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: 8304205
• 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/8304205
• 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.

描述(申请人提供)：Omenn综合征是一种人类疾病，表现出免疫缺陷和自身免疫的不同寻常的组合。患者缺乏成熟的T细胞或B细胞，免疫反应差。另一方面，患者表现出大量的血清抗体，自身反应性抗体水平升高。重组激活基因(RAG)的亚型突变是与Omenn综合征相关的一些最典型的遗传缺陷。RAG蛋白是B、T淋巴细胞发育过程中受体基因重组的关键蛋白，RAG基因亚型突变导致成熟淋巴细胞数量有限。然而，该病中自身免疫的原因尚不清楚。在过去的几年里，我们的研究小组在B细胞发育早期的B细胞分化和耐受性研究方面进行了合作。我们最近已经证明，即使在骨髓中未成熟的B细胞中也会发生同型转换，这与流行的模式相反，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细胞开关大大增加。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细胞中的同型转换会导致中枢耐受检查点的崩溃，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，在缺乏早期B细胞同型转换的564Igi小鼠中，自身免疫力大大降低，支持了我们的假设，即早期B细胞转换可以规避耐受，并可能导致自身免疫性疾病。类似于SLE的564Igi小鼠模型有效地复制了人类SLE的许多特征，但564Igi株中的基因靶向抗RNA抗体基因是一种在人类SLE患者中没有的遗传结构。我们想要测试早期B细胞转换在自身免疫发展中的作用，这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Omenn综合征疾病的小鼠模型。这些基因具有针对基因的亚形性RAG基因，因此类似于亚形性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是相同的。我们将使用不能在未成熟的B细胞中进行同型转换的Omenn综合征小鼠模型变体来测试这些细胞是否表现出降低的自身免疫力。我们的测试将表明，通过同型转换导致的耐受性崩溃是否可能是各种B细胞自身免疫性疾病的共同特征。