Marginal Zone B Cell Repertoire

描述（由申请人提供）：我们最近已经表明，成人MZ B细胞含有20%的缺乏N区多样性的序列，这是胎儿衍生细胞的标志。通过使用由TdT+和TdT-骨髓细胞组成的混合骨髓嵌合体，我们已经证明，我们在MZ和FO B细胞之间观察到的库差异受到基于BCR的选择这些亚群的极大影响。在这些小鼠的分析过程中，我们观察到从骨髓中的未成熟B细胞到脾脏中的成熟B细胞的所有B细胞亚群的库中的意外和显著差异。由于在骨髓嵌合体中过渡T1区室和MZ B细胞之间对N-IgH序列和λ轻链的选择性偏好的相似性，我们提出具有不同库的MZ B细胞亚群可能直接从T1过渡区室分化而不经历T2阶段。因此，我们假设MZ区室可能是由不同的子集与不同的剧目，我们将集中在这个新的假设在这个补助金。我们最近发现了一种小鼠，它只具有直接与T1细胞分化的MZ细胞亚群，为我们提供了一种独特的方法来进行本申请中提出的研究。这里提出的实验将表征我们相信已经发现的脾脏中的多个MZ前体群体和B细胞分化的新途径。我们将使用微阵列评估这些MZ和FO B细胞亚群在微生物、蛋白质、自身抗原和聚糖特异性方面的库差异。我们还将评估这些亚群和这些库如何随年龄变化，因为其中一个MZ亚群似乎具有胎儿起源。不同脾脏亚群中潜在不同和可能变化的库的信息对于可能靶向MZ B群体的疫苗设计策略以及理解生命不同阶段对血源性病原体的应答将是关键信息。公共卫生相关性：边缘带B细胞对血液传播的病原体（包括许多细菌）做出快速反应。我们提出边缘区B细胞可以根据BCR库差异、细胞表面表型和分化历史进行细分。我们将分析这些边缘区B细胞亚群对自身抗原、聚糖和细菌病原体的抗体库，并确定抗体库是否随年龄变化。不同脾脏亚群中潜在不同和可能变化的库的信息对于可能靶向MZ B群体的疫苗设计策略以及理解生命不同阶段对血源性病原体的应答将是关键信息。

DESCRIPTION (provided by applicant): We have recently shown that adult MZ B cells contain 20% of sequences that lack N region diversity, a hallmark of fetally-derived cells. Through the use of mixed bone marrow chimeras comprised of TdT+ and TdT- bone marrow cells, we have demonstrated that the differences in repertoire that we observed between MZ and FO B cells was greatly influenced by BCR-based selection into these subsets. During the analyses of these mice, we observed unexpected and striking differences in the repertoires of all subpopulations of B cells from immature B cells in the bone marrow through the mature B cells in the spleen. Due to the similarity in the selective preferences for N- IgH sequences and also for lambda light chains between the transitional T1 compartment and MZ B cells in the bone marrow chimeras, we propose that a subset of MZ B cells with a distinct repertoire may have directly differentiated from the T1 transitional compartment without going through the T2 stage. We thus hypothesize that the MZ compartment may be comprised of distinct subsets with distinct repertoires, and we will focus on this novel hypothesis in this grant. We have recently identified a mouse that has only the subset of MZ cells that directly differentiates from T1 cells, providing us with a unique approach to the studies proposed in this application. The experiments presented here will characterize the multiple MZ precursor populations and novel pathways of B cell differentiation in the spleen that we believe we have uncovered. We will assess the differences in the repertoires of these subsets of MZ and FO B cells with regard to microbial, protein, autoantigen and glycan specificities using microarrays. We will also assess how these subsets and these repertoires change with age, since one of the MZ subsets appears to have a fetal origin. This information of potentially different and possibly changing repertoires in different splenic subsets will be critical information for vaccine design strategies that may target MZ B populations, and for understanding the response to blood-borne pathogens at different stages of life. PUBLIC HEALTH RELEVANCE: Marginal zone B cells make rapid responses to blood-borne pathogens, including many bacteria. We propose that the marginal zone B cells can be subdivided based on BCR repertoire differences, cell surface phenotype, and differentiation history. We will analyze the antibody repertoire of these subsets of marginal zone B cells to autoantigens, glycans, and bacterial pathogens, and will determine if the repertoire changes with age. This information of potentially different and possibly changing repertoires in different splenic subsets will be critical information for vaccine design strategies that may target MZ B populations, and for understanding the response to blood-borne pathogens at different stages of life.