目标:在SLE中,抗dsDNA可以与抗其他染色质成分的自身抗体共存,比如组蛋白和核小体.这些抗体诱导1型干扰素的产生,SLE的标志。我们测量了抗核抗体(ANA)亚特异性,并研究了它们与炎症生物标志物(包括干扰素调节的趋化因子)的关联。
方法:我们纳入了93名苏丹人和480名瑞典性SLE患者以及匹配的对照(N=104+192)。靶向ANA亚特异性抗体:dsDNA,Sm,Sm/U1RNPcomplex,U1RNP,SSA/Ro52,SSA/Ro60,SSB/La,核糖体P,对所有受试者的PCNA和组蛋白进行定量,抗核小体只在瑞典病人身上,基于珠子的多重免疫测定。用邻近延伸测定技术或ELISA测定72种血浆生物标志物的水平。
结果:在苏丹患者中,研究的抗体与9/72的生物标志物显著相关.抗组蛋白抗体与MCP-3和S100A12以及干扰素I诱导因子MCP-1和CXCL10显示出最强的正相关。与CXCL10和S100A12相关的抗dsDNA抗体,但在多变量分析中,与抗组蛋白不同,协会失去了意义。在瑞典患者中,MCP-1、CXCL10、SA100A12也表现出与抗组蛋白和抗核小体抗体更强的关联,与抗dsDNA和其他ANA亚特异性相比。在多元回归模型中,抗组蛋白/核小体保留了最强的关联。当排除抗组蛋白或抗核小体阳性患者时,MCP-1/CXCL10和抗dsDNA之间的关联丢失。相比之下,当排除抗dsDNA阳性患者时,与抗组蛋白和抗核小体的关联仍然显着。
结论:在两个不同种族血统的队列中,与抗dsDNA或其他ANA亚特异性相比,靶向染色质的自身抗体与IFN诱导的炎症生物标志物的相关性更强.我们的结果表明,抗组蛋白/核小体自身抗体可能是SLE中1型干扰素活性的主要驱动因素。
OBJECTIVE: In SLE, anti-dsDNA can co-occur with autoantibodies against other chromatin components, like histones and nucleosomes. These antibodies induce type-1 interferon production, a hallmark of SLE. We measured antinuclear antibody (ANA) sub-specificities and investigated their associations to inflammatory biomarkers including interferon-regulated chemokines.
METHODS: We included 93 Sudanese and 480 Swedish SLE patients and matched controls (N = 104 + 192). Autoantibodies targeting ANA-subspecificites: dsDNA, Sm, Sm/U1RNPcomplex, U1RNP, SSA/Ro52, SSA/Ro60, SSB/La, ribosomal P, PCNA and histones were quantified in all subjects, anti-nucleosome only in the Swedish patients, with a bead-based multiplex immunoassay. Levels of 72 plasma biomarkers were determined with Proximity Extension Assay technique or ELISA.
RESULTS: Among Sudanese patients, the investigated antibodies significantly associated with 9/72 biomarkers. Anti-histone antibodies showed the strongest positive correlations with MCP-3 and S100A12 as well as with interferon I-inducible factors MCP-1 and CXCL10. Anti-dsDNA antibodies associated with CXCL10 and S100A12, but in multivariate analyses, unlike anti-histone, associations lost significance.Among Swedish patients, MCP-1, CXCL10, SA100A12 also demonstrated stronger associations to anti-histone and anti-nucleosome antibodies, compared with anti-dsDNA and other ANA sub-specificities. In multiple regression models, anti-histone/nucleosome retained the strongest associations. When excluding anti-histone or anti-nucleosome positive patients, the associations between MCP-1/CXCL10 and anti-dsDNA were lost. In contrast, when excluding anti-dsDNA positive patients, associations with anti-histone and anti-nucleosome remained significant.
CONCLUSIONS: In two cohorts of different ethnical origin, autoantibodies targeting chromatin correlate stronger with IFN-induced inflammatory biomarkers than anti-dsDNA or other ANA sub-specificities. Our results suggest that anti-histone/nucleosome autoantibodies may be main drivers of type-1 interferon activity in SLE.