RECAPITULATION OF AUTOIMMUNITY IN TRANSGENIC MICE

在编码抗体的VH片段之间存在重叠 针对外源抗原的二次免疫反应和较少的 在胎儿、自身反应性和/或CD5B细胞中表达。因此， 这些“核心”抗体的拟议功能可能是相关的。这 IDEA预测，自身免疫的起源与机制有关 规范主要的VH曲目的发展。一个这样的舞台和 组织限制性机制是靶向的程序性重组 VH基因。靶向事件的一个建议的决定因素是染色质 可获得性，可能是由先前的生殖系转录产生的 指定的VH。我们建议研究这一机制及其 主要在转基因小鼠中产生自身抗体的后果 其包含足以指导VDJ人类序列IGH微环 重组。在小圈子中使用的VH基因满足上述核心 胎儿B细胞、自身反应性B细胞和CD5B的表达标准 细胞。我们的计划包括正常和正常的体内表达研究 自身免疫菌株和体外细胞培养实验旨在 剖析生殖系转录和转录的顺式/反式/作用调节因子 染色质可及性。

There is an overlap between Vh segments encoding antibodies involved in secondary immune responses against exogenous antigens and those few that are expressed in fetal, autoreactive, and/or CD5 B cells. Consequently, the proposed functions for such 'core' antibodies might be related. This idea predicts that the origin of autoimmunity is linked to mechanisms that regulate primary Vh repertoire development. One such stage and tissue-restricted mechanism is the programmed recombination of targeted Vh genes. A proposed determinant of the targeting event is chromatin accessibility, potentially generated by prior germline transcription of the specified Vh. We propose to study this mechanism and its consequences for autoantibody production primarily in transgenic mice that contain human sequence IgH miniloci sufficient to direct VDJ recombination. Vh genes employed in the miniloci satisfy the above core criteria of expression in fetal B cells, autoreactive B cells and CD5 B cells. Our plan includes in vivo expression studies in normal and autoimmune strains and in vitro cell culture experiments aimed at dissecting cis/trans/acting regulators of germline transcription and chromatin accessibility.