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: 10025784
• 负责人: Jennifer Marie Dan
• 金额: $ 15.89万
• 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/10025784
• 关键词: Immunology; Recurrent; Group; Streptococcus; Tonsillitis

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.

摘要 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。复发性扁桃体炎（RT）病史 提示转诊进行扁桃体切除术这是一个长期存在的谜，为什么只有一些儿童得到链球菌喉咙。到 为了回答这个问题，我们开发了一个队列的儿童谁经历了扁桃体切除术，无论是RT由于 GAS或非RT原因。我们收集了216个扁桃体，以确定RT儿童是否有 扁桃体生发中心（GC）对GAS的反应受损，使其易于复发感染。 在扁桃体生发中心内是GC T滤泡辅助（Tfh）细胞，一种专门的CD4+ T细胞， 为GC B细胞提供帮助，以指导亲和力成熟、体细胞高度突变的记忆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细胞显著减少。我们鉴定了“高危”HLA II类等位基因， 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果。 使用我们的新的活CD4+ T细胞检测来鉴定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细胞形成的偏好。有趣的是，由于我们有配对的血液样本，我们 观察到针对关键GAS毒力因子链球菌的循环抗体显著减少 热原性外毒素A（SpeA），滴度较低，临床上与侵袭性GAS易感性相关 疾病最后，我们已经鉴定了异常SpeA诱导的颗粒酶B+ GC Tfh细胞，其具有细胞溶解性。 活性，我们将其称为“杀伤Tfh”细胞。这些“杀手Tfh”细胞可以解释在 RT扁桃体。我们假设RT患儿对GAS感染复发具有免疫易感性。 在此，我们将测试与这种倾向相关的特定假设，重点关注宿主对GAS的反应， 评估我们已经鉴定的“高危”HLA等位基因的作用和GAS淬灭适应性免疫的能力 通过诱导“杀手Tfh”细胞的反应。 这个K08提案，如果得到资助，将支持我成为一名独立的医生科学家的目标。 在培训期间，我将学习人体免疫学的先进技术， 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一个合作环境。我 导师Shane Crotty和共同导师维克托Nizet都是各自领域的世界知名专家， 老年中心和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 作为一名医生，科学家通过应用人类免疫学的先进技术来解决临床 问题