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

含 IgA 的免疫复合物在 SLE 浆细胞样树突细胞激活中的作用

• 批准号: 10170270
• 负责人: Jessica A Hamerman
• 金额: $ 21.76万
• 依托单位: BENAROYA RESEARCH INST AT VIRGINIA MASON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-22 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170270
• 关键词: Antibodies; Antigen-Antibody Complex; Antigens; Antinuclear Antibodies; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Responses; Binding; CD32 Antigens; Cells; Complex; Dendritic Cells; Dendritic cell activation; Deposition; Development; Disease; Endosomes; Fc Receptor; Fc(alpha) receptor; Future; Human; IgA receptor; IgE; Immune; Immune response; Immunoglobulin A; Immunoglobulin G; Interferon-alpha; Interferons; Leukocytes; Lupus; Mediating; Nucleic Acid Binding; Nucleic Acids; Organ; Pathogenesis; Pathologic; Patients; Plasma Cells; Production; Proteins; Reagent; Research Institute; Research Project Grants; Role; Sampling; Serum; Signal Transduction; Systemic Lupus Erythematosus; T cell response; TLR7 gene; Testing; Toll-like receptors; cytokine; disease registry; experimental study; human data; immune activation; novel; pleiotropism; receptor binding; repository; response; stoichiometry; synergism; uptake

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.

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，其特征在于存在 抗核酸及其相关蛋白的循环自身抗体，称为抗核抗体 抗体（ANA）。含有ANA和来自死亡细胞的自身抗原的免疫复合物在SLE中是病理性的 由于器官中的免疫复合物沉积，它们还通过增强SLE中的前馈回路， 白细胞中的自身免疫反应可以内吞这些复合物。ANA免疫复合物促进 核酸通过结合抗体Fc部分的受体进入内体，其中内体- 常驻Toll样受体（TLR）可在结合核酸时促进细胞因子产生。重要的是， 大多数研究都集中在IgG同种型ANA免疫复合物的摄取和功能上， 患者通常具有多种同种型的ANA，包括IgE和伊加。浆细胞样树突状细胞（pDC）是 一种内化ANA IC的白细胞，与SLE发病机制有关。pDC使用内体TLR 7和TLR 9 对核酸作出反应，导致I型IFN的分泌。这些细胞因子具有多效性作用， 免疫反应，所有这些都促进SLE中的免疫激活。pDC表达IgG结合Fc受体 FcγRII（CD 32），通过其内化含IgG的ANA IC。最近，pDC已被证明 表达FcεRI并内化含IgE的ANA IC，导致pDC IFNα的产生。IgE代表 仅占总血清抗体的~0.01%。相比之下，伊加占血清抗体的~15%，伊加ANA有 在约1/2的SLE患者中发现了IgA，但伊加在ANA IC中的作用尚未见报道。另夕h 尚未描述pDC上存在人特异性伊加Fc受体FcαRI（CD 89）。我们发现 新的初步数据表明，人pDC表达伊加FcR FcαRI（CD 89），SLE血清中的伊加是一种免疫调节因子。 IC介导的pDC IFNα分泌的关键组分。我们建议1）确定伊加的作用 抗smRNP免疫复合物活化中的自身抗体，和2）测试来自SLE的pDC 患者对含IgA的免疫复合物的应答增加。本提案中的实验将使用 来自健康对照受试者和狼疮患者的人类样本可通过Benaroya Research获得 免疫介导疾病登记和储存研究所。