MECHANISMS OF AUTOANTIBODY PRODUCTION IN SLE

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。特异性抗核抗体(如抗DNA、抗Sm)与系统性红斑狼疮(SLE)密切相关。为什么这些特异性在狼疮中产生，而不是在其他自身免疫性疾病中产生，原因尚不清楚。在非自身免疫倾向的小鼠中，Pristane可以诱导类似的自身抗体。初步研究强烈表明IL-4和促炎细胞因子IL-6、IL-12和IFNy与不同的自身抗体亚群的形成有关。将细胞因子环境从Th2改变为Th1可以改变特定品系小鼠产生的自身抗体。因此，细胞因子的过度产生可能是决定自身抗体表型的关键因素。我们发现SLE患者的自身抗体表型也会发生变化。我们假设，与小鼠一样，细胞因子的过度产生可能是决定自身抗体特异性的关键因素，即SLE中的自身抗体表型可能是不同细胞因子介导的不同形式SLE的标志物。将对该模型的几个预测进行评估。我们将寻找人类自身抗体表型，定义为一组自身抗体一起产生的频率比随机预测的更高(目标1)。例如，抗Sm和抗Ku之间存在很强的关联性。我们希望能找到更多的例子。这些表型的频率将在非裔美国人、高加索人和其他SLE队列中确定。然后，我们将确定自身抗体表型是否与某些细胞因子过度生产的模式相关(目标2)。通过使用替代标记物，将直接在血液中测量各种细胞因子，并在受影响的组织中间接测量各种细胞因子，其中一些有助于小鼠自身抗体的形成。最后，我们将开展前瞻性研究，以探索过量生产IFNy是否可能会增加人类狼疮自身抗体亚集的形成风险(目标3)。我们推测，可能有某些狼疮患者，包括许多非裔美国人，过度生产IFNY。另一组SLE患者，最常见的是高加索人，可能会过度产生一组不同的细胞因子。这可能有助于解释种族之间的一些显著的血清学差异。因此，与小鼠狼疮一样，人类系统性红斑狼疮可能是几种临床表现重叠但发病机制不同的疾病。如果是这样的话，这可能对自身免疫的早期诊断和治疗具有重要意义。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Antinuclear antibodies of particular specificities (e.g. anti-DNA, anti-Sm) are highly associated with systemic lupus erythematosus (SLE). Why these specificities are produced in lupus, but not other autoimmune diseases, is unexplained. Similar autoantibodies can be induced in non-autoimmune prone mice by pristane. Preliminary studies strongly implicate IL-4 and the proinflammatory cytokines IL-6, IL-12, and IFNy in the formation of different subsets of autoantibodies. Altering the cytokine milieu from Th2 to Th1 can change the autoantibodies produced by a given strain of mouse. Thus, cytokine overproduction may be a key factor determining the autoantibody phenotype. We have found that autoantibody phenotypes in SLE patients also can change. We hypothesize that, as in the mouse, cytokine overproduction may be a critical factor determining autoantibody specificity, i.e. autoantibody phenotypes in SLE may be markers for different forms of SLE mediated by different cytokines. Several predictions of this model will be evaluated. We will look for human ¿autoantibody phenotypes¿, defined as groups of autoantibodies produced together more frequently than predicted by chance (Aim 1). For instance, anti-Sm and anti-Ku are strongly associated with one another. We expect to find additional examples. The frequencies of these phenotypes will be determined in African-American, Caucasian, and other SLE cohorts. We will then determine whether the autoantibody phenotypes correlate with certain patterns of cytokine overproduction (Aim 2). A variety of cytokines, some of them contributing to autoantibody formation in mice, will be measured directly in the blood and indirectly in affected tissues through the use of surrogate markers. Finally, we will carry out prospective studies to explore the possibility that the overproduction of IFNy, which drives anti-nRNP/Sm autoantibody production in mice, increases the risk of developing a subset of autoantibodies in human lupus (Aim 3). We hypothesize that there may be certain lupus patients, including many African-Americans, who overproduce IFNy. Another group of SLE patients, most commonly Caucasians, may overproduce a different set of cytokines. This may help explain some of the striking serological differences between races. Thus, like murine lupus, human SLE may be several diseases with overlapping clinical manifestations but a different pathogenesis. If so, there could be significant implications for the early diagnosis of autoimmunity and its treatment.