Murine gene knock-in models fo Omenn Syndrome and leaky SCID

Omenn 综合征和渗漏 SCID 的小鼠基因敲入模型

基本信息

批准号：
8102818
负责人：
Luigi Daniele Notarangelo
金额：
$ 47.91万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8102818
关键词：
Abelson murine leukemia virus Accounting Address Adoptive Transfer Affect Agonist Animal Model Antigens Architecture Atopic Dermatitis Autoantibodies Autoimmune Process Autologous B-Cell Development B-Lymphocytes Binding Bone Marrow Cell Line Cell physiology Clinical Colitis Cytomegalovirus Data Defect Dendritic Cells Development Disease Environmental Risk Factor Exfoliative Dermatitis Exposure to Functional disorder Generations Genes Genetic Hair Hassall&apos s Corpuscle Hematopoietic Stem Cell Transplantation Histones Home environment Human IL2RG gene IL7R gene IgE Immune Immune System Diseases Immune Tolerance Immunoglobulins Immunologic Deficiency Syndromes Impairment Individual Infant Infection Infiltration Knock-in Mouse Lead Lymphoid Lysine Mediating Modeling Molecular Murid herpesvirus 1 Mus Mutant Strains Mice Mutation Organ Other Genetics Oxazolone Patients Peripheral Phenotype Principal Investigator Process Rag1 Mouse Regulation Regulatory T-Lymphocyte Residual state Role SCID Mice Serum Severities Signal Transduction Skin Specific Pathogen Frees Stromal Cells Structure Syndrome T-Cell Development T-Lymphocyte Testing Thymic epithelial cell Thymus Gland Tissues Transcript V(D)J Recombination Wild Type Mouse antigen challenge autoreactive T cell central tolerance disease phenotype germ free condition immunopathology in vivo in vivo Model microbial mouse model mutant novel parainfluenza virus pathogen prevent programs research study thymocyte transcription factor

项目摘要

Omenn syndrome (OS) is a combined immunodeficiency characterized by severe tissue damage due to infiltrating, activated, oligoclonal and anergic T lymphocytes. Most patients with OS lack circulating B lymphocytes and show profound hypogammaglobulinemia, but normal or elevated serum IgE. We have found that most patients with OS carry hypomorphic mutations of the RAG genes that decrease but do not abolish V(D)J recombination. However, hypomorphic mutations in genes involved in V(D)J recombination may also cause leaky SCID, with accumulation of activated and anergic T cells, without tissue damage. We have found that the transcription factor Aire and tissue-specific transcripts are poorly expressed in the thymus of patients with OS, raising the possibility that negative selection of autoreactive T cells may not be properly in place. In addition, development of regulatory T cells (Tregs) is likely to be altered in OS, as the thymus of these patients lacks Hassall's corpuscles, which are involved in Tregs development. Finally, environmental factors may also be involved in the pathophysiology of OS, as it has been shown that the disease phenotype in infants with hypomorphic RAG mutations can be dramatically modified by exposure to pathogens. We will take advantage of three recently developed murine models of hypomorphic rag2, ragl, and Iig4 mutations to investigate the cellular and molecular mechanisms that underlie OS and leaky SCID. Our overall hypothesis is that the variable clinical and immunological phenotype associated with hypomorphic mutations in genes involved in V(D)J recombination reflects a different degree of impairment of V(D)J recombination that affects deletional and non deletional mechanisms of central tolerance, and that the resulting phenotype may be modified by environmental factors. To test this hypothesis,we will evaluate the V(D)J recombination activity of the mutants. We will analyze negative selection in these models, and use adoptive transfer to assess the role of impaired function of Tregs. Finally, we will challenge the mice with TLR agonists, MCMV and oxazolone to precipitate or accelerate the disease phenotype. We expect that detailed characterization of these unique animal models will provide critical information to understand the pathophysiology of OS and leaky SCID, but also of other, more common, disorders of immune regulation. The information that will be collected might be useful also for development of novel and more appropriate forms of treatment of these severe conditions of immune deficiency and dysreactivity.

Omenn综合征（OS）是一种合并的免疫缺陷，其特征是由于严重组织损害浸润，活化，寡克隆和厌食T淋巴细胞。大多数OS患者缺乏循环b 淋巴细胞并表现出严重的低磁性血症，但血清IgE正常或升高。我们有发现大多数OS患者携带降低但不降低但不降低的抹布基因的低形态突变废除V（d）J重组。然而，涉及V（d）J重组的基因的低形态突变可能会导致漏水的SCID，并积累活化的T细胞，而无需组织损伤。我们发现，转录因子AIRE和组织特异性转录本在 OS患者的胸腺，增加了自动反应性T细胞的阴性选择的可能性。正确到位。此外，调节性T细胞（TREG）的发展可能会在OS中改变，因为这些患者的胸腺缺乏与Tregs发育有关的Hassall的小体。最后，环境因素也可能参与OS的病理生理学，因为已经表明可能会通过暴露来显着修饰患有肤色抹布突变的婴儿的疾病表型病原体。我们将利用最近开发的himorioric rag2，ragl的三种鼠模型和IIG4突变，以研究OS和SCID渗漏的细胞和分子机制。我们的总体假设是，可变的临床和免疫表型与 V（d）J重组中涉及的基因中的低形态突变反映了不同程度的损害 v（d）J重组，会影响中央耐受性的缺失和非缺失机制，并且产生的表型可以通过环境因素来改变。为了检验该假设，我们将评估突变体的V（d）J重组活性。我们将分析在这些模型中进行负面选择，并使用收养转移来评估功能受损的作用 Tregs。最后，我们将用TLR激动剂，MCMV和恶唑酮挑战小鼠以沉淀或加速疾病表型。我们希望这些独特的动物模型的详细表征将为了解OS和SCID的病理生理学，但也了解其他更常见的疾病免疫调节。将收集的信息可能也可用于开发新颖和对这些严重的免疫缺陷和功能障碍的严重条件的治疗形式。