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）：抗体应答的表观遗传下调和自身免疫的抑制表观遗传标记（包括组蛋白修饰、DNA甲基化和微小RNA）与遗传程序“相互作用”以调节B细胞功能，例如类别转换DNA重组（CSR）、体细胞超突变（SHM）和浆细胞分化，从而告知抗体应答。表观遗传失调可导致异常抗体应答，以及介导自身免疫的复合遗传易感性，包括系统性狼疮（SLE），其中大量浆细胞分泌的针对核抗原的严重突变和类别转换（主要是IgG）自身抗体产生广泛的组织和器官损伤。 通过我们在体外人类和小鼠B细胞以及正常和狼疮易感小鼠中令人信服的初步发现，我们假设表观遗传调节剂组蛋白去乙酰化酶抑制剂（HDIs）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，并预防自身免疫和“治愈”狼疮晚期小鼠。我们还认为，HDIs抑制抗体和自身抗体的反应，通过上调选定的microRNA的表达，通过增强乙酰化和这些microRNA宿主基因的转录。正如我们的初步数据所表明的，我们认为HDIs上调miR-155，miR-181 b，miR-93以下调AID（CSR/SHM的核心），miR-146 a以下调转录因子Irf 5和（通过Stat 1）T-bet（在CSR到IgG 2a和狼疮中很重要），miR-127和miR-125 b以下调Blimp 1/Xbp 1（对浆细胞分化至关重要）。 Casali实验室是唯一准备测试这些新的假设，由于其在B细胞生物学，分子CSR/SHM和自身免疫过去25年的成就记录，以及最近建立的尖端表观遗传方法。我们将分析HDI（丙戊酸、丁酸、辛二酰苯胺异羟肟酸）对正常C57 BL/6和Balb/c小鼠中T依赖性和T非依赖性抗体应答的影响，以及对狼疮易感MRL/Faslpr/lpr和B6.NZM/Sle1.Sle2.Sle3小鼠中自身抗体应答和自身免疫的影响（目的1）。我们将讨论AID、Irf 5、T-bet、Blimp 1和Xbp 1的下调，这是通过增强这些microRNA“宿主基因”的乙酰化作用（HDI介导）上调miR-155、miR-181 b、miR-93、miR-146 a、miR-127和miR-125 b实现的（Aim 2）。最后，我们将使用在AID+ B细胞中缺乏Dicer或Drosha或在Aicda和Prdm 1 mRNA中缺乏microRNA靶向位点的狼疮易感小鼠来确定microRNA在介导自身免疫的HDI抑制中的作用，并在狼疮小鼠中鉴定全基因组HDI易感的microRNA/靶mRNA对（目的3）。我们的建议是非常重要和创新的，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领域产生持续的影响。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剂提供了合理的机制基础。!