Adv Exp Med Biol. 2014;809:163-83. doi: 10.1007/978-1-4939-0398-6_10.
The anti-inflammatory and immune regulatory functions of the ubiquitin-editing and NF-kappaB inhibitory protein A20 are well documented in vitro, and in multiple animal models. The high rank held by A20 in the cell's physiologic anti-inflammatory defense mechanisms is highlighted by the striking phenotype of A20 knockout mice, characterized by cachexia, multi-organ failure, and premature death. Even partial depletion of A20, as in A20 heterozygous mice, significantly alters NF-kappaB activation in response to pro-inflammatory activators, even though these mice are phenotypically unremarkable at baseline. A recent burst of genome wide association studies (GWAS), fueled by advances in genomic technologies and analysis tools, uncovered associations between single nucleotide polymorphisms (SNPs) at the TNFAIP3/A20 gene locus and multiple autoimmune and inflammatory diseases in humans. Interestingly, some of these studies emphasized significant associations between TNFAIP3/A20 SNPs imparting decreased expression or loss of NF-kappaB inhibitory function, and susceptibility to systemic lupus erythematosus (SLE) and coronary artery disease (CAD). These clinical data phenocopy partial loss of A20 in mouse models of inflammatory diseases, thereby incriminating TNFAIP3/A20 deficiency as a pathogenic culprit in autoimmune and inflammatory diseases. In this chapter, we undertook a thorough review of studies that explored association between TNFAIP3/A20 SNPs and human autoimmune and inflammatory diseases. Beyond the prognostic value of TNFAIP3/ A20 SNPs for assessing disease risk, their implication in the pathogenic processes of these maladies prompts the pursuit of A20-targeted therapies for disease prevention/treatment in patients harboring susceptibility haplotypes.
A20 在体外和多种动物模型中具有抗炎和免疫调节功能，这一点已有充分的文献记载。A20 在细胞生理抗炎防御机制中的重要地位，突出表现在 A20 敲除小鼠的显著表型上，其特征为恶病质、多器官衰竭和早逝。即使 A20 部分缺失，如 A20 杂合子小鼠，也会显著改变 NF-κB 对促炎激活物的激活，尽管这些小鼠在基线时表型无明显异常。最近，由于基因组技术和分析工具的进步，全基因组关联研究（GWAS）大量涌现，发现了 TNFAIP3/A20 基因座上的单核苷酸多态性（SNP）与人类多种自身免疫和炎症性疾病之间的关联。有趣的是，其中一些研究强调了 TNFAIP3/A20 SNP 赋予 NF-κB 抑制功能降低或丧失的表达或缺失与系统性红斑狼疮（SLE）和冠心病（CAD）易感性之间的显著关联。这些临床数据与炎症性疾病小鼠模型中 A20 的部分缺失相吻合，从而将 TNFAIP3/A20 缺陷归咎于自身免疫和炎症性疾病的致病罪魁祸首。在这一章中，我们对探讨 TNFAIP3/A20 SNP 与人类自身免疫和炎症性疾病之间关联的研究进行了全面回顾。除了 TNFAIP3/A20 SNP 对评估疾病风险的预后价值外，它们对这些疾病发病机制的影响促使人们寻求针对 A20 的治疗方法，以预防/治疗携带易感性单倍型的患者的疾病。
