Mechanisms driving extrafollicular polyreactive B cell lineages in partial RAG deficiency

部分 RAG 缺陷中滤泡外多反应性 B 细胞谱系的驱动机制

• 批准号: 10705171
• 负责人: Jolan Eszter Walter
• 金额: $ 48.7万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705171
• 关键词: Acceleration; Age; Antibodies; Antibody Response; Antibody-Producing Cells; Antigens; Apoptosis; Autoantibodies; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmunity; Automobile Driving; B-Cell Activation; B-Cell Antigen Receptor; B-Lymphocyte Subsets; B-Lymphocytes; CTLA4 gene; Cell Count; Cell Lineage; Cell secretion; Cells; Characteristics; Chronic; Clinical; Coculture Techniques; Common Variable Immunodeficiency; Communicable Diseases; Contracts; Data; Development; Disease; Etiology; Event; Gene Expression; Generations; Genes; Genetic; Genetic Predisposition to Disease; Genetic Recombination; Germ-Free; Goals; Helper-Inducer T-Lymphocyte; Hereditary Disease; Herpesviridae; Human; Human Herpesvirus 4; Humoral Immunities; Hyperactivity; Immune; Immunity; Immunologic Deficiency Syndromes; Immunologic Stimulation; Impairment; Individual; Infection; Inflammation; Inflammatory; Interferon Type II; International; Intervention; Mediating; Microbe; Modeling; Molecular; Mus; Pathogenesis; Patients; Persons; Phenotype; Play; Population; Predisposition; Production; Proliferating; Rag1 Mouse; Receptor Signaling; Refractory; Regulatory T-Lymphocyte; Research; Research Personnel; Severities; Signal Pathway; Signal Transduction; Site; Stimulus; Surface; Systemic Lupus Erythematosus; T cell therapy; T-Cell Activation; T-Lymphocyte; TLR7 gene; Testing; Toll-like receptors; Variant; Virus; Virus Diseases; anti-CD20; autoreactive B cell; autoreactivity; chronic infection; cohort; congenital immunodeficiency; cytokine; cytopenia; experimental study; improved; innovation; interleukin-21; microbial; mouse model; novel; recombinase; response; therapy design; transcription factor; transcriptome

PROJECT SUMMARY Patients with congenital immunodeficiencies, such as combined immunodeficiencies (CID) with partial recombinase activating gene (RAG) deficiency (pRD) are highly vulnerable to chronic infections and refractory autoimmune disorders. RAG1/2 are key to creating and censoring the B cell receptor diversity. In case of pRD, developing B cells that are naturally autoreactive may remain reactive to self in the periphery and be unable to mount efficient antibody responses. This results in chronic antigen exposure that can activate T and B cells. We propose to focus on two specific cell populations: hyperactive T follicular helper (Tfh) cells and innate-like extrafollicular polyreactive B cells, as markers of autoimmunity. The latter resemble age-associated B cells (ABCs), which accumulate with infections and with age. Normally, ABCs are highly sensitive to innate immune stimulation by microbes and inflammatory cytokines and play a key role in controlling viral infections by producing protective antibodies. After the infection resolves, ABC numbers contract markedly. However, with chronic infections, ABCs or ABC-like cells expand, persist and produce antibodies that are less protective against microbes and more reactive to self, especially in individuals with particular genetic immunodeficiencies. Sustained expansion of polyreactive ABCs parallels microbial/antigen load (toll-like receptor stimulation) and expansion of Tfh cells, which secrete the inflammatory cytokines, interferon gamma (IFNand interleukin 21 (IL-21). It is unclear which stimuli and cell signaling pathways are dominant in promoting ABC autoreactivity in pRD or other CID s. Our long-term goal is to understand how autoreactive ABCs emerge in CID in order to develop effective immune modulatory treatments. We hypothesize that the susceptibility to infections of patients with pRD results in increased, continual microbial/antigen presence and chronic low-grade inflammation throughout the body. In response, Tfh cells secrete inflammatory cytokines abundantly (IFNand IL-21), which together with chronic microbial stimulation induces ABC-like cells to expand and become autoantibody-secreting cells and present autoantigens to Tfh cells, which sustains them. Thus, ABC-like cell abundance and autoreactivity is perpetuated in pRD. Our specific aims are to 1) identify likely drivers of ABC- like cells in pRD patients and 2) dissect mechanisms contributing to ABC-like cell generation and persistence using pRD mouse models. Our innovative research strategies include studying an international cohort of pRD patients in parallel with using novel mouse models, exposing mice to varying levels of microbes, and correlating gene expression changes with ABC developmental characteristics and autoimmune severity of patients. Our proposed study is significant because it will likely illuminate how dysfunctional ABC-like cells develop in persons susceptible to chronic infections and lead to therapies that modify specific B cell signaling pathways to improve humoral immunity and reduce autoimmunity in pRD and other CID.

项目摘要 患有先天性免疫缺陷的患者，例如伴有部分免疫缺陷的联合免疫缺陷（CID）， 重组酶激活基因（RAG）缺陷（pRD）是非常脆弱的慢性感染和难治性 自身免疫性疾病RAG 1/2是产生和审查B细胞受体多样性的关键。在pRD的情况下， 天然自身反应性的发育中的B细胞可能在外周中保持对自身的反应性， 产生有效的抗体反应。这导致可激活T和B细胞的慢性抗原暴露。 我们建议将重点放在两个特定的细胞群：过度活跃的T滤泡辅助（Tfh）细胞和先天性类 滤泡外多反应性B细胞，作为自身免疫的标志物。后者类似于年龄相关的B细胞 （ABC），随着感染和年龄的增长而积累。通常，ABC对先天免疫非常敏感， 通过微生物和炎性细胞因子的刺激，在控制病毒感染中发挥关键作用， 产生保护性抗体。感染消退后，ABC数字显著收缩。但随着 慢性感染，ABC或ABC样细胞扩大，持续存在并产生保护性较低的抗体 对微生物的抵抗力更强，对自身的反应更强烈，特别是在具有特定遗传免疫缺陷的个体中。 多反应性ABC的持续扩增与微生物/抗原负荷（toll样受体刺激）平行， 扩增Tfh细胞，其分泌炎性细胞因子、干扰素γ（IFN γ和白细胞介素21 （IL-21）。目前还不清楚哪些刺激和细胞信号通路在促进ABC自身反应性中占主导地位， pRD或其他CID。我们的长期目标是了解自身反应性ABC如何在CID中出现， 开发有效的免疫调节治疗。我们假设，感染的易感性， 患有pRD的患者导致增加的、持续的微生物/抗原存在和慢性低级别 全身炎症。作为响应，Tfh细胞大量分泌炎性细胞因子（IFN γ和IFN γ）。 IL-21），其与慢性微生物刺激一起诱导ABC样细胞扩增并成为 自身抗体分泌细胞和呈递自身抗原Tfh细胞，维持他们。因此，ABC样细胞 丰度和自身反应性在pRD中持续存在。我们的具体目标是：1）确定ABC的可能驱动因素- pRD患者中的ABC样细胞和2）剖析有助于ABC样细胞产生和持续存在的机制 使用pRD小鼠模型。我们的创新研究策略包括研究国际pRD队列 同时使用新型小鼠模型，将小鼠暴露于不同水平的微生物， 将基因表达变化与ABC发育特征和自身免疫严重性相关联， 患者我们提出的研究是重要的，因为它可能会阐明功能失调的ABC样细胞 在对慢性感染易感的人中发展，并导致改变特定B细胞信号传导的疗法 改善体液免疫和减少pRD和其他CID中的自身免疫的途径。