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）：抗体反应的表观遗传下调和自身免疫性表观遗传标记的抑制（包括组蛋白修饰，DNA甲基化和microRNA）与遗传程序“相互作用”以调节B细胞功能，例如类别开关DNA重组（CSR）等B细胞功能，体细胞超数（SHM）和浆细胞分化，从而告知抗体反应。表观遗传失调可能会导致异常的抗体反应，以及对介导自身免疫性（包括全身性狼疮（SLE））的复合遗传易感性，其中大量突变和类别切换（主要是IgG）自抗体对核抗原的自身抗原，这是大量的血浆细胞，血浆细胞的秘密。产生广泛的组织和器官损伤。 在我们在体外的人和小鼠B细胞中以及在正常和狼疮易发的小鼠体内引起的初步发现引起的，我们假设表观遗传调节剂组蛋白脱乙酰基酶抑制剂（HDIS）抑制了CSR/SHM和自身抗体反应，并在狼疮的高级阶段预防自身免疫和“治愈”小鼠。我们还认为，HDIS通过增强乙酰化和这些microRNA宿主基因的转录来抑制抗体和自身抗体反应。正如我们的初步数据所建议的那样，我们争辩说，HDIS上调miR-155，miR-181b，miR-93以下调辅助（CSR/SHM的中心），miR-146a，以下调转录因子IRF5和（通过STAT1）T-Bet （对于CSR至关重要的IgG2A和狼疮），miR-127和miR-125b下调Blimp1/XBP1（对于浆细胞分化至关重要）。 Casali Lab唯一准备测试这些新的假设，这是由于其在过去25年中的B细胞生物学，分子CSR/SHM和自身免疫性以及最近建立的最先进的表观遗传方法的记录。我们将分析HDI（丙戊酸，丁酸酯，suberoylanilide羟丙酸）对正常C57BL/6和BALB/C小鼠的T依赖性和T-独立抗体反应的影响/lpr和b6.nzm/sle1.sle22.sle3小鼠（AIM 1）。我们将解决AID，IRF5，T-BET，BLIMP1和XBP1的下调，如（HDI介导的）MiR-155，miR-181b，miR-93，miR-93，miR-146a，miR-146a，miR-127和miR-的针对（HDI介导的）上调125b通过增强这些microRNA“宿主基因”的乙酰化（AIM 2）。最后，我们将使用缺少DICER或DROSHA在AID+ B细胞中缺少DICER或DROSHA的小鼠或缺乏AICDA和PRDM1 mRNA中缺乏MicroRNA靶向位点的小鼠，并识别MicroRNA在AICDA和PRDM1 mRNA中缺乏dicer或drosha在介导HDI抑制自身免疫性中的作用，并识别全基因组对基因组的HDI-Subsubsibles-subsubsibles-subsubsubsubsubsubsubsuspipsubsuptiblemorna/target狼疮小鼠中的mRNA对（AIM 3）。我们的提议非常重要和创新，因为它解决了狼疮的核心表观遗传机制，并将对表观遗传学，免疫调节和自身免疫的领域产生持续的影响。最后，这是精美的转化，因为（在昂贵的生物制剂进入临床试验时）证明是使用廉价且可用的表观遗传调节剂作为自身免疫性疾病的疗法的合理机械基础。呢