The Immunology of Recurrent Group A Streptococcus Tonsillitis

复发性 A 族链球菌扁桃体炎的免疫学

• 批准号: 9905482
• 负责人: Jennifer Marie Dan
• 金额: $ 19.44万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-24 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9905482
• 关键词: Acute; Address; Affinity; Alleles; Antibiotics; Antibodies; Antibody Affinity; Antibody Response; Antigens; B cell differentiation; B-Lymphocytes; Bacteria; Bioinformatics; Biological Assay; Blood specimen; CD4 Positive T Lymphocytes; Cellular Assay; Cellular biology; Child; Childhood; Clinical; Cytotoxic T-Lymphocytes; Data; Development; Disease; Disease susceptibility; Evolution; Exposure to; Frequencies; Funding; Goals; Granzyme; Helper-Inducer T-Lymphocyte; Human; Hypersensitivity; Immune Evasion; Immune response; Immunity; Immunologics; Immunology; Impairment; Institutes; Learning; Lymphoid Tissue; Measures; Memory B-Lymphocyte; Mentors; Outcome Study; Patients; Pharyngeal structure; Pharyngitis; Physicians; Predisposition; Process; Recording of previous events; Recurrence; Research Project Grants; Rheumatic Fever; Rheumatic Heart Disease; Risk; Role; Scientist; Signal Transduction; Specific qualifier value; Statistical Data Interpretation; Streptococcal Infections; Streptococcus pyogenes; Structure of germinal center of lymph node; Superantigens; T cell response; Techniques; Testing; Time; Tonsil; Tonsillectomy; Tonsillitis; Toxic Shock Syndrome; Training; Translational Research; Up-Regulation; Virulence Factors; acquired immunity; adaptive immune response; cell type; cohort; collaborative environment; erythrogenic toxin; experimental study; novel; prevent; programs; recurrent infection; response; risk variant; skills; transcription factor; transcriptomics

Abstract Recurrent GAS tonsillitis or strep throat is a common pediatric disease. A history of recurrent tonsillitis (RT) prompts a referral for tonsillectomy. It is a long-standing mystery why only some children get strep throat. To answer this question, we developed a cohort of children who had undergone tonsillectomies for either RT due to GAS or non-RT reasons. We have accrued 216 tonsils to determine whether children with RT have an impaired tonsillar germinal center (GC) response to GAS, predisposing them to recurrent infection. Within the tonsillar germinal center are GC T follicular helper (Tfh) cells, specialized CD4+ T cells that provide help to GC B cells to instruct the development of affinity matured, somatically hypermutated memory B cells and antibodies. In our cohort, we observed that RT tonsils have significantly smaller germinal centers with significantly fewer GC Tfh and GC B cells. We identified `At Risk' HLA Class II alleles reminiscent of `At Risk' alleles for toxic shock syndrome and rheumatic heart disease, an adverse sequellae of untreated strep throat. Using our novel live CD4+ T cell assay to identify GAS-specific GC Tfh cells, we discerned that RT tonsils have a bias against GAS-specific GC Tfh cell formation. Intriguingly, as we have paired blood specimens, we observed significantly fewer circulating antibodies against a critical GAS virulence factor streptococcal pyrogenic exotoxin A (SpeA), with a lower titer clinically associated with a predisposition for invasive GAS disease. Finally, we have identified aberrant SpeA-induced granzyme B+ GC Tfh cells endowed with cytolytic activity, which we refer to as `killer Tfh' cells. These `killer Tfh' cells may explain the smaller germinal centers in RT tonsils. We hypothesize that children with RT have an immunosusceptibility to recurrent GAS infections. Herein, we will test specific hypotheses related to this predisposition, focusing on the host response to GAS by evaluating the role of `At Risk' HLA alleles we have identified and GAS's ability to quench an adaptive immune response by inducing `killer Tfh' cells. This K08 proposal, if funded, will support me in my goal to become an independent physician-scientist. During the training period, I will learn advance techniques in human immunology, acquire expertise in bioinformatics and statistical analyses, and apply these skills to translational research projects. La Jolla Institute for Allergy and Immunology (LJI) provides a collaborative environment for the proposed studies. My mentor Shane Crotty and co-mentor Victor Nizet are both world-renowned experts in their respective fields of germinal center and Tfh cell biology and GAS infections. This project will allow me to continue my development as a physician-scientist by applying advanced techniques in human immunology to addressing clinical problems.

抽象的 复发性 GAS 扁桃体炎或链球菌性咽喉炎是一种常见的儿科疾病。有复发性扁桃体炎 (RT) 病史 提示转诊进行扁桃体切除术。为什么只有部分儿童会患链球菌性咽喉炎，这一直是个谜。到 回答这个问题，我们研究了一组因放疗而接受过扁桃体切除术的儿童 由于 GAS 或非 RT 原因。我们收集了 216 个扁桃体来确定患有 RT 的儿童是否患有 扁桃体生发中心 (GC) 对 GAS 的反应受损，容易反复感染。 扁桃体生发中心内有 GC T 滤泡辅助 (Tfh) 细胞，这是一种专门的 CD4+ T 细胞， 帮助 GC B 细胞指导亲和力成熟、体细胞超突变记忆 B 的发育 细胞和抗体。在我们的队列中，我们观察到 RT 扁桃体的生发中心明显较小 GC Tfh 和 GC B 细胞明显减少。我们鉴定出“处于危险中”的 HLA II 类等位基因，让人想起“处于危险中” 中毒性休克综合征和风湿性心脏病的等位基因，这是未经治疗的链球菌性咽喉炎的不良后遗症。 使用我们新颖的活 CD4+ T 细胞测定来识别 GAS 特异性 GC Tfh 细胞，我们发现 RT 扁桃体具有 对 GAS 特异性 GC Tfh 细胞形成的偏见。有趣的是，当我们有配对的血液样本时，我们 观察到针对关键 GAS 毒力因子链球菌的循环抗体显着减少 热原性外毒素 A (SpeA)，其滴度较低，临床上与侵袭性 GAS 倾向相关 疾病。最后，我们鉴定了异常的 SpeA 诱导的颗粒酶 B+ GC Tfh 细胞，该细胞具有细胞溶解能力。 活性，我们将其称为“杀伤性 Tfh”细胞。这些“杀手 Tfh”细胞可能解释了较小的生发中心 RT 扁桃体。我们假设 RT 儿童对复发性 GAS 感染具有免疫敏感性。 在这里，我们将测试与这种倾向相关的具体假设，重点关注宿主对 GAS 的反应： 评估我们已确定的“处于危险中”HLA 等位基因的作用以及 GAS 抑制适应性免疫的能力 通过诱导“杀伤性 Tfh”细胞做出反应。 这个 K08 提案如果获得资助，将支持我实现成为一名独立医师科学家的目标。 在培训期间，我将学习人类免疫学的先进技术，获得以下方面的专业知识： 生物信息学和统计分析，并将这些技能应用于转化研究项目。拉霍亚 过敏和免疫学研究所 (LJI) 为拟议的研究提供了协作环境。我的 导师 Shane Crotty 和联合导师 Victor Nizet 都是各自领域的世界知名专家 生发中心和 Tfh 细胞生物学和 GAS 感染。这个项目将使我能够继续我的发展 作为一名医师科学家，应用人类免疫学的先进技术来解决临床问题 问题。