B cell subsets and immunity to cryptococcosis

描述（由申请人提供）：目前，HIV相关隐球菌病（隐球菌病，CD）的唯一已知风险因素是CD 4 T细胞的严重丢失，但这不能区分将发展CD的HIV感染（HIV+）患者和不会发展CD的患者。在未感染HIV的患者中没有CD的生物标志物。我们的研究小组发现，有CD病史或后来发展为CD的HIV阳性个体的IgM记忆B细胞水平低于从未患过CD的人，并且降低的水平是CD状态的一个强有力的独立预测因素。已知在HIV中耗尽的IgM记忆B细胞产生天然IgM（nIgM），其结合保守的微生物决定簇并提供现成的病原体防御。因此，IgM记忆B细胞可以保护免受新生隐球菌（CN）。对这一概念的支持来自我们实验室的研究，这些研究表明，缺乏血清IgM的小鼠（分泌型，sIgM-/-小鼠）在肺部感染CN后的存活率低于IgM充足的小鼠，这与肺泡巨噬细胞对CN的吞噬作用降低有关，而CN的吞噬作用随着幼稚血清IgM的过继转移而增加。尽管对获得性抗体（即来自被动或主动免疫）的抗CN保护作用了解很多，但B细胞在对CD的天然抗性中的作用仍是一个谜。本申请提出确定nIgM和其来源的B细胞是否介导针对CN的保护。我们建议在小鼠中进行研究，以确定IgM记忆B细胞、B-1 B细胞及其产物nIgM的小鼠同源物在对CN的免疫中的作用，以及控制其活性的机制，并进行人体研究，以确定IgM记忆B细胞表达是否是CD的合适生物标志物并寻找CD相关基因。本研究的目的是：1）确定B-1 B细胞在小鼠抗CN中的作用; 2）确定B-1 B细胞和/或nIgM增强对CN免疫的机制; 3）将IgM记忆B细胞表达与人CD联系起来并寻找CN相关的分子谱。这些目标将对临床医学产生影响，为生物标志物的发现提供信息，以克服早期诊断的障碍，开发新的疫苗和疗法，以克服有效预防和治疗的障碍，并通过揭示CN-宿主相互作用的新机制来影响基础科学。

DESCRIPTION (provided by applicant): Currently, the only known risk factor for HIV-associated cryptococcal disease (cryptococcosis, CD) is profound loss of CD4T cells, but this cannot discriminate HIV-infected (HIV+) patients who will develop CD from those who will not. There are no biomarkers for CD in HIV-uninfected patients. Our group discovered that HIV+ individuals with a history of or who later developed CD had lower levels of IgM memory B cells than those who never had CD and that a reduced level was a strong independent predictor of CD status. IgM memory B cells, known to be depleted in HIV, produce natural IgM (nIgM) that binds conserved microbial determinants and provides ready-made pathogen defense. Thus, IgM memory B cells could protect against Cryptococcus neoformans (CN). Support for this concept comes from studies from our laboratory demonstrating that mice which lack serum IgM (secretory, sIgM-/- mice) exhibited reduced survival after pulmonary infection with CN than IgM sufficient mice, which was associated with reduced alveolar macrophage phagocytosis of CN that increased with adoptive transfer of na¿ve serum IgM. Although much is known about acquired antibody (i.e. from passive or active immunization) protection against CN, the role of B cells in natural resistance to CD is an enigma. This application proposes to determine whether nIgM and the B cells from which it is derived mediate protection against CN. We propose studies in mice to determine the role of mouse homologs of IgM memory B cells, B-1 B cells, and their product nIgM, in immunity to CN, the mechanisms that govern their activity, and human studies to determine whether IgM memory B cell expression is a suitable biomarker for CD and seek CD-associated genes. The following aims are proposed: 1) To determine the role of B-1 B cells in protection against CN in mice; 2) To identify mechanisms by which B-1 B cells and/or nIgM potentiate immunity to CN; 3) To link IgM memory B cell expression to human CD and seek CN-associated molecular profiles. These aims will have an impact on clinical medicine, informing biomarker discovery to overcome barriers to early diagnosis, development of new vaccines and therapies to overcome barriers to effective prevention and treatment, and impact basic science by revealing novel mechanisms of CN-host interaction.