Implications of B10-like cell expansion in a model of impaired receptor editing

B10 样细胞扩增对受体编辑受损模型的影响

基本信息

批准号：
9244625
负责人：
Patrick C. Swanson
金额：
$ 21.83万
依托单位：
CREIGHTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-08 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9244625
关键词：
Acetates Adoptive Transfer Animals Antibodies Antibody Formation Antibody-Producing Cells Antigens Area Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Process Autoimmunity B cell repertoire B-Cell Development B-Lymphocyte Subsets B-Lymphocytes Binding Bone Marrow Cell Communication Cells Chronic Lymphocytic Leukemia Clinical Competence Complication Coupled Data Defect Disease Etiology Exhibits Failure Feedback Frequencies Genes Humoral Immunities Immune system Immunoglobulin M Immunoglobulins Immunophenotyping Immunosuppression Immunosuppressive Agents Impairment In Vitro Incidence Inflammatory Response Interleukin-10 Ionomycin Lead Lecithin Light Lipopolysaccharides Lymphocytosis Mediating Membrane Modeling Mus Mutation Outcome Pathogenicity Patients Pattern Phenotype Plasma Cells Play Population Production Property Receptors, Antigen, B-Cell Regulatory Pathway Reporting Role Site Sjogren&apos s Syndrome Specificity Stimulus T-Lymphocyte Testing Transgenes Transgenic Mice Work autoreactive B cell autoreactive T cell autoreactivity base cytokine cytopenia experimental study insight interleukin-21 novel phorbol-12-myristate prevent receptor response

项目摘要

PROJECT SUMMARY/ABSTRACT Although B cells are best known for providing humoral immunity through the production of antigen-specific antibodies, accumulating evidence suggests some B cell subsets can function to negatively regulate inflammatory responses by producing the immunosuppressive cytokine IL10. Perhaps the best characterized of these subsets is the B10 B cell, which is distinctive for its CD5+CD1dhiCD19hi phenotype and ability to secrete IL10 in response to mitogenic stimuli. B10 B cells are thought to promote antigen-specific suppression of autoreactive T cells through an IL10 (B cell) – IL21 (T cell) feedback loop established by cognate B cell-T cell interactions. Interestingly, some CD5+ B cell populations have a propensity to react with membrane- associated self-antigens and may also produce IL10 like B10 B cells. Furthermore, certain diseases associated with expanded CD5+ B cells, such as chronic lymphocytic leukemia and Sjögren’s syndrome, show an increased incidence of autoimmune cytopenias that occur when antibodies attack the host’s own cells. Together, these data raise the possibility that the IL10-dependent feedback mechanism may function in reverse to help constrain B cells reactive to membrane antigens, and that breakdown of this regulatory loop may cause B cell-intrinsic autoimmune manifestations. We previously generated transgenic mice (called dnRAG1 mice) which exhibit a receptor editing defect used to alter B cell receptor specificity away from self- reactivity. These animals show an expanded CD5+ B cell population and impaired antibody production. We have found that dnRAG1 CD5+ B cells share the immunophenotype and IL10-competence of B10 B cells, leading us to hypothesize that a failure to successfully edit B cell receptor specificity against certain self- antigens may cause the B cell to acquire B10-like properties to suppress B cell-intrinsic autoimmunity. Consistent with this hypothesis, we show here that IL10-deficiency in dnRAG1 mice leads to elevated IgM production. This hypothesis will be further tested by analyzing wild-type and dnRAG1 mice on IL10+/+ and IL10-/- backgrounds to compare spontaneous and stimulation-induced antibody levels, autoantigen reactivity profiles, immunoglobulin variable gene usage patterns, and the frequency of IgM antibody-producing cells. We will also determine whether adoptively transferring CD5+ B cells from IL10+/+ dnRAG1 mice into IL10-/- dnRAG1 mice can restore immune suppression in these animals. Furthermore, we will test whether impaired receptor editing in mice expressing a site-directed phosphatidylcholine (PtC)-specific heavy chain transgene enhances CD5+ B cell accumulation and IL10-competence, and suppresses total or PtC-specific IgM production. The results obtained from this study may reveal an important new mechanism for how B cell-intrinsic autoimmunity against certain self-antigens are suppressed, and will identify autoantigens that may be subjected to tolerance induction by receptor editing. This work may also suggest an etiology for certain autoimmune manifestations, like cytopenias, that can arise as a clinical complication in diseases associated with expanded CD5+ B cells.

项目摘要/摘要尽管B细胞以通过产生抗原特异性提供体液免疫而闻名抗体，积累的证据表明，某些B细胞子集可以负调节通过产生免疫抑制细胞因子IL10来产生炎症反应。也许是最好的特征这些子集的是B10 B细胞，它的CD5+CD1DHICD19HI表型和能力与众不同。秘密IL10响应有丝分裂刺激。 B10 B细胞被认为促进抗原特异性抑制通过IL10（B细胞） - IL21（T细胞）反馈回路，由Cognate B Cell-T建立细胞相互作用。有趣的是，某些CD5+ B细胞群体有望与膜反应相关的自我抗原，也可能产生IL10，例如B10 B细胞。此外，某些疾病与扩展的CD5+ B细胞相关，例如慢性淋巴细胞性白血病和Sjögren综合征当抗体攻击宿主自己的细胞时，会增加自身免疫性细胞质的事件。这些数据一起增加了IL10依赖性反馈机制的可能性反向以帮助约束B细胞反应对膜抗原的反应，并破坏该调节环可能导致B细胞中性自身免疫性表现。我们以前产生了转基因小鼠（称为 DNRAG1小鼠），其表现出用于改变自我自我的B细胞受体特异性的受体编辑缺陷反应性。这些动物显示出扩展的CD5+ B细胞群体和抗体产生受损。我们已经发现DNRAG1 CD5+ B细胞具有B10 B细胞的免疫表型和IL10能力，导致我们假设未能成功编辑B细胞受体特异性针对某些自我抗原可能导致B细胞获得类似B10的特性，以抑制B细胞中的自身免疫。与这一假设一致，我们在这里表明DNRAG1小鼠的IL10缺陷导致IgM升高生产。该假设将通过在IL10+/+和 IL10 - / - 背景比较赞助和刺激诱导的抗体水平，自身抗原反应性特征，免疫球蛋白可变基因使用模式以及IgM抗体产生细胞的频率。我们还将确定是否适当地将IL10+/+ DNRAG1小鼠中的CD5+ B细胞转移到IL10 - / - DNRAG1中小鼠可以恢复这些动物的免疫抑制。此外，我们将测试接收器是否受损表达位置定向磷脂酰胆碱（PTC）特异性重链转化的小鼠的编辑增强 CD5+ B细胞的积累和IL10能力，并抑制总或PTC特异性IgM产生。这从这项研究中获得的结果可能揭示了B细胞中性自身免疫的重要新机制针对某些自我抗原被抑制，并将识别可能受到耐受性的自动抗原通过受体编辑诱导。这项工作还可能暗示某些自身免疫性表现的病因，像细胞质一样，这可能是与扩展的CD5+ B细胞相关的疾病的临床并发症。