Distinct Single Cell Gene Expression in Peripheral Blood Monocytes Correlates With Tumor Necrosis Factor Inhibitor Treatment Response Groups Defined by Type I Interferon in Rheumatoid Arthritis

Frontiers in Immunology

Timothy B. Niewold¹  Zhongbo Jin²  Wei Fan³  Danielle Vsetecka⁴  Jessica M. Dorschner⁴  Clement J. Michet⁴  Eric Matteson⁴  Kerry Wright⁴  Thomas Mason⁴  John M. Davis⁴  Scott Persellin⁴  Betty Dicke⁴  Mark A. Jensen⁵  Theresa L. Wampler Muskardin⁵  Yogita Ghodke-Puranik⁵ 

[1] Department of Medicine, Colton Center for Autoimmunity, New York University School of Medicine, New York, NY, United States;Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL, United States;Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China;Division of Rheumatology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, United States;Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York, NY, United States;

关键词: type I interferon;    tumor necrosis factor-alpha;    monocyte;    single cell;    rheumatoid arthritis;    janus kinase 1;   

DOI  :  10.3389/fimmu.2020.01384

来源: DOAJ

【 摘 要 】

Previously, we demonstrated in test and validation cohorts that type I IFN (T1IFN) activity can predict non-response to tumor necrosis factor inhibitors (TNFi) in rheumatoid arthritis (RA). In this study, we examine the biology of non-classical and classical monocytes from RA patients defined by their pre-biologic treatment T1IFN activity. We compared single cell gene expression in purified classical (CL, n = 342) and non-classical (NC, n = 359) monocytes. In our previous work, RA patients who had either high IFNβ/α activity (>1.3) or undetectable T1IFN were likely to have EULAR non-response to TNFi. In this study comparisons were made among patients grouped according to their pre-biologic treatment T1IFN activity as clinically relevant: “T1IFN undetectable (T1IFN ND) or IFNβ/α >1.3” (n = 9) and “T1IFN detectable but IFNβ/α ≤ 1.3” (n = 6). In addition, comparisons were made among patients grouped according to their T1IFN activity itself: “T1IFN ND,” “T1IFN detected and IFNβ/α ≤ 1.3,” and “IFNβ/α >1.3.” Major differences in gene expression were apparent in principal component and unsupervised cluster analyses. CL monocytes from the T1IFN ND or IFNβ/α >1.3 group were unlikely to express JAK1 and IFI27 (p < 0.0001 and p 0.0005, respectively). In NC monocytes from the same group, expression of IFNAR1, IRF1, TNFA, TLR4 (p ≤ 0.0001 for each) and others was enriched. Interestingly, JAK1 expression was absent in CL and NC monocytes from nine patients. This pattern most strongly associated with the IFNβ/α>1.3 group. Differences in gene expression in monocytes among the groups suggest differential IFN pathway activation in RA patients who are either likely to respond or to have no response to TNFi. Additional transcripts enriched in NC cells of those in the T1IFN ND and IFNβ/α >1.3 groups included MYD88, CD86, IRF1, and IL8. This work could suggest key pathways active in biologically defined groups of patients, and potential therapeutic strategies for those patients unlikely to respond to TNFi.

【 授权许可】

Unknown