Selection of the B Cell Repertoire in Senescence

 描述（由申请方提供）：在小鼠和人的老年期，B淋巴细胞生成受损，内在B细胞缺陷导致IG同种型转换和体细胞超变不良。老年通过干扰以下各项导致B淋巴细胞生成不良：1）前B/前B细胞功能; 2）普通淋巴祖细胞（CLP）的发育;以及3）淋巴偏向性造血干细胞（L-HSC）的维持。这有助于外周中B细胞数量和组成的改变，并且还改变了B细胞抗体特异性的“读出”。后者可能导致对传染病的保护不力。 老年小鼠（和人类）的细胞是促炎性的并表达TNF α。特别地，老年小鼠中的炎症相关B细胞（ABC）是促炎性的，并且代表了在老年时广泛扩增的新的B细胞亚群。到2岁时，ABC可以构成脾脏和骨髓中多达一半的成熟B细胞。在老年小鼠中，TNF α通过干扰IG同种型转换而降低外周B细胞功能。在老年小鼠的骨髓中，ABC通过TNF α诱导B细胞前体的凋亡。此外，在老年小鼠中受ABC影响较小的那些B细胞前体表达较低水平的替代轻链（SLC）。SLC是前B细胞受体（preBCR）的关键成分;老年小鼠中preBCR的受损影响B细胞抗体库的“读出”。这被视为B细胞的频率增加 其与细菌表位磷酸胆碱反应，对T15独特型呈阴性，并且具有低亲和力。这些与“老年”相关的抗PC B细胞产生的抗肺炎球菌抗体较少。在本提案中，我们将检测促炎性B细胞（包括ABC）在相对晚期阶段（前B/前B）以及早期阶段（共同类造血祖细胞[CLP];造血干细胞[HSC]）发育（特定目的1和2）下调B淋巴细胞生成中的作用。此外，我们将确定促炎性B细胞（包括ABC）在改变B细胞库的“读出”和抑制成熟B细胞中的IG同种型转换和体细胞超变中的作用（具体目标3）.最后， 我们将测试在老年小鼠中促炎性B细胞及其亚群的消耗是否“恢复”B细胞发育并“修复”老年中所见的功能性B细胞缺陷。

 DESCRIPTION (provided by applicant): In old age, in both mice and humans, B lymphopoiesis is compromised and intrinsic B cell defects contribute to poor Ig isotype switch and somatic hypermutation. Old age causes poor B lymphopoiesis by interfering with: 1) pro-B/pre-B cell function; 2) development of common lymphoid progenitors (CLP); and 3) maintenance of lymphoid-biased hematopoietic stem cells (L-HSC). This contributes to alterations in B cell numbers and composition in the periphery and also changes the "read-out" of B cell antibody specificities. The latter can result in poor protection to infectious diseases. cells in old mice (and humans) are pro-inflammatory and express TNFa. In particular, the Age-associated B cells (ABC) in old mice are pro-inflammatory and represent a novel B cell subset which expands extensively in old age. By 2 years of age, ABC can constitute up to one- half of mature B cells in spleen and bone marrow. In old mice, TNFa diminishes peripheral B cell function by interfering with Ig isotype switching. In the bone marrow of old mice, ABC, via TNFa, induce apoptosis in B cell precursors. Moreover, those B cell precursors which are less affected by ABC in old mice express lower levels of the surrogate light chain (SLC). The SLC is a key constituent of the pre-B cell receptor (preBCR); compromise of the preBCR in old mice affects the "read-out" of the B cell antibody repertoire. This is seen as an increased frequency of B cells which are reactive with the bacterial epitope phosphorylcholine, are negative for the T15 idiotype, and are of low affinity. These "old-age" related anti-PC B cells produce less protective antibodies to pneumococci. In this proposal, we will test the role of pro-inflammatory B cells, including ABC, in down-regulating B lymphopoiesis at relatively late stages (pro-B/pre-B) as well as early stages (Common Lymphoid Progenitors [CLP]; hematopoietic stem cells [HSC]) of development (Specific Aims 1 and 2). Furthermore, we will determine effects of pro-inflammatory B cells, including ABC, in both altering the "read- out" of the B cell repertoire and inhibiting Ig isotype switch and somatic hypermutation in mature B cells (Specific Aim 3). Finally, we will test whether depletion of pro-inflammatory B cells and their subsets in old mice "rejuvenates" B cell development and "repairs" the functional B cell deficiencies seen in old age.