Sex-based differences in anti-viral immunity and SLE

描述（由申请人提供）：SLE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 SLE病因学表明遗传和环境因素 影响疾病转归。 SLE与既往疾病之间存在强相关性 感染爱泼斯坦巴尔病毒（EBV），但不与其他病毒， 报道 然而，一些研究未能找到病毒的证据， SLE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，以及多个遗传基因座控制的事实， SLE的易感性。 新西兰小鼠易患SLE，遗传 已经鉴定了控制这些小鼠中疾病易感性的基因座。 C57/BL 6同源小鼠品系携带以下三种中的一种或多种： 已经产生了指定为Sle 1、2和3的易感性基因座。 它有 已经表明，至少两个基因座的存在是高表达所必需的。 疾病复发。 我们认为，小鼠病毒的EBV同源物， 替代了第二个位点的存在，并可能引发疾病， 与单一基因座同源的小鼠。 我们还认为，这种影响可能不同， 在男性和女性中，部分原因是对感染的反应更强烈 在后者。 我们有一个γ疱疹病毒感染的小鼠模型， 与人类的EBV感染非常相似，并且像EBV一样，能够诱导 非特异性B细胞活化和自身抗体产生，但不 在C57 BL/6小鼠中诱导明显自身免疫性疾病。 因此， 携带小鼠γ疱疹病毒（MHV-68）的同源小鼠可提供有用的模型 来检验我们的假设，并剖析病毒 引发自身免疫性疾病 在本研究中，我们将确定 对MHV-68感染的免疫应答存在性别差异。 我们将确定是否感染易感小鼠，携带一个或多个 SLE易感位点，与MHV-68可诱发或加重自身免疫 以及这种效应在雄性和雌性小鼠中是否不同。 我们还将 确定是否有基因的表达被类似地修饰， 疾病位点和病毒感染的存在，以及它们是否 表达与自身免疫性疾病的诱导相关。

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.