Immunopathogenesis of Group A Streptococcal Infection

A 族链球菌感染的免疫发病机制

• 批准号: 6830899
• 负责人: Malak Y.S. Kotb
• 金额: $ 12.6万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6830899
• 关键词: Immunopathogenesis; Group; Streptococcal; Infection

DESCRIPTION (provided by applicant): We reported that the host immunogenetic makeup influences the clinical outcome of invasive GAS disease. Specific HLA class II haplotypes conferred strong protection from the severe forms of the invasive disease, while others increased the risk for SSD. We also determined the underlying mechanism for these genetic associations by demonstrating that the presentation of Strep SAgs by the class II DRB1*1501/DQB1*0602 haplotype, which was strongly associated with protection from SSD (P=0.0007), elicited significantly lower inflammatory responses as compared to their presentation by either risk or neutral haplotypes (P<0.0001). Patients with this protective haplotype mounted significantly reduced responses to the GAS SAgs (low responders) and were less likely to develop SSD. By contrast patients who lacked this protective haplotypes or had the DRB1*14/DQB1*0503 risk haplotypes were high responders to the Strep SAgs and were more likely to develop SSD. Thus, HLA class II allelic variations contribute to differences in the severity of invasive GAS disease by regulating inflammatory responses to Strep SAgs. In this supplement proposal we focus on evaluating the role of HLA class II molecules in modulating GAS infection outcome in vivo using HLA transgenic mice carrying disease associated HLA allele/haplotypes. The information that will be generated in these studies will provide an in vivo validation for our epidemiological and in vitro HLA association studies.

描述（由申请人提供）：我们报告说，宿主的免疫剂化妆会影响侵入性气体疾病的临床结果。 特定的HLA II类单倍型赋予了严重形式的侵入性疾病的强烈保护，而其他人则增加了SSD的风险。我们还通过证明II级DRB1*1501/DQB1*0602单倍型的呈现链球菌的呈现，确定了这些遗传关联的潜在机制，与SSD的保护密切相关（P = 0.0007），这与较低的炎症响应相比，与其呈现的较低的炎症响应相比，与<0.000 <0。<0. <0. <0. <0. <0. <0. <0. <0. <0. <0. <0. <0. <0. <0. <0. <0. <0. <0. <0. <0. <0。<0. <0. <0. <0. 这种保护性单倍型的患者可显着减少对气体凹陷的反应（低响应者），并且不太可能发展SSD。相比之下，缺乏这种保护性单倍型或具有DRB1*14/DQB1*0503风险单倍型的患者对链球菌下垂的反应者很高，并且更有可能发展SSD。因此，HLA II类等位基因变异通过调节对链球菌下垂的炎症反应而导致侵入性气体疾病严重程度的差异。 在此补充建议中，我们着重于评估HLA II类分子在体内使用携带疾病相关HLA等位基因/单倍型的HLA转基因小鼠在体内调节气体感染结果中的作用。这些研究将产生的信息将为我们的流行病学和体外HLA关联研究提供体内验证。