BXSB小鼠是研究系統(tǒng)性紅斑狼瘡的主要模型,，其Y染色體上的Yaa座位的復(fù)制能夠加速自身免疫疾病傾向的小鼠發(fā)病,。最新的研究表明，Yaa座位上TLR7基因的復(fù)制足以促進(jìn)自身免疫疾病的發(fā)生,。
來自美國的Bolland研究小組通過增加或者減少TLR7的基因量,，研究了TLR7基因的復(fù)制在Yaa小鼠發(fā)病中的作用。首先,，他們將Yaa小鼠與TLR7基因缺陷的小鼠進(jìn)行雜交,，使TLR7的基因量恢復(fù)到正常水平。在受TLR7的配體刺激時,，這些小鼠脾臟細(xì)胞的增殖數(shù)量和野生型一致,，RNA自身抗體的產(chǎn)生得到明顯改善,。然后將帶有4個到32個TLR7基因拷貝的六種轉(zhuǎn)基因小鼠與野生型小鼠進(jìn)行比較，發(fā)現(xiàn)TLR7的表達(dá)強度與RNA自身抗體的產(chǎn)生和腎小球腎炎直接相關(guān),。并且,，只要TLR7的表達(dá)量增加4至8倍，就會引起DC,、T細(xì)胞和B細(xì)胞的明顯活化,。研究認(rèn)為，TLR7及其相關(guān)的信號通路將可能成為治療自身免疫疾病的潛在靶點,。（科學(xué)網(wǎng)）
原始出處:
Immunity
Volume 27, Issue 5, 26 November 2007, Pages 801-810
doi:10.1016/j.immuni.2007.09.009
Control of Toll-like Receptor 7 Expression Is Essential to Restrict Autoimmunity and Dendritic Cell Proliferation
Jonathan A. Deane1, Prapaporn Pisitkun1, Rebecca S. Barrett1, Lionel Feigenbaum3, Terrence Town4, Jerrold M. Ward2, Richard A. Flavell4 and Silvia Bolland1, ,
1Laboratory of Immunogenetics, NIAID/NIH, Rockville, MD 20852, USA
2Infectious Disease Pathogenesis Section, Comparative Medicine Branch, NIAID/NIH, Rockville, MD 20852, USA
3Laboratory Animal Science Program, Science Applications International Corporation (SAIC), NCI/NIH, Frederick, MD 21702, USA
4Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
Received 13 August 2007; revised 13 September 2007; accepted 17 September 2007. Published online: November 8, 2007. Available online 8 November 2007.
Summary
Nucleic acid-binding innate immune receptors such as Toll-like receptor 7 (TLR7) and TLR9 have been implicated in the development of some autoimmune pathologies. The Y chromosome-linked genomic modifier Yaa, which correlates with a duplication of Tlr7 and 16 other genes, exacerbates lupus-like syndromes in several mouse strains. Here we demonstrated that duplication of the Tlr7 gene was the sole requirement for this accelerated autoimmunity, because reduction of Tlr7 gene dosage abolished the Yaa phenotype. Further, we described new transgenic lines that overexpressed TLR7 alone and found that spontaneous autoimmunity developed beyond a 2-fold increase in TLR7 expression. Whereas a modest increase in Tlr7 gene dosage promoted autoreactive lymphocytes with RNA specificities and myeloid cell proliferation, a substantial increase in TLR7 expression caused fatal acute inflammatory pathology and profound dendritic cell dysregulation. These results underscore the importance of tightly regulating expression of TLR7 to prevent spontaneous triggering of harmful autoreactive and inflammatory responses.
Author Keywords: MOLIMMUNO; CELLIMMUNO
