IgA-containing immune complexes in plasmacytoid dendritic cell activation in SLE

项目摘要 系统性红斑狼疮(SLE)是一种复杂的自身免疫性疾病，以 抗核酸及其相关蛋白质的循环自身抗体，称为抗核抗体 抗体(ANA)。含有ANA和死亡细胞自身抗原的免疫复合体在SLE中是病理性的 由于免疫复合体在器官中的沉积，它们还通过增强 白细胞中的自身免疫反应可以吞噬这些复合体。ANA免疫复合体促进 核酸通过与抗体的Fc部分结合的受体进入内体，其中内体- 驻留的Toll样受体(TLRs)可以促进结合核酸的细胞因子的产生。重要的是 大多数研究都集中在免疫球蛋白同型ANA免疫复合体的摄取和功能上，尽管SLE 患者通常有多种同工型的ANA，包括IgE和IgA。浆细胞样树突状细胞(PDCs)是 一种内化ANA IC的白细胞，与SLE的发病机制有关。PDC使用内体TLR7和TLR9 对核酸作出反应，导致I型干扰素的分泌。这些细胞因子具有多效性。 免疫反应，所有这些都促进了SLE的免疫激活。PDC表达与Ig G结合的Fc受体 FcγRII(CD32)，通过它内化含Ig G的抗核抗体IC。最近，PDC已经被证明是 表达FcεRI，内化含Ig E的ANA IC，诱导pDC干扰素α的产生。然而，IgE代表 仅占血清总抗体的0.01%。相比之下，IgA占血清抗体的15%，而IgA和ANA则有 在1/2的SLE患者中发现了IgA，但IgA在ANA IC中的作用尚未被研究。此外， 人特异性Ig A Fc受体FcαRI(CD89R)的存在尚未在pDC上被描述。在这里，我们展示 新的初步数据表明，人pDC表达IgA FCR FcαRI(CD89)，而SLE血清中的IgA是一种 IC介导的pDC干扰素α分泌的关键成分。我们建议1)确定免疫球蛋白A的作用 自身抗体在抗smRNP免疫复合体激活中的作用，以及2)检验来自SLE的PDC的假设 患者对含有IgA的免疫复合体的反应增强。该提案中的实验将使用 通过Benaroya Research获得来自健康对照受试者和狼疮患者的人类样本 建立免疫介导型疾病登记和储存库。

Project Summary Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by the presence of circulating autoantibodies to nucleic acids and to proteins with which they associate, termed anti-nuclear antibodies (ANA). Immune complexes containing ANA and self-antigen from dying cells are pathological in SLE due to immune complex deposition in organs, and they also promote a feed forward loop in SLE by enhancing autoimmune responses in leukocytes that can endocytose these complexes. ANA immune complexes facilitate nucleic acid entry to the endosome via receptors binding the Fc portion of antibodies, where the endosomal- resident Toll-like receptors (TLRs) can promote cytokine production upon binding nucleic acids. Importantly, most studies have focused on IgG isotype ANA immune complex uptake and function despite the fact that SLE patients often have ANAs of multiple isotypes, including IgE and IgA. Plasmacytoid dendritic cells (pDCs) are one leukocyte that internalizes ANA ICs implicated in SLE pathogenesis. pDCs use endosomal TLR7 and TLR9 to respond to nucleic acids, resulting in the secretion of type I IFNs. These cytokines have pleiotropic effects on the immune response, all of which promote immune activation in SLE. pDCs express the IgG binding Fc receptor FcγRII (CD32) through which they internalize IgG-containing ANA IC. Recently, pDC have been shown to express FcεRI and internalize IgE-containing ANA IC leading to pDC IFNα production. However, IgE represents only ~0.01% of total serum antibodies. In contrast, IgA makes up ~15% of serum antibodies and IgA ANA have been identified in ~1/2 of SLE patients, yet the function of IgA in ANA IC has not been studied. Additionally, the presence of the human-specific IgA Fc receptor FcαRI (CD89) has not been described on pDC. Here, we show novel preliminary data that human pDC express the IgA FcR FcαRI (CD89), and that IgA in SLE serum is a critical component of IC-mediated pDC IFNα secretion. We propose to 1) Determine the role of IgA autoantibodies in anti-smRNP immune complex activation, and 2) Test the hypothesis that pDC from SLE patients have increased responses to IgA-containing immune complexes. Experiments in this proposal will use human samples from healthy control subjects and lupus patients available through the Benaroya Research Institute Immune Mediated Disease Registry and Repository.