BLyS and IFN responses to antigen challenge in human SLE

描述(申请人提供)：系统性红斑狼疮(SLE)以B细胞异常激活为特征。循环中的浆母细胞产生的自身抗体有助于疾病的表现。根据遗传分析，SLE中B细胞的异常激活可能是由于控制B细胞激活的机制固有的过度激活，和/或由于暴露于异常抗原而刺激这些途径，例如含有来自未被错误清除的凋亡细胞的核小体物质的免疫复合体。已发表的和初步的观察表明，IFN1的增加、BLyS的增加和浆母细胞的诱导之间存在机械联系。SLE中BLyS/BAFF-R系统固有的高活性可能是由IFN1引起的，可推动SLE中B细胞的激活。正如初步数据所记录的那样，这项提议的研究人员有独特的分析方法来分析人类的BLyS和IFN1反应。为了诱导依赖BLyS或IFN1的免疫反应，我们将用肺炎球菌被膜抗原或流感病毒抗原挑战SLE受试者(不处于活动发作或接受细胞毒治疗)和健康对照组。众所周知，肺炎能诱导强大的浆母细胞反应，流感疫苗已被证明能激活干扰素诱导的基因。我们将确定在对任何一种抗原的免疫反应中，SLE和健康受试者在BLyS的产生、IFN1通路的诱导或浆母细胞的产生方面是否有所不同。我们的长期目标是确定在人类系统性红斑狼疮中是否存在诱导B细胞激活的内在机制的过度活跃。在这项R21中，我们建议进行一项初步的、有限的研究，旨在衡量SLE和健康受试者之间这些反应的变异性，因为我们需要开发执行适当的功率计算所需的数据。考虑到预期的反应变异性，我们的目标是：目标1.测量SLE和健康受试者对肺炎球菌和流感疫苗的浆母细胞反应的变异性，目标2.确定BLyS或BAFF-R的占有率是否在对肺炎球菌多糖或病毒抗原的正常免疫反应中发生增加，如果是，则确定在SLE和健康受试者中这种反应的变异性，目标3.确定血清IFN1或IFN1诱导的PBMC基因的增加是否发生在对肺炎球菌多糖或病毒抗原的正常免疫反应中，如果是，确定SLE和健康受试者之间这种反应的变异性。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is characterized by abnormal activation of B cells. Circulating plasmablasts produce autoantibodies that contribute to disease manifestations. The abnormal activation of B cells in SLE could result from inherent hyperactivity of the mechanisms that control B cell activation, as suggested by genetic analyses, and/or from stimulation of these pathways by exposure to abnormal antigens, such as immune complexes containing nucleosomal material from improperly cleared apoptotic cells. Published and preliminary observations suggest a mechanistic link between increased IFN1, increased BLyS and the induction of plasmablasts. An inherent hyperactivity, perhaps induced by IFN1, of the BLyS/BAFF-R system in SLE could drive B cell activation in SLE. The investigators on this proposal have unique assays for analysis of the BLyS and IFN1 responses in humans, as documented in the preliminary data. To induce a BLyS- or IFN1-dependent immune response, we will challenge SLE subjects (not in active flare or undergoing cytotoxic therapy) and healthy controls with either pneumococcal capsule antigens or with influenza viral antigens. Pneumbvax is known to induce a robust plasmablast response and the flu vaccine has been shown to activate IFN-inducible genes. We will determine whether the production of BLyS, the induction of IFN1 pathways or the generation of plasmablasts differs between the SLE and healthy subjects during an immune response to either type of antigen. Our long-term goal is to determine whether or not there is an inherent hyperactivity of the mechanisms that induce B cell activation in human SLE. In this R21, we propose an initial, limited study designed to measure the variability in these responses between SLE and healthy subjects because we need to develop the data required to perform a proper power calculation. Given the expected variability in responses, our aims are: Aim 1. Measure the variability in plasmablasts responses to pneumovax and flu vaccine in SLE and healthy subjects, Aim 2. Determine whether an increase in BLyS or BAFF-R occupancy occur in a normal immune response to either pneumococcal polysaccharides or viral antigens and, if so, the variability in this response in SLE and healthy subjects, Aim 3. Determine whether an increase in serum IFN1 or in IFNl-induced genes in PBMC occurs in a normal immune response to either pneumococcal polysaccharides or viral antigens and, if so, the variability in this response between SLE and healthy subjects.