ROLE OF APPENDIX AND GALT IN DEVELOPMENT OF THE PRIMARY HUMAN IMMUNE REPERTOIRE

附录和 GALT 在人类初级免疫库发育中的作用

• 批准号: 6099079
• 负责人: Rose Mage
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6099079
• 关键词: B lymphocyte; antibody formation; autoimmunity; cell differentiation; child (0-11); developmental immunology; gut associated lymphoid tissue; human subject; ileocolonic region; immunocytochemistry; laboratory rabbit; polymerase chain reaction; tissue /cell culture

Our studies in the rabbit have shown that the young appendix is an important site of development of the cells destined to produce protective antibodies. The rabbit appendix has functions similar to those of the avian bursa of Fabricius. In the young rabbit, there is rapid growth and expansion of B lymphocytes in the appendix, and positive and negative selection events occur. We believe that the cells that survive selection in the appendix seed the peripheral lymphoid system and undergo self renewal to maintain the primary repertoire. The data on rabbit have led us to initiate an evaluation of the role of human appendix and GALT in development of the human immune repertoire and mucosal immunity. We started by asking at what age lymphoid development is most pronounced in the human appendix. Our conclusions are based on preliminary results of examinations 8-18 specimens by various stainings. Hematoxylin and eosin staining of paraffin sections of normal human appendix was first used to examine stages of germinal center (GC) development. At 4 days, only primary follicles were found. Lymphoid follicles appeared to develop rapidly within the first year of life and be maintained or gradually increased in size and number during childhood. Lymphoid development in appendix tissue from an 8 month old child resembled that from a 10 year old. In the samples from ages 4 months to 16 years, GC were evident with clearly defined light and dark zones. Lymphoid follicles had begun to atrophy in the sample from a 16 year old. No follicles were evident in one specimen from a 25-year-old. It appears that follicles begin to diminish in size and number during the teen years. The distribution of cells bearing common B and T cell markers at various ages was investigated by staining paraffin sections for IgM, IgD and IgA positive B cells and plasma cells and for CD4 and CD8 positive T cells. In a sample from a 4-day-old child, plasma cells (PC) were absent, anti-IgM stained most follicular cells whereas anti-IgD stained cells irregularly within the follicle and anti-IgA did not stain. Ig staining patterns were similar in the samples from 4 months to 16 years: GC were IgM+, mantle zones were IgD+, and GC light zones were weakly IgA+. CD4+ and CD8+ cells were found mainly in the T cell areas bordering the GC. Numbers of CD4+ and CD8+ cells varied greatly between GC from the same donor although T cells were found in the follicles from the earliest age examined. Do GC of the human appendix undergo the developmental changes seen in the rabbit appendix which are suggestive of transformation from a primary to secondary lymphoid organ? The distributions of B cells expressing IgM, IgD and IgA, and of T cells bearing CD4 appear similar throughout development as long as GC are present. It is uncertain whether this holds true for CD8+ cells. Double staining for possible double-positive cells is necessary and is in progress. Our finding of CD4 T cells in the germinal centers of developing human appendix suggests that it may function as a secondary lymphoid organ but does not exclude the possibility that it may also play a role as a primary lymphoid organ. The human appendix shares some characteristics of a "mammalian bursa equivalent"; the morphology of its follicles and the fact that the GC involute with age (Dasso et al., 1998 and ms in preparation).

我们对兔子的研究表明，年轻的兔子 阑尾是细胞发育的重要部位 产生保护性抗体。兔子阑尾有功能 与鸟类法氏囊类似。在幼年的兔子身上， B淋巴细胞快速生长和扩增 附录，并发生正向和负向选择事件。我们 相信在阑尾选择中存活下来的细胞 周围淋巴系统并进行自我更新以维持 主要曲目。关于兔子的数据促使我们发起了一项 评估人类阑尾和 GALT 在 人类免疫系统和粘膜的发育 免疫。我们首先询问淋巴在什么年龄发育 在人类阑尾中最为明显。我们的结论是 根据 8-18 个样本的初步检查结果 各种染色。石蜡苏木精和伊红染色 首先使用正常人阑尾切片来检查 生发中心（GC）发育阶段。 4天后，仅 发现了初级卵泡。淋巴滤泡似乎 在生命的第一年内迅速发展并维持或 在童年时期，其体型和数量逐渐增加。淋巴 8 个月大儿童阑尾组织的发育 就像10岁的孩子一样。在 4 岁的样本中 几个月到 16 年，GC 明显，光线清晰， 黑暗区域。样本中的淋巴滤泡已开始萎缩 从16岁开始。一份标本中没有明显的卵泡 25岁。卵泡的大小似乎开始缩小 青少年时期的数量。承载细胞的分布 不同年龄段常见的 B 细胞和 T 细胞标记物的研究 IgM、IgD 和 IgA 阳性 B 细胞的石蜡切片染色 浆细胞以及 CD4 和 CD8 阳性 T 细胞。在样本中 4 天大的孩子，浆细胞 (PC) 缺失，抗 IgM 大多数滤泡细胞染色，而抗 IgD 染色细胞 卵泡内不规则，抗 IgA 未染色。免疫球蛋白染色 4 个月至 16 岁的样本中的模式相似：GC 为 IgM+，外套膜区为 IgD+，GC 亮区为 弱IgA+。 CD4+和CD8+细胞主要存在于T细胞中 与 GC 相邻的细胞区域。 CD4+ 和 CD8+ 细胞的数量 尽管 T 细胞不同，但来自同一供体的 GC 之间差异很大 从最早检查的年龄起就在毛囊中发现了。进行气相色谱 人类阑尾经历以下发育变化 兔子的阑尾暗示着从 初级淋巴器官到次级淋巴器官？ B细胞的分布 表达 IgM、IgD 和 IgA 以及携带 CD4 的 T 细胞出现 只要存在 GC，整个开发过程都是类似的。这是 不确定这是否适用于 CD8+ 细胞。双重染色 对于可能的双阳性细胞的检测是必要的并且正在进行中。 我们在发育中的生发中心发现了 CD4 T 细胞 人类阑尾表明它可能具有辅助功能 淋巴器官，但不排除它也可能 发挥初级淋巴器官的作用。人类阑尾 具有“哺乳动物法氏囊等效物”的一些特征；这 其卵泡的形态以及 GC 渐开线的事实 年龄（Dasso 等人，1998 年，MS 正在准备中）。