B Cell Development in Aging

描述（由申请方提供）：老化与疫苗接种效力降低以及肺炎球菌、流感和西尼罗河病毒等病原体感染后发病率和死亡率增加相关。多种获得性缺陷可能导致老年人产生针对新遇到的病原体的保护性抗体的能力降低。在老年小鼠中，负责产生针对初次感染的保护性抗体的滤泡（FO）B细胞的数量减少，这与造血干细胞（HSC）的FO B细胞生成能力的降低相关。因此，B淋巴细胞生成减少可能是衰老相关的体液免疫力下降的原因，以新遇到的病原体。类似的缺陷似乎存在于人类中，其中来自老年人供体的移植骨髓（BM）干细胞通常不能产生B细胞。这种B淋巴管疾病的分子基础尚不清楚。我们的长期目标是了解这种缺陷并开发纠正它的方法。尽管老年小鼠比年轻小鼠含有更多的HSC，但这些细胞表现出基因转录失调和选择性损伤产生B细胞的能力。造血细胞从HSC发育通过转录因子表达/功能的有序序列进行，这些转录因子控制谱系特化、定型和进展。这一事件的顺序在一定程度上受到参与这些过程的基因的染色质可及性的控制。染色质可及性受组蛋白修饰（例如乙酰化、甲基化、磷酸化等）调节。和DNA CpG二核苷酸的甲基化。关于影响造血早期步骤的组蛋白修饰和DNA甲基化的模式以及这些模式在衰老过程中如何改变，我们知之甚少。在这里，我们建议解决的假设，转录失调和缺陷的B细胞的生成能力的老化HSC的表观遗传变化和随之而来的基因组不稳定的后果。我们的方法将涉及使用离体HSC以及来自免疫老化或年轻小鼠的条件转化HSC系。后者保留了原始成体干细胞的功能表型，并为生物化学研究提供了无限的材料供应。此外，这些细胞可以通过遗传操作来确定HSC缺陷中特定改变的作用。将在体内和OP 9培养系统中研究来自这些HSC的B细胞发育，在OP 9培养系统中复制衰老相关的B淋巴细胞生成缺陷。公共卫生相关性：一部分老年人由于获得性免疫缺陷而生活质量差，这降低了他们抵抗感染的能力。这些人需要更多的医疗护理和住院治疗，对公共卫生的影响主要是经济方面的。我们的研究将试图确定这种免疫下降的基础和纠正它的策略。

DESCRIPTION (provided by applicant): Aging is associated with decreased efficacy of vaccination, and increased morbidity and mortality following infection by agents such as pneumococcus, influenza and West Nile virus. Multiple acquired defects may contribute to the reduced ability of elderly individuals to produce protective antibodies against newly encountered pathogens. In aged mice, follicular (FO) B cells responsible for generation of protective antibodies to primary infection are reduced in numbers, and this is correlated with reduction in the FO B cell generative capacity of hematopoietic stem cells (HSCs). Thus, decreased B lymphopoiesis may be causal in the aging- associated decline in humoral immunity to newly encountered pathogens. A similar defect appears to exist in humans where transplanted bone marrow (BM) stem cells from older adult human donors often fail to give rise to B cells. The molecular basis of this B lymphopause is unknown. It is our long-term goal to understand this defect and develop approaches to correct it. Although aged mice contain significantly more HSCs than their young counterparts, these cells exhibit dysregulation of gene transcription and selective impairment in the ability to give rise to B cells. Hematopoietic cell development from HSCs proceeds through an ordered sequence of expression/function of transcription factors, which control lineage specification, commitment and progression. This sequence of events is controlled, in part, by chromatin accessibility of the genes involved in these processes. Chromatin accessibility is regulated by histone modification (e.g. acetylation, methylation, phosphorylation, etc.) and methylation of DNA CpG dinucleotides. Little is known regarding the patterns of histone modification and DNA methylation that impact early steps in hematopoiesis, and how these patterns might be altered during aging. Here we propose to address the hypotheses that dysregulation of transcription and defective B cell generative capacity of aged HSCs is the consequence of epigenetic changes and attendant genomic destabilization. Our approach will involve the use of ex vivo HSCs as well as conditionally transformed HSC lines derived from immunologically aged or young mice. The latter retain the functional phenotype of the originating adult stem cells, and provide an unlimited supply of material for biochemical studies. Further, these cells can be manipulated genetically to establish the role of specific alterations in HSC defects. B cell development from these HSCs will be studied both in vivo and in the OP9 culture system in which aging-associated B lymphopoietic defects are replicated. PUBLIC HEALTH RELEVANCE: A proportion of aged individuals suffer poor quality of life due to acquired immune defects that reduce their ability to fight infection. Such people require increased medical care and hospitalization, impacting public health primarily in economic terms. Our studies will attempt to define the basis of this immune decline and strategies to correct it.