Inflammatory Triggers in B Cell Autoimmunity

外周界自身反应性B细胞的来源是什么？我们已经证明炎症 通过诱导早期迁移到血液和外周血中影响早期B细胞发育 淋巴组织这种动员是由IL-1和TNF α介导的，并且与IL-1和TNF α的增加相关。 自身反应性外周B细胞的频率。一些证据表明，自身抗体 反应，即使是那些以lg类别转换（CSR）和超突变（SHM）抗体为特征的反应， 可以绕过锗酸盐中心（GC）反应。在人类和小鼠中，AID表达通常是 据信仅限于GC内的B细胞，其中Ig体细胞超突变（SHM）和类别转换（class-switch 重组（CSR）是最活跃的。在鸟类、兔子和绵羊胎儿组织中的AID表达 通过基因转换和/或在没有激活的情况下的SHM使一抗库多样化 被外源性抗原感染最近，我们和其他人证明，未成熟和过渡性B细胞 在组成型表达AID的小鼠中。在这些发育不成熟的细胞中，AID水平较低，但 足以推动CSR和SHM。我们现在已经证明了在小鼠中类似的AID表达水平。 人未成熟和过渡性B细胞，最显著的是在人胎肝（FL）中。持续增 FL中AID信息的量（标准化为Igf 5）与人扁桃体（一种组织）的AID信息的量相当 高度富集GC B细胞。我们将研究发育调节的AID表达， 人原、前和未成熟/过渡B细胞，以确定早期AID的后果 表达，特别是其在自身反应性外周B淋巴细胞产生中的作用。这些 在正常受试者中的实验将扩展到自身免疫性疾病患者，并可能揭示 另一个导致突变的、自身反应的B细胞在正常边界外成熟的途径 中央宽容。

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.