Epigenetic downregulation of the antibody response and inhibition of autoimmunity

抗体反应的表观遗传下调和自身免疫的抑制

• 批准号: 8658530
• 负责人: Paolo Casali
• 金额: $ 28.64万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-14 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8658530
• 关键词: Acetylation; Address; Affinity; Antibodies; Antibody Formation; Antigens; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocytes; Butyrates; CD40 Ligand; Cell physiology; Cells; Cellular biology; Chromatin; Clinical Trials; DNA; DNA Methylation; Data; Down-Regulation; Epigenetic Process; FDA approved; Functional RNA; Gene Silencing; Generations; Genes; Genetic Predisposition to Disease; Genetic Programming; Genetic Recombination; Genetic Transcription; Genetic Variation; Histone Acetylation; Histone Deacetylase Inhibitor; Histones; Human; Immune; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin Somatic Hypermutation; In Vitro; Injury; Insulin-Dependent Diabetes Mellitus; Islet Cell; Lead; Lupus; Mediating; Messenger RNA; MicroRNAs; Modification; Molecular; Monozygotic Twinning; Monozygotic twins; Mus; Mutate; Nature; Nuclear Antigens; Organ; Pathway interactions; Patients; Penetrance; Physiological; Plasma Cells; Play; Production; Proteins; RNA Degradation; Research; Role; SLEB1 gene; SLEB2 gene; SLEB3 gene; Signal Transduction Pathway; Site; Staging; Systemic Lupus Erythematosus; T-Independent Antigens; T-bet protein; TNFSF5 gene; Testing; Therapeutic; Time; Tissues; Translations; Up-Regulation; Valproic Acid; Vorinostat; base; crosslink; cytokine; epigenome; epigenomics; genome-wide; histone modification; human DICER1 protein; immunoregulation; inhibiting antibody; innovation; killings; lupus prone mice; microbial; novel; overexpression; pathogen; plasma cell differentiation; prevent; response; sound; stem; transcription factor; tumor

DESCRIPTION (provided by applicant): Epigenetic downregulation of the antibody response and inhibition of autoimmunity Epigenetic marks (including histone modifications, DNA methylation and microRNAs) "interact" with genetic programs to regulate B cell functions, such as class switch DNA recombination (CSR), somatic hypermutation (SHM) and plasma cell differentiation, thereby informing the antibody response. Epigenetic dysregulation can result in aberrant antibody responses, and compound genetic susceptibility to mediate autoimmunity, including systemic lupus (SLE), in which heavily mutated and class-switched (mainly IgG) autoantibodies to nuclear antigens, as secreted by large numbers of plasma cells, produce widespread tissue and organ injury. Prompted by our compelling preliminary findings in human and mouse B cells in vitro, and in normal and lupus-prone mice, we hypothesize that the epigenetic modulators histone deacetylase inhibitors (HDIs) inhibit CSR/SHM, plasma cell differentiation and, therefore, specific antibody and autoantibody responses, and prevent autoimmunity and "cure" mice in an advanced stage of lupus. We also argue that HDIs inhibit antibody and autoantibody responses by upregulating expression of selected microRNAs through enhanced acetylation and transcription of those microRNA host genes. As suggested by our preliminary data, we contend that HDIs upregulate miR-155, miR-181b, miR-93 to downregulate AID (central to CSR/SHM), miR- 146a to downregulate transcription factors Irf5 and (through Stat1) T-bet (important in CSR to IgG2a and lupus), miR-127 and miR-125b to downregulate Blimp1/Xbp1 (critical for plasma cell differentiation). The Casali lab is uniquely poised to test these novel hypotheses, owing to its record of accomplishment in B cell biology, molecular CSR/SHM and autoimmunity over the last 25 years, and the recently established cutting-edge epigenetic approaches. We will analyze the impact of HDIs (valproic acid, butyrate, suberoylanilide hydroxamic acid) on T-dependent and T-independent antibody responses in normal C57BL/6 and Balb/c mice, and autoantibody responses and autoimmunity in lupus-prone MRL/Faslpr/lpr and B6.NZM/Sle1.Sle2.Sle3 mice (Aim 1). We will address the downregulation of AID, Irf5, T-bet, Blimp1 and Xbp1, as targeted by (HDI-mediated) upregulation of miR-155, miR-181b, miR-93, miR-146a, miR-127 and miR-125b through enhanced acetylation of these microRNA "host genes" (Aim 2). Finally, we will define the role of microRNAs in mediating HDI inhibition of autoimmunity using lupus-prone mice lacking Dicer or Drosha in AID+ B cells or lacking microRNA targeting sites in Aicda and Prdm1 mRNAs, and identify genome-wide HDI-susceptible microRNA/target mRNA pairs in lupus mice (Aim 3). Our proposal is highly significant and innovative, as it addresses core epigenetic mechanisms of lupus and will have sustained impact on the fields of epigenetics, immunoregulation and autoimmunity. Finally, it is exquisitely translational, as (at the time when expensive biologics enter clinical trials) it provies a sound mechanistic basis for use of inexpensive and available epigenetic modulators as therapeutics in autoimmune diseases. !

