A role for human endogenous retrovirus-K (HML-2) in rheumatoid arthritis: investigating mechanisms of pathogenesis
A role for human endogenous retrovirus-K (HML-2) in rheumatoid arthritis: investigating mechanisms of pathogenesis
复制标题
DOI：
10.1111/j.1365-2249.2010.04110.x
复制
发表时间：
2010-06-01
影响因子：
4.6
通讯作者：
Nelson, P. N.
中科院分区：
文献类型：
--
作者：
Freimanis, G.;Hooley, P.;Nelson, P. N.
人类内源性逆转录病毒(HERV)是人类基因组中古老逆转录病毒感染的残留物。这些分子化石与现在的外源性逆转录病毒有相似之处，以前曾被认为与类风湿性关节炎(RA)的免疫病理学有关。探讨了HERV-K在RA中的发病机制，如分子模拟等。为了阐明HERV在RA中的作用，对与自身免疫有关的潜在自身抗原进行了扫描，以确定其与逆转录病毒表位的序列一致性。合成模拟共有表位的逆转录病毒短肽，用于检测类风湿关节炎患者和疾病对照的抗血清。还建立了一种新的实时聚合酶链式反应(PCR)方法，以准确地定量Herv-K(HML-2)Gag的表达水平，相对于标准化的管家基因表达。血清学和分子检测均显示，与疾病对照组相比，RA患者的Herv-K(HML-2)GAG活性显著增加。实时定量聚合酶链式反应检测发现，与炎症性疾病和健康对照组相比，RA患者HERV-K mRNA水平显著上调。外源病毒蛋白表达和致炎细胞因子也对Herv-K(HML-2)转录起调控作用。根据我们的数据，可以得出结论，与对照组相比，RA患者的HERV-K(HML-2)GAG活性显著升高。此外，还发现了影响滑膜内HERV活性的其他因素。RA患者在血清学和转录水平上的显著差异可能表明，RA是许多独立疾病实体的总称，其中特定的HERV基因多态性可能在疾病的发展中发挥作用。
P>Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections within the human genome. These molecular fossils draw parallels with present-day exogenous retroviruses and have been linked previously with immunopathology within rheumatoid arthritis (RA). Mechanisms of pathogenesis for HERV-K in RA such as molecular mimicry were investigated. To clarify a role for HERVs in RA, potential autoantigens implicated in autoimmunity were scanned for sequence identity with retroviral epitopes. Short retroviral peptides modelling shared epitopes were synthesized, to survey anti-serum of RA patients and disease controls. A novel real-time polymerase chain reaction (PCR) assay was also developed to quantify accurately levels of HERV-K (HML-2) gag expression, relative to normalized housekeeping gene expression. Both serological and molecular assays showed significant increases in HERV-K (HML-2) gag activity in RA patients, compared to disease controls. The real-time PCR assay identified significant up-regulation in HERV-K mRNA levels in RA patients compared to inflammatory and healthy controls. Exogenous viral protein expression and proinflammatory cytokines were also shown to exert modulatory effects over HERV-K (HML-2) transcription. From our data, it can be concluded that RA patients exhibited significantly elevated levels of HERV-K (HML-2) gag activity compared to controls. Additional factors influencing HERV activity within the synovium were also identified. The significant variation in RA patients, both serologically and transcriptionally, may be an indication that RA is an umbrella term for a number of separate disease entities, of which particular HERV polymorphisms may play a role in development.