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Abstract：
The \"X chromosome-nucleolus nexus\" hypothesis provides a comprehensive explanation of how autoantibodies can develop following cellular stress. The hypothesis connects autoimmune diseases with the impact of environmental factors, such as viruses, through epigenetic disruption. The inactive X chromosome, a major epigenetic structure in the female cell\'s nucleus, is a key component of the hypothesis. The inactive X is vulnerable to disruption due to the following: (1) its heavy requirements for methylation to suppress gene expression, (2) its peripheral location at the nuclear envelope, (3) its late replication timing, and (4) its frequently observed close association with the nucleolus. The dynamic nucleolus can expand dramatically in response to cellular stress and this could disrupt the neighboring inactive X, particularly during replication, leading to expression from previously suppressed chromatin. Especially vulnerable at the surface of the inactive X chromosome would be genes and elements from Xp22 to the terminus of the short arm of the X. Expression of these genes and elements could interfere with nucleolar integrity, nucleolar efficiency, and future nucleolar stress response, and even lead to fragmentation of the nucleolus. Ribonucleoprotein complexes assembled in the nucleolus could be left in incomplete states and inappropriate conformations, and/or contain viral components when the nucleolus is disrupted and these abnormal complexes could initiate an autoimmune response when exposed to the immune system. Epitope spreading could then lead to an autoimmune reaction to the more abundant normal complexes. Many autoantigens reported in lupus and other autoimmune diseases are, at least transiently, nucleolar components.
摘要：
“X染色体-核仁关系”假说提供了对自身抗体如何在细胞应激后发展的全面解释。该假设将自身免疫性疾病与环境因素的影响联系起来，如病毒，通过表观遗传破坏。不活跃的X染色体，女性细胞核中的主要表观遗传结构，是该假设的关键组成部分。由于以下原因，无活性的X很容易被破坏：（1）其对甲基化的大量需求以抑制基因表达，(2)其在核包络处的外围位置，(3)其复制时间较晚，（4）经常观察到的与核仁的紧密联系。动态核仁可以响应细胞应激而急剧扩张，这可能会破坏邻近的无活性X，特别是在复制过程中，导致以前抑制的染色质表达。在无活性X染色体表面特别脆弱的是从Xp22到X短臂末端的基因和元件。这些基因和元件的表达可能会干扰核仁完整性，核仁效率，和未来的核仁应激反应，甚至导致核仁碎裂.组装在核仁中的核糖核蛋白复合物可能处于不完整状态和不适当的构象，和/或当核仁被破坏时含有病毒组分,并且这些异常复合物在暴露于免疫系统时可引发自身免疫应答。然后表位扩散可能导致对更丰富的正常复合物的自身免疫反应。在狼疮和其他自身免疫性疾病中报道的许多自身抗原是，至少是短暂的，核仁成分。