描述(由申请人提供)：表观遗传下调抗体反应和抑制自身免疫表观遗传标记(包括组蛋白修饰、DNA甲基化和microRNAs)与遗传程序相互作用，调节B细胞功能，如类开关DNA重组(CSR)、体细胞高突变(SHM)和浆细胞分化，从而通知抗体反应。表观遗传失调可导致异常的抗体反应和复合遗传易感性，以介导包括系统性红斑狼疮(SLE)在内的自身免疫。在SLE中，大量浆细胞分泌的针对核抗原的严重突变和类别转换的自身抗体(主要是Ig G)会引起广泛的组织和器官损伤。根据我们在体外对人类和小鼠B细胞以及在正常和易患狼疮的小鼠中的令人信服的初步发现，我们假设表观遗传调节剂组蛋白脱乙酰酶抑制物(HDI)抑制CSR/SHM、浆细胞分化，从而抑制特异性抗体和自身抗体反应，并防止自身免疫并在狼疮晚期“治愈”小鼠。我们还认为，HDI通过增强这些microRNA宿主基因的乙酰化和转录，上调选定的microRNAs的表达，从而抑制抗体和自身抗体反应。根据我们的初步数据，我们认为HDI上调miR-155、miR-181b、miR-93下调AID(CSR/SHM的中心)，miR-146a下调转录因子IRF5和(通过STAT1)T-bet(在CSR中对IgG2a和狼疮起重要作用)，miR-127和miR-125b下调Blimp1/XBP1(对浆细胞分化至关重要)。卡萨利实验室在过去25年里在B细胞生物学、分子CSR/SHM和自身免疫方面取得的成就，以及最近建立的尖端表观遗传学方法，使其能够独一无二地准备测试这些新的假说。我们将分析HDIs(丙戊酸、丁酸、异羟肟酸)对正常C57BL/6和Balb/c小鼠T依赖和T非依赖抗体反应的影响，以及对狼疮易感MRL/Faslpr/LPR和B6.NZM/Sle1.Sle2.Sle3小鼠自身抗体反应和自身免疫的影响(目标1)。我们将解决AID、IRF5、T-BET、Blimp1和XBP1的下调，因为(HDI介导)通过增强这些microRNA“宿主基因”的乙酰化上调miR-155、miR-181b、miR-93、miR-146a、miR-127和miR-125b(目标2)。最后，我们将确定microRNAs在利用AID+B细胞中缺乏DICER或DROSHA的狼疮易感小鼠或在Aicda和Prdm1 mRNAs中缺乏microRNA靶点的狼疮易感小鼠的HDI抑制自身免疫中的作用，并在狼疮小鼠中识别全基因组对HDI敏感的microRNA/靶mRNA对(目标3)。我们的建议具有重要意义和创新性，因为它解决了狼疮的核心表观遗传机制，并将在表观遗传学、免疫调节和自身免疫领域产生持续影响。最后，它是精致的翻译，因为(在昂贵的生物制剂进入临床试验的时候)它为使用廉价和可用的表观遗传调节剂作为自身免疫性疾病的治疗药物提供了可靠的机制基础。好了！