Using single-gene deletions to identify checkpoints in the progression of systemic autoimmunity
Using single-gene deletions to identify checkpoints in the progression of systemic autoimmunity
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DOI：
10.1111/j.1749-6632.2003.tb06053.x
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发表时间：
2003-01-01
期刊：
影响因子：
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通讯作者：
Kono, DH
中科院分区：
文献类型：
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作者：
Pollard, KM;Hultman, P;Kono, DH
系统性红斑狼疮是一种病因不明的多基因疾病。为了研究特定基因在狼疮中的作用，我们研究了单基因缺失小鼠的疾病特征。总共有17个基因被研究。缺乏某些基因，如CD 40 L、CD 28或Igh 6，可消除自身免疫的诱导。其他基因，如Igh 5，IL-4或ICAM-1，对疾病的发展几乎没有影响。在IL-6缺陷小鼠中观察到中间效应，而β 2-微球蛋白的缺乏导致高丙种球蛋白血症和IgG 1自身抗体的丢失，但抗染色质抗体或肾小球沉积物几乎没有变化。最有趣的观察结果是与干扰素-γ（IFN-γ）的表达或功能相关的基因。小鼠狼疮中IFN-γ水平的降低与自身抗体水平和免疫复合物介导的病理学的降低相关。参与IFN-γ表达上调的基因，如IL-12、STAT-4或ICE，并不显著影响自身免疫，而IFN-γ或IFN-γ受体的缺失导致自身抗体应答和免疫病理学大大降低。缺乏IRF-1（一种对IFN-γ应答的基因）导致抗染色质抗体的选择性保留，但肾小球病理学很少。这些研究表明，IFN-γ的基线水平的存在，而不是表达增加，对自身免疫很重要。此外，如IRF-1敲除所示，IFN-γ/IFN-γ受体相互作用后信号通路和基因表达的特定缺陷可能仅影响某些疾病参数。IFN-γ影响其他免疫相关基因的表达和功能，如IL-4、IL-6和β 2-微球蛋白，这一点并没有逃过我们的注意。因此，这些基因可能是IFN-γ/IFN-γ受体相互作用后促进自身免疫发展的下游事件的一部分。
Systemic lupus erythematosus is a multigenic disorder of unknown etiology. To investigate the roles that specific genes play in lupus, we have examined the disease profiles in mice with single-gene deletions. In total, some 17 genes have been studied. Absence of certain genes, such as CD40L, CD28, or Igh6, abrogated induction of autoimmunity. Other genes, such as Igh5, IL-4, or ICAM-1, had little effect on the development of disease. Intermediate effects were observed in IL-6-deficient mice, while absence of beta2-microglobulin resulted in loss of hypergammaglobulinemia and IgG1 autoantibodies, but produced little change in anti-chromatin antibodies or glomerular deposits. The most interesting observations were obtained with genes related to the expression or function of interferon-gamma (IFN-gamma). Reductions in IFN-gamma levels in murine lupus are associated with reductions in both autoantibody levels and immune-complex-mediated pathology. Genes involved in up-regulation of IFN-gamma expression, such as IL-12, STAT-4, or ICE, did not significantly influence autoimmunity, whereas absence of IFN-gamma or IFN-gamma receptor led to greatly reduced autoantibody response and immunopathology. Absence of IRF-1, a gene expressed in response to IFN-gamma, resulted in selective retention of anti-chromatin antibodies but little glomerular pathology. These studies suggest that the presence of a baseline level of IFN-gamma, rather than increased expression, is important for autoimmunity. Furthermore, as the IRF-1 knockout demonstrates, specific defects in signaling pathways and gene expression subsequent to IFN-gamma/IFN-gamma receptor interaction may influence only certain disease parameters. It has not escaped our attention that IFN-gamma influences the expression and function of other immunologically relevant genes, such as IL-4, IL-6, and beta2-microglobulin. Thus, these genes may be part of the downstream events following IFN-gamma/IFN-gamma receptor interaction that promote the development of autoimmunity.