱导或激活Stat 1、Stat 3、促分裂原活化蛋白激酶NF-κ B、II类反式激活因子RPX 5和IFN调节因子1。CpG残基不是这种效应的原因，ds多核苷酸的作用可以在除甲状腺细胞外的多种细胞类型中显示。我们认为，这种现象是一个合理的机制，可以解释如何病毒感染的组织或组织损伤触发自身免疫性疾病，它是潜在的相关基因治疗过程中诱导的宿主免疫反应。
Abnormal expression of major histocompatibility complex (MHC) class I and class II in various tissues is associated with autoimmune disease. Autoimmune responses can be triggered by viral infections or tissue injuries. We show that the ability of a virus or a tissue injury to increase MHC gene expression is duplicated by any fragment of double-stranded (ds) DNA or dsRNA introduced into the cytoplasm of nonimmune cells. Activation is sequence-independent, is induced by ds polynucleotides as small as 25 bp in length, and is not duplicated by single-stranded polynucleotides. In addition to causing abnormal MHC expression, the ds nucleic acids increase the expression of genes necessary for antigen processing and presentation: proteasome proteins (e.g., LMP2), transporters of antigen peptides; invariant chain, HLA-DM, and the costimulatory molecule B7.1. The mechanism is different from and additive to that of gamma-interferon (gamma IFN), i.e., ds polynucleotides increase class I much more than class II, whereas gamma IFN increases class II more than class I. The ds nucleic acids also induce or activate Stat1, Stat3, mitogen-activated protein kinase, NF-kappa B, the class II transactivator, RPX5, and the IFN regulatory factor 1 differently from gamma IFN. CpG residues are not responsible for this effect, and the action of the ds polynucleotides could be shown in a variety of cell types in addition to thyrocytes. We suggest that this phenomenon is a plausible mechanism that might explain how viral infection of tissues or tissue injury triggers autoimmune disease; it is potentially relevant to host immune responses induced during gene therapy.