Hakim Frances T, Memon Sarfraz, Jin Ping, Imanguli Matin M, Wang Huan, Rehman Najibah, Yan Xiao-Yi, Rose Jeremy, Mays Jacqueline W, Dhamala Susan, Kapoor Veena, Telford William, Dickinson John, Davis Sean, Halverson David, Naik Haley B, Baird Kristin, Fowler Daniel, Stroncek David, Cowen Edward W, Pavletic Steven Z, Gress Ronald E
Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
J Immunol. 2016 Nov 1;197(9):3490-3503. doi: 10.4049/jimmunol.1601054. Epub 2016 Sep 30.
Although chronic graft-versus-host disease (CGVHD) is the primary nonrelapse complication of allogeneic transplantation, understanding of its pathogenesis is limited. To identify the main operant pathways across the spectrum of CGVHD, we analyzed gene expression in circulating monocytes, chosen as in situ systemic reporter cells. Microarrays identified two interrelated pathways: 1) IFN-inducible genes, and 2) innate receptors for cellular damage. Corroborating these with multiplex RNA quantitation, we found that multiple IFN-inducible genes (affecting lymphocyte trafficking, differentiation, and Ag presentation) were concurrently upregulated in CGVHD monocytes compared with normal subjects and non-CGVHD control patients. IFN-inducible chemokines were elevated in both lichenoid and sclerotic CGHVD plasma and were linked to CXCR3 lymphocyte trafficking. Furthermore, the levels of the IFN-inducible genes CXCL10 and TNFSF13B (BAFF) were correlated at both the gene and the plasma levels, implicating IFN induction as a factor in elevated BAFF levels in CGVHD. In the second pathway, damage-/pathogen-associated molecular pattern receptor genes capable of inducing type I IFN were upregulated. Type I IFN-inducible MxA was expressed in proportion to CGVHD activity in skin, mucosa, and glands, and expression of TLR7 and DDX58 receptor genes correlated with upregulation of type I IFN-inducible genes in monocytes. Finally, in serial analyses after transplant, IFN-inducible and damage-response genes were upregulated in monocytes at CGVHD onset and declined upon therapy and resolution in both lichenoid and sclerotic CGVHD patients. This interlocking analysis of IFN-inducible genes, plasma analytes, and tissue immunohistochemistry strongly supports a unifying hypothesis of induction of IFN by innate response to cellular damage as a mechanism for initiation and persistence of CGVHD.
尽管慢性移植物抗宿主病（CGVHD）是同种异体移植的主要非复发并发症，但其发病机制的了解仍很有限。为了确定CGVHD整个谱系中的主要作用途径，我们分析了循环单核细胞中的基因表达，选择其作为原位全身报告细胞。微阵列鉴定出两条相互关联的途径：1）干扰素诱导基因，以及2）细胞损伤的天然受体。通过多重RNA定量对这些结果进行确证，我们发现与正常受试者和非CGVHD对照患者相比，CGVHD单核细胞中多个干扰素诱导基因（影响淋巴细胞运输、分化和抗原呈递）同时上调。在苔藓样和硬化性CGHVD血浆中，干扰素诱导趋化因子均升高，并与CXCR3淋巴细胞运输相关。此外，干扰素诱导基因CXCL10和TNFSF13B（BAFF）的水平在基因和血浆水平上均相关，这表明干扰素诱导是CGVHD中BAFF水平升高的一个因素。在第二条途径中，能够诱导I型干扰素的损伤/病原体相关分子模式受体基因上调。I型干扰素诱导的MxA在皮肤、粘膜和腺体中的表达与CGVHD活性成比例，TLR7和DDX58受体基因的表达与单核细胞中I型干扰素诱导基因的上调相关。最后，在移植后的系列分析中，在CGVHD发作时，单核细胞中的干扰素诱导基因和损伤反应基因上调，在苔藓样和硬化性CGVHD患者接受治疗并病情缓解后下降。对干扰素诱导基因、血浆分析物和组织免疫组化的这种连锁分析有力地支持了一个统一的假说，即细胞损伤的先天反应诱导干扰素是CGVHD发生和持续的机制。
