Inflammatory Triggers in B Cell Autoimmunity

外周自身反应性B细胞的来源是什么？我们已经证明了炎症 通过诱导早期移居血液和外周血细胞影响早期B细胞发育 淋巴组织。这种动员是由IL-1和TNFcc介导的，并与 自身反应性外周B细胞的频率。一些证据表明，自身抗体 应答，即使是以LG类转换(CSR)和高突变(SHM)抗体为特征的应答 可以绕过生发中心(GC)反应。在人类和小鼠中，艾滋病的表达通常是 据信仅限于GC内的B细胞，其中LG体细胞高度突变(SHM)和类别切换 重组(CSR)最为活跃。在鸟类、兔子和绵羊体内，艾滋病在胎儿组织中的表达 在没有激活的情况下通过基因转换和/或SHM使一次抗体库多样化 通过外源抗原。最近，我们和其他人证明了未成熟和过渡性B细胞 在小鼠体内结构性表达AID。在这些发育不成熟的细胞中，援助水平很低，但 足以推动CSR和SHM。我们现在已经展示了类似水平的艾滋病在 人未成熟和过渡性B细胞，最显著的是在人胎肝(FL)。事实上， FL中的AID信息量(归一化为Igf5)与人类扁桃体组织中的量相当 对GC B细胞高度浓缩。我们将研究发育调节的AID在 人类前、前和未成熟/过渡性B细胞用于确定早期艾滋病的后果 表达，特别是它在产生自身反应性外周B淋巴细胞中的作用。这些 在正常受试者身上的实验将扩展到自身免疫性疾病的患者，并可能揭示 另一种导致突变的、自我反应的B细胞在正常范围外成熟的途径 中心宽容。

What is the source of self-reactive B cells in the periphery? We have demonstrated that inflammation influences early B cell development by inducing early emigration into the blood and peripheral lymphoid tissues. This mobilization is mediated by IL-1 and TNFcc and is correlated with increases in the frequency of auto-reactive peripheral B cells. Some evidence suggests that auto-antibody responses, even those characterized by lg class-switched (CSR) and hypermutated (SHM) antibody may bypass the germinal center (GC) reaction. In humans and mice, AID expression is generally believed to be restricted to B cells within GC where lg somatic hypermutation (SHM) and class-switch recombination (CSR) are most active. In birds, rabbits, and sheep AID expression in fetal tissues diversifies the primary antibody repertoire by gene conversion and/or SHM in the absence of activation by exogenous antigens. Recently, we and others demonstrated that immature and transitional B cells in mice constitutively express AID. AID levels are low in these developmental^ immature cells, but sufficient to drive CSR and SHM. We have now demonstrated similar levels of AID expression in human immature and transitional B cells, and most remarkably, in human fetal liver (FL). Indeed, the quantity of AID message (normalized to Igf5) in FL is comparable to that of human tonsil, a tissue highly enriched for GC B cells. We shall investigate developmentally regulated AID expression in human pro-, pre-, and immature/transitional B cells to determine the consequences of early AID expression, and especially its role in the generation of auto-reactive, peripheral B lymphocytes. These experiments in normal subjects will be extended to patients with autoimmune disease and may reveal another pathway leading to mutated, self-reactive B cells that mature outside the normal boundaries of central tolerance.