Division of Rheumatology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
Ann Rheum Dis. 2021 Feb;80(2):194-202. doi: 10.1136/annrheumdis-2019-216786. Epub 2020 Oct 1.
Congenital heart block (CHB) with immune cell infiltration develops in the fetus after exposure to maternal Ro/La autoantibodies. CHB-related serology has been extensively studied, but reports on immune-cell profiles of anti-Ro/La-exposed neonates are lacking. In the current study, we characterised circulating immune-cell populations in anti-Ro/La+mothers and newborns, and explored potential downstream effects of skewed neonatal cell populations.
In total, blood from mothers (n=43) and neonates (n=66) was sampled at birth from anti-Ro/La+ (n=36) and control (n=30) pregnancies with or without rheumatic disease and CHB. Flow cytometry, microarrays and ELISA were used for characterising cells and plasma.
Similar to non-pregnant systemic lupus erythematosus and Sjögren-patients, anti-Ro/La+mothers had altered B-cell subset frequencies, relative T-cell lymphopenia and lower natural killer (NK)-cell frequencies. Surprisingly, their anti-Ro/La exposed neonates presented higher frequencies of CD56CD16 NK cells (p<0.01), but no other cell frequency differences compared with controls. Type I and II interferon (IFN) gene-signatures were revealed in neonates of anti-Ro/La+ pregnancy, and exposure of fetal cardiomyocytes to type I IFN induced upregulation of several NK-cell chemoattractants and activating ligands. Intracellular flow cytometry revealed IFNγ production by NK cells, CD8 and CD4 T cells in anti-Ro/La exposed neonates. IFNγ was also detectable in their plasma.
Our study demonstrates an increased frequency of NK cells in anti-Ro/La exposed neonates, footprints of type I and II IFN and an upregulation of ligands activating NK cells in fetal cardiac cells after type I IFN exposure. These novel observations demonstrate innate immune activation in neonates of anti-Ro/La+pregnancy, which could contribute to the risk of CHB.
在母体 Ro/La 自身抗体暴露后，胎儿会发生先天性心脏传导阻滞（CHB）伴免疫细胞浸润。已广泛研究了 CHB 相关的血清学，但缺乏针对 Ro/La 暴露新生儿免疫细胞谱的报告。在本研究中，我们对 Ro/La 阳性母亲和新生儿的循环免疫细胞群进行了特征描述，并探讨了新生儿细胞群体偏倚的潜在下游影响。
共采集了 43 名 Ro/La 阳性母亲（n=43）和 66 名新生儿（n=66）的血液，这些新生儿来自于有或无风湿性疾病和 CHB 的 Ro/La 阳性（n=36）和对照组（n=30）妊娠。使用流式细胞术、微阵列和 ELISA 来描述细胞和血浆。
与非妊娠系统性红斑狼疮和干燥综合征患者类似，Ro/La 阳性母亲的 B 细胞亚群频率发生改变，相对 T 细胞淋巴细胞减少，NK 细胞频率降低。令人惊讶的是，与对照组相比，其 Ro/La 暴露的新生儿具有更高的 CD56CD16 NK 细胞频率（p<0.01），但没有其他细胞频率差异。在 Ro/La 阳性妊娠的新生儿中揭示了 I 型和 II 型干扰素（IFN）基因特征，并且胎儿心肌细胞暴露于 I 型 IFN 会诱导几种 NK 细胞趋化因子和激活配体的上调。通过体内流式细胞术检测到 Ro/La 暴露的新生儿中 NK 细胞、CD8 和 CD4 T 细胞产生 IFNγ。其血浆中也可检测到 IFNγ。
我们的研究表明，Ro/La 暴露的新生儿中 NK 细胞的频率增加，I 型和 II 型 IFN 的痕迹，以及 I 型 IFN 暴露后胎儿心肌细胞中激活 NK 细胞的配体的上调。这些新的观察结果表明，Ro/La 阳性妊娠新生儿的固有免疫激活，这可能导致 CHB 的风险增加。
