Division of Rheumatology, Department of Medicine, Anschutz Medical Campus, Aurora, CO, USA.
Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
Arthritis Res Ther. 2021 May 22;23(1):147. doi: 10.1186/s13075-021-02531-w.
Axial spondyloarthritis (axSpA) has strong connections with intestinal inflammation as occurs in Crohn's disease (CD). However, the immunologic mechanisms that distinguish axSpA, CD, and those with features of both diseases (CD-axSpA) are unknown. This study aimed to address this question by initial unbiased single cell RNA-sequencing (scRNAseq) on a pilot cohort followed by validating findings using flow cytometry and ELISA in a larger cohort.
Two individuals each with CD, axSpA, CD-axSpA, and healthy controls (HC) were recruited for a pilot discovery scRNAseq cohort, and the validation cohort consisted of 18 axSpA, 24 CD, 13 CD-axSpA, and 17 HC that was evaluated by flow cytometry on PBMCs and ELISAs for plasma cytokines.
Uniquely, PBMCs from subjects with CD-axSpA demonstrated a significant increase in granzyme B+ T cells of both CD4+ and CD8+ lineages by both scRNAseq and flow cytometry. T cell maturation was also greater in those with CD-axSpA, particularly the CD4+ granzyme B+ population. Pathway analysis suggested increased interferon response genes in all immune cell populations within CD-axSpA. Although IFN-γ was elevated in the plasma of a subset of subjects with CD-axSpA, IL-6 was also significantly elevated.
Our findings support the presence of a chronic interferonopathy in subjects with CD-axSpA characterized by interferon signaling by pathway analysis and an expansion of mature, cytotoxic T cells. These data indicate fundamental immunological differences between CD-axSpA and both of the putative "parent" conditions, suggesting that it is a distinct disease with unique natural history and treatment needs.
强直性脊柱炎（axSpA）与克罗恩病（CD）等肠道炎症有很强的关联。然而，区分 axSpA、CD 和同时具有这两种疾病特征的疾病（CD-axSpA）的免疫机制尚不清楚。本研究旨在通过对一个试点队列进行初始无偏单细胞 RNA 测序（scRNAseq），然后在更大的队列中使用流式细胞术和 ELISA 验证发现来解决这个问题。
每个患有 CD、axSpA、CD-axSpA 和健康对照（HC）的个体均被招募入一个试点发现 scRNAseq 队列，验证队列包括 18 例 axSpA、24 例 CD、13 例 CD-axSpA 和 17 例 HC，通过 PBMC 流式细胞术和 ELISA 评估血浆细胞因子。
独特的是，通过 scRNAseq 和流式细胞术，CD-axSpA 患者的 PBMC 中 CD4+和 CD8+谱系的 granzyme B+T 细胞均显著增加。那些患有 CD-axSpA 的人的 T 细胞成熟度也更高，尤其是 CD4+granzyme B+群体。通路分析表明，在 CD-axSpA 所有免疫细胞群体中，干扰素反应基因增加。虽然 CD-axSpA 亚组的血浆中 IFN-γ 升高，但 IL-6 也显著升高。
我们的研究结果支持在 CD-axSpA 患者中存在慢性干扰素病，其特征是通过通路分析和成熟、细胞毒性 T 细胞的扩增来进行干扰素信号传递。这些数据表明 CD-axSpA 与两个假定的“亲本”疾病之间存在根本的免疫学差异，表明其是一种具有独特自然史和治疗需求的独特疾病。
