B cell subsets and immunity to cryptococcosis

B 细胞亚群和隐球菌病免疫

• 批准号: 9132490
• 负责人: Liise-anne Pirofski
• 金额: $ 31.98万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9132490
• 关键词: AIDS/HIV problem; Active Immunization; Address; Adoptive Transfer; Africa South of the Sahara; Alveolar Macrophages; Anti-Retroviral Agents; Antibodies; Antifungal Agents; Antigens; B-Lymphocyte Subsets; B-Lymphocytes; Basic Science; Binding; Biological Factors; Biological Markers; Blood; Brain; CD4 Positive T Lymphocytes; Carbohydrates; Cells; Cessation of life; Clinical Medicine; Clinical Sciences; Complication; Containment; Cryptococcus; Cryptococcus neoformans; Cryptococcus neoformans infection; Development; Diagnosis; Diagnostic; Disease; Disease Outbreaks; Early Diagnosis; Effector Cell; Encapsulated; Exhibits; Far East; Gene Expression; Genes; Goals; HIV; HIV Infections; Homologous Gene; Human; Human Activities; Immunity; Immunocompromised Host; Immunoglobulin M; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Immunotherapy; Individual; Infection; Inflammation; Inflammatory Response; Laboratories; Life; Link; Lung; Mediating; Memory B-Lymphocyte; Molecular Profiling; Mus; Natural Resistance; Organ Transplantation; Pacific Northwest; Passive Immunization; Pathology; Patients; Phagocytosis; Play; Polysaccharides; Predisposition; Prevention; Public Health; Recording of previous events; Recurrence; Resistance; Risk; Risk Factors; Role; Serum; Solid; Source; Southeastern Asia; Streptococcus pneumoniae; Transplant Recipients; Transplantation; Vaccine Therapy; Vaccines; Work; antigen binding; burden of illness; cohort; glucuronoxylomannan; humoral immunity deficiency; interest; macrophage; microbial; mouse model; novel; novel strategies; novel vaccines; pathogen; peripheral blood; preclinical study; prevent; secretory IgM

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.

描述（由适用提供）：目前，与HIV相关的隐球菌疾病（隐球菌，CD，CD）唯一已知的危险因素是CD4T细胞的严重丧失，但这无法区分受HIV感染的患者（HIV+）患者，他们会从不会从不会不会的人开发CD。在艾滋病毒未感染的患者中，CD没有生物标志物。我们的小组发现，具有或后来患有CD病史的HIV+个体的IgM记忆B细胞低于从未有CD的人，并且水平降低是CD状态的强烈独立预测指标。 IgM记忆B细胞（已知在HIV中耗尽）产生了结合成本的微生物确定剂并提供现成的病原体防御的天然IGM（NIGM）。这就是IgM记忆B细胞可以预防新虫（CN）。对这个概念的支持来自我们的实验室的研究，表明缺乏血清IGM（分泌，Sigm - / - 小鼠）的小鼠暴露于CN肺部感染后的生存率降低，而不是IGM足够的小鼠，这与肺泡巨型巨噬细胞的CN减少有关，与Na ve ve ve ve ve ve Veserum igm igm降低的CN相关。尽管对获得CN的获得的获得的抗体（即，从被动或主动免疫抑制）保护众所周知，但B细胞在自然抗CD中的作用是一种谜。该应用程序提出的建议是确定NIGM和B细胞是否从中得出了介质保护对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细胞的小鼠同源物及其产物NIGM在对CN的免疫抑制中的作用，控制其活性的机制以及人类研究以确定IGM记忆B细胞表达是否是CD的合适生物标志物，并寻求CD相关基因。提出了以下目的：1）确定B-1 B细胞在针对CN中CN中的作用； 2）确定B-1 B细胞和/或NIGM潜在免疫CN的机制； 3）将IgM记忆B细胞表达与人CD联系起来，并寻求与CN相关的分子谱。这些目标将对临床医学产生影响，告知生物标志物发现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-HOST相互作用的新机制来影响基础科学。