B1a Cell Function in Sickle Cell Disease

 描述（由申请人提供）：镰状细胞病（SCD）是最常见的血红蛋白疾病，全球每年有30万名新生儿受影响。肺炎链球菌是肺炎最常见的原因。镰状细胞（SS）患者对S.肺炎感染率高于一般人群。肺炎球菌感染的风险增加主要归因于SS患者缺乏功能性脾脏。然而，SS患者仍然比由于SCD以外的原因而缺乏功能性脾脏的人更容易受到影响。抗生素、疫苗接种和羟基脲治疗等干预措施有助于抵消这种增加的风险;然而，肺炎球菌感染仍然对SS患者构成很大的风险。SS患者感染控制不佳主要是由于抗生素耐药性和非疫苗血清型的出现。肺炎。最近，已经证明SS环境本身导致S.肺炎以及疫苗效力的差异。因此，本研究的长期目标是更好地了解SCD中的免疫系统，这将有助于开发新的预防策略和/或治疗S。SS患者的肺炎感染。具体而言，该提案的直接目标是确定长期给予镰状细胞患者的SCD和/或治疗是否对特定的B细胞亚群有影响，这提供了对S的必要的直接保护。肺炎感染。 小鼠B-1a细胞主要在胎儿发育期间产生。这些细胞对于立即保护和因此从S.肺炎感染。胎儿来源的B-1a细胞提供抗S.肺炎克雷伯氏菌的感染归因于它们自发分泌的非免疫（天然）IgM，由于N-区添加的最小插入和很少的体细胞超突变，其是种系样的。已经表明，在SCD小鼠模型中，脾B-1a细胞的数量显著减少。我们假设，SCD中天然IgM保护水平的变化是由于B-1a细胞池对单独SS环境和/或SCD中常用疗法的响应的功能和/或库相关改变所致。为了检验这一假设并确定SS环境和/或该疾病的常用治疗是否导致保护性天然IgM的变化，我们将进行以下目标：1）确定B-1a细胞库的功能是否在镰状细胞病中发生变化;和2）评估镰状细胞病中天然IgM保护免受SS的能力。肺炎感染。该项目将确定SCD和/或治疗这种疾病对B-1a细胞提供即时保护免受S.肺炎感染。对SS免疫系统的进一步了解将提供新的信息，可能导致S的策略和/或治疗。SS患者的肺炎感染。

 DESCRIPTION (provided by applicant): Sickle cell disease (SCD) is the most common hemoglobin disorder with 300,000 infants born affected each year globally. Streptococcus pneumoniae is the most common cause of pneumonia. Sickle cell (SS) patients are 600 times more susceptible to S. pneumoniae infections than the general population. This increased risk of pneumococcal infection is attributed mainly to lack of a functional spleen in SS patients. However, SS patients are still more susceptible than persons lacking a functional spleen for reasons other than SCD. Interventions such as antibiotics, vaccination, and hydroxyurea treatment have helped counteract this increased risk; yet, pneumococcal infection still poses a great risk for SS patients. Poor infection control in SS patients is mainly due to antibiotic resistance and the emergence of non-vaccine serotypes of S. pneumoniae. Recently, it has been demonstrated the SS environment itself leads to increased virulent strains of S. pneumoniae as well as differences in vaccine efficacy. Therefore, the long-term goal of this study is to gain a greater comprehension of the immune system in SCD, which will enable development of new preventative strategies and/or treatment of S. pneumoniae infection in SS patients. Specifically, the immediate goal of this proposal is to determine whether SCD and/or treatments given to sickle cell patients long-term have an affect on a specific subset of B cells, which provide the essential immediate protection from S. pneumoniae infection. Murine B-1a cells arise mainly during fetal development. These cells are essential for immediate protection and therefore survival from S. pneumoniae infection. The unique ability of fetal derived B-1a cells to provide protection against S. pneumoniae is attributed to their spontaneously secreted non-immune (natural) IgM, which is germline-like due to minimal insertion of N-region additions and little somatic hypermutation. It has been shown that the number of splenic B-1a cells is significantly reduced in a mouse model of SCD. We hypothesize that the level of natural IgM protection changes in SCD as a result of functional and/or repertoire associated alterations to the B-1a cell pool in response to the SS environment alone and/or commonly used therapies in SCD. To test this hypothesis and determine whether the SS environment and/or common treatments for this disease leads to a change in protective natural IgM we will perform the following aims: 1) Determine whether the function of the B-1a cell pool changes in sickle cell disease; and, 2) Evaluate the ability of natural IgM in sickle cell disease to protect against S. pneumoniae infection. This project will determine the effect SCD and/or treatments for this disease has on the ability of B-1a cells to provide immediate protection from S. pneumoniae infection. This further understanding of the SS immune system will provide new information that will likely lead to strategies and/or treatments of S. pneumoniae infection in SS patients.