Testing a role for activation-induced deaminase in Omenns syndrome B-cell autoimm

测试激活诱导的脱氨酶在 Omenns 综合征 B 细胞自身免疫中的作用

• 批准号: 8176094
• 负责人: ERIK SELSING
• 金额: $ 8.25万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-20 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8176094
• 关键词: Affect; Anti-DNA Antibodies; Antibodies; Antibody-Producing Cells; Antigen-Antibody Complex; Autoantibodies; Autoimmune Diseases; Autoimmunity; B cell differentiation; B-Cell Development; B-Lymphocytes; Biological Assay; Bone Marrow; Cells; Chromatin; Coupled; Development; Disease; Exhibits; Failure; Gene Mutation; Gene Proteins; Gene Targeting; Generations; Genes; Genetic; Genetic Recombination; Germ; Human; Immune response; Immunoglobulin Class Switching; Immunologic Deficiency Syndromes; Infection; Lead; Lupus Erythematosus; Lymphocyte; Lymphoid Tissue; Lymphopenia; Mature B-Lymphocyte; Mature Lymphocyte; Mature T-Lymphocyte; Measures; Modeling; Mouse Strains; Mus; Mutation; Organ; Parents; Patients; Peripheral; Persons; Process; RNA; Receptor Gene; Reporting; Research; Research Design; Role; Serum; Surface; Syndrome; System; T-Lymphocyte; Testing; Tissues; Variant; activation-induced cytidine deaminase; central tolerance; cytokine; fighting; human disease; interleukin-21; mouse model; mutant; receptor

DESCRIPTION (provided by applicant): Omenn syndrome is a human disease that exhibits an unusual combination of immunodeficiency coupled with autoimmunity. Patients have few mature T cells or B cells, and have poor immune responses. On the other hand, patients show substantial serum antibodies with elevated levels of self-reactive antibodies. Hypomorphic mutations in recombination-activating genes (RAG) are some of the best-characterized genetic defects associated with Omenn syndrome. RAG proteins are critical for recombination of receptor genes during development of B and T lymphocytes and hypomorphic RAG mutations lead to limited generation of mature lymphocytes. However, the causes of autoimmunity in the disease are not clear. During the past several years, our research groups have collaborated on studies of B cell differentiation and tolerance during early B cell development. We have recently shown that isotype switching occurs even in immature B cells in the bone marrow, counter to the prevailing paradigm that switching was limited to activated mature B cells. We have also found that immature B cell switching is greatly elevated in a mouse strain (564Igi strain) that models human System Lupus Erythematosus (SLE), and develops autoimmune disease. Because isotype switched B cells respond more strongly to stimulation, we have hypothesized that isotype switching in immature B cells can lead to a breakdown of central tolerance checkpoints and can result in autoimmune disease. We have also developed mutant 564Igi variants that either can or cannot undergo isotype switching in immature B cells. Preliminary studies indicate that autoimmunity is greatly reduced in 564Igi mice that lack early B-cell isotype switching, supporting our hypothesis that early B-cell switching can circumvent tolerance and can lead to autoimmune disease. The SLE-like 564Igi mouse model effectively reproduces many features of human SLE, but the gene- targeted anti-RNA antibody genes in the 564Igi strain are a genetic construct that is not found in human SLE patients. We want to test the role of early B-cell switching in the development of autoimmunity arising from a genetic mutation known to be involved in human autoimmunity. Recent reports have described mouse models of the human Omenn syndrome disease. These have a gene-targeted hypomorphic RAG gene and, thereby, are analogous to patients with hypomorphic RAG. The mouse models replicate the lymphopenia, the serum antibody levels, and the autoimmunity of the human disease. Furthermore, some features of Omenn syndrome, such as anti-RNA, anti-chromatin and anti-DNA antibodies, as well as elevated serum cytokines that regulate isotype switching, are shared with SLE. We will use Omenn syndrome mouse model variants that cannot undergo isotype switching in immature B cells to test whether these exhibits reduced autoimmunity. Our tests will indicate whether or not tolerance breakdown through isotype switching might be a common feature of various B cell autoimmune diseases. PUBLIC HEALTH RELEVANCE: Antibody producing cells (B cells) are critical for making antibodies to fight infections from many different germs. B cells are born in the bone marrow; in the process of making B cells that can attack many different germs, the body makes many B cells that could attack a person's own cells and organs (self-reactive B cells). Self-reactive B cells are known to be deleted or inactivated in the bone marrow, this process is called tolerance. Sometimes tolerance fails and this can cause autoimmunity. In one mouse model of autoimmunity, we have found that tolerance failure appears to be caused by B cells that change one of their surface receptors in a particular way. Our proposed studies are designed to find out whether this mechanism for tolerance failure is a general one that occurs in other B cell autoimmune diseases.

描述（由申请人提供）：Omenn综合征是一种人类疾病，表现为免疫缺陷与自身免疫的不寻常组合。患者体内成熟的T细胞或B细胞较少，免疫反应较差。另一方面，患者表现出大量血清抗体，自身反应性抗体水平升高。重组激活基因（RAG）的亚形态突变是与Omenn综合征相关的一些最具特征的遗传缺陷。在B淋巴细胞和T淋巴细胞的发育过程中，RAG蛋白对受体基因的重组至关重要，低形态RAG突变导致成熟淋巴细胞的产生有限。然而，该病自身免疫的原因尚不清楚。在过去的几年中，我们的研究小组合作研究了早期B细胞发育过程中的B细胞分化和耐受性。我们最近的研究表明，同型转换甚至发生在骨髓中未成熟的B细胞中，这与普遍的模式相反，即转换仅限于激活的成熟B细胞。我们还发现，在模拟人类系统红斑狼疮（SLE）并发展为自身免疫性疾病的小鼠品系（564Igi品系）中，未成熟B细胞转换大大升高。由于同型转换的B细胞对刺激的反应更强烈，我们假设未成熟B细胞的同型转换可能导致中心耐受检查点的破坏，并可能导致自身免疫性疾病。我们还开发了突变的564Igi变体，可以或不能在未成熟的B细胞中进行同型转换。初步研究表明，缺乏早期b细胞同型转换的564Igi小鼠自身免疫力大大降低，这支持了我们的假设，即早期b细胞转换可以规避耐受性并导致自身免疫性疾病。SLE样564Igi小鼠模型有效再现了人类SLE的许多特征，但564Igi菌株中的基因靶向抗rna抗体基因是人类SLE患者中未发现的遗传结构。我们想测试早期b细胞转换在自身免疫发展中的作用，这种自身免疫是由一种已知与人类自身免疫有关的基因突变引起的。最近的报道描述了人类奥曼综合征的小鼠模型。这些具有基因靶向的拟态RAG基因，因此类似于拟态RAG患者。小鼠模型复制了人类疾病的淋巴细胞减少、血清抗体水平和自身免疫。此外，Omenn综合征的一些特征，如抗rna、抗染色质和抗dna抗体，以及调节同型转换的血清细胞因子升高，与SLE有共同之处。我们将使用在未成熟B细胞中不能进行同型转换的Omenn综合征小鼠模型变体来测试这些变体是否表现出降低的自身免疫。我们的试验将表明，通过同型转换的耐受性破坏是否可能是各种B细胞自身免疫性疾病的共同特征。