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.

抽象的 复发性气体扁桃体炎或链球菌性喉咙是一种常见的小儿疾病。复发性扁桃体炎史（RT） 提示转介扁桃体切除术。这是一个长期以来的谜，为什么只有一些孩子会得到链球菌的喉咙。到 回答这个问题，我们开发了一群为任何RT进行扁桃体切除术的孩子 出于气体或非RT原因。我们已经累积了216个扁桃体，以确定RT儿童是否有 扁桃体生发中心（GC）对气体的反应受损，使其复发感染。 在扁桃体生发中心内是GC T卵泡辅助器（TFH）细胞，专门的CD4+ T细胞 为GC B细胞提供帮助，以指导亲和力成熟的，体积超重的内存B 细胞和抗体。在我们的队列中，我们观察到RT扁桃体具有明显较小的生发中心 GC TFH和GC B细胞明显少得多。我们确定了“处于风险”的HLA II类等位基因 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喉咙的不良后遗症。 使用我们新颖的活CD4+ T细胞测定法鉴定气体特异性GC TFH细胞，我们发现RT扁桃体具有 反对气体特异性GC TFH细胞形成的偏置。有趣的是，正如我们配对的血样一样，我们 观察到针对关键气体毒力因子链球菌的循环抗体明显较少 充气外毒素A（SPEA），较低滴度在临床上与侵入性气体的易感性相关 疾病。最后，我们已经确定了异常的SPEA诱导的颗粒B+ GC TFH细胞，并赋予了细胞溶解度 活动，我们称为“杀手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儿童具有复发气体感染的免疫敏感性。 在此，我们将测试与此易感性相关的特定假设，重点是 评估我们已经确定的“处于危险” HLA等位基因的作用和气体的能力消除适应性免疫 通过诱导“杀手TFH”细胞的响应。 该K08提案（如果资助）将支持我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方面的提前技术，获得专业知识 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。 La Jolla 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Co-Mentor Victor Nizet都是各自领域的世界知名专家 生发中心和TFH细胞生物学和气体感染。这个项目将使我继续发展 作为医师科学家，通过在人类免疫学中应用高级技术来解决临床 问题。