Sex-based differences in anti-viral immunity and SLE

描述(申请人提供)：系统性红斑狼疮是一种流行的自身免疫性疾病 女性的发病率明显高于男性。研究：关于 系统性红斑狼疮的病因学表明，遗传因素和环境因素都是 影响疾病的外显性。系统性红斑狼疮与既往 感染了Epstein Barr病毒(EBV)，但没有感染其他病毒 据报道。然而，一些研究未能找到病毒感染的证据 系统性红斑狼疮的病因。这可能是由于EBV感染的高流行率， 未知的宿主/病毒参数，以及多个遗传位点控制的事实 对系统性红斑狼疮易感性。新西兰小鼠易患系统性红斑狼疮，基因 已经确定了控制这些小鼠疾病易感性的基因座。 C57/BL6同源小鼠品系携带三种或三种以上 已经产生了命名为SLE 1、2和3的易感基因座。它有 已证明至少有两个基因座的存在是高血压病的必要条件 疾病外显性。我们认为EBV的小鼠病毒同源物可以 替代第二个基因座的存在，并可能在 小鼠有一个相同的基因座。我们还建议，这种影响可能有所不同。 在男性和女性中，部分原因是对感染的反应更强烈 在后者中。我们有一个伽马疱疹病毒感染的小鼠模型，它 与人类中的EBV感染非常相似，与EBV一样，能够诱导 非特异性B细胞激活和自身抗体产生，但不 诱导C57BL/6小鼠出现明显的自身免疫性疾病。因此，人的感染 携带小鼠伽马疱疹病毒(MHV-68)的同源小鼠可能提供一个有用的模型 用来检验我们的假设并剖析病毒可以 引发自身免疫性疾病。在本研究中，我们将确定是否 对MHV-68感染的免疫反应存在性别差异。 我们将确定是否感染了携带一种或多种易感小鼠 携带MHV-68的SLE易感基因可诱发或加重自身免疫 以及这种影响在雄性和雌性小鼠身上是否有所不同。我们还将 确定是否存在其表达被类似修饰的基因 疾病部位的存在和病毒感染，以及他们的 该基因的表达与自身免疫性疾病的诱发有关。

DESCRIPTION (provided by applicant): SLE is a prevalent autoimmune disease with a significantly higher incidence in females than in males. Studies on the etiology of SLE indicate that both genetic and environmental factors influence disease penetrance. A strong correlation between SLE and previous infection with Epstein Barr virus (EBV), but not with other viruses has been reported. However, some studies have failed to find evidence of a viral etiology for SLE. This may be due to the high prevalence of EBV infection, unknown host/virus parameters, and the fact that multiple genetic loci control susceptibility to SLE. New Zealand mice are susceptible to SLE, and genetic loci that control disease susceptibility in these mice have been identified. C57/BL6 congenic mouse strains carrying one or more of three of the susceptibility loci designated Sle 1, 2, and 3 have been generated. It has been shown that the presence of at least two loci is necessary for high disease penetrance. We propose that a mouse viral homologue of EBV could substitute for the presence of a second locus, and could trigger disease in mice congenic for a single locus. We also suggest that this effect may differ in males and females, due, in part, to the more vigorous response to infection in the latter. We have a mouse model of gammaherpesvirus infection, which closely resembles EBV infection in humans and, like EBV, is able to induce non-specific B cell activation and autoantibody production, but does not induce overt autoimmune disease in C57BL/6 mice. Therefore, infection of the congenic mice with mouse gammaherpesvirus (MHV-68) may provide a useful model in which to test our hypothesis and to dissect mechanisms by which viruses can trigger autoimmune disease. In the present study, we will determine whether there are sex-based differences in the immune response to MHV-68 infection. We will determine whether infection of susceptible mice, bearing one or more Sle susceptibility locus, with MHV-68 can induce or exacerbate autoimmune disease and whether this effect differs in male and female mice. We will also determine whether there are genes whose expression is similarly modified by the presence of disease loci and the viral infection and whether their expression correlates with the induction of autoimmune disease.