Identification of enhanced IFN-γ signaling in polyarticular juvenile idiopathic arthritis with mass cytometry

Throm, Allison A.; Moncrieffe, Halima; Orandi, Amir B.; Pingel, Jeanette T.; Geurs, Theresa L.; Miller, Helen C.; Daugherty, Allyssa L.; Malkova, Olga; Lovell, Daniel J.; Thompson, Susan D.; Grom, Alexei A.; Cooper, Megan A.; Oh, Stephen T.; French, Anthony R.

doi:10.1172/jci.insight.121544

Cited by 21 publications

(21 citation statements)

References 39 publications

(45 reference statements)

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“…In blood, we did not observe any significant difference in the count of the four main DC subsets between both forms of juvenile arthritis, suggesting that the distribution of DC subsets in the blood is not informative. This is consistent with the recent study by Throm et al showing no difference in pDC and mDCs distribution between treatment-naive and remission patients with JIA and with matched controls using mass cytometry ( 39 ). In contrast, in the SF, we observed a very significant accumulation of CD141 + cDCs and CD123 + pDCs in JIA patients with a clear cut-off value of 7 for pDCs and these results were confirmed after adjustment for age.…”

Section: Discussionsupporting

confidence: 93%

Differential Accumulation and Activation of Monocyte and Dendritic Cell Subsets in Inflamed Synovial Fluid Discriminates Between Juvenile Idiopathic Arthritis and Septic Arthritis

et al. 2020

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Despite their distinct etiology, several lines of evidence suggest that innate immunity plays a pivotal role in both juvenile idiopathic arthritis (JIA) and septic arthritis (SA) pathophysiology. Indeed, monocytes and dendritic cells (DC) are involved in the first line of defense against pathogens and play a critical role in initiating and orchestrating the immune response. The aim of this study was to compare the number and phenotype of monocytes and DCs in peripheral blood (PB) and synovial fluid (SF) from patients with JIA and SA to identify specific cell subsets and activation markers associated with pathophysiological mechanisms and that could be used as biomarkers to discriminate both diseases. The proportion of intermediate and non-classical monocytes in the SF and PB, respectively, were significantly higher in JIA than in SA patients. In contrast the proportion of classical monocytes and their absolute numbers were higher in the SF from SA compared with JIA patients. Higher expression of CD64 on non-classical monocyte was observed in PB from SA compared with JIA patients. In SF, higher expression of CD64 on classical and intermediate monocyte as well as higher CD163 expression on intermediate monocytes was observed in SA compared with JIA patients. Moreover, whereas the number of conventional (cDC), plasmacytoid (pDC) and inflammatory (infDC) DCs was comparable between groups in PB, the number of CD141 + cDCs and CD123 + pDCs in the SF was significantly higher in JIA than in SA patients. CD14 + infDCs represented the major DC subset in the SF of both groups with potent activation assessed by high expression of HLA-DR and CD86 and significant up-regulation of HLA-DR expression in SA compared with JIA patients. Finally, higher activation of SF DC subsets was monitored in SA compared with JIA with significant up-regulation of CD86 and PDL2 expression on several DC subsets. Our results show the differential accumulation and activation of innate immune cells between septic and inflammatory arthritis. They strongly indicate that the relative high numbers of CD141 + cDC and CD123 + pDCs in SF are specific for JIA while the over-activation of DC and monocyte subsets is specific for SA.

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Section: Discussionsupporting

confidence: 93%

Differential Accumulation and Activation of Monocyte and Dendritic Cell Subsets in Inflamed Synovial Fluid Discriminates Between Juvenile Idiopathic Arthritis and Septic Arthritis

et al. 2020

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“…One of the most prominent application of HDcyto technology is the investigation of human pathologies, as it allows a deep understanding of inter‐cellular perturbations and the identification of disease‐specific signatures that may serve as diagnostic biomarkers or, eventually, therapeutic targets. HDcyto has already proved to be a powerful platform for the investigation of idiopathic syndromes and pathologies with incomplete understanding of disease‐driving mechanisms .…”

Section: Identification Of Molecular Signatures and Disease‐associatementioning

confidence: 99%

“…Mass cytometric immune profiling of autoimmune diseases revealed pathophysiological modes of action which provide the rationale for new therapeutic strategies, otherwise overlooked . A combination of mass cytometry and machine learning detected a pro‐inflammatory monocyte signature in pediatric and adult systemic lupus erythematosus (SLE) patients which was reverted upon blockade of interferon (IFN)/JAK pathway in an in‐vitro setting .…”

Section: Identification Of Molecular Signatures and Disease‐associatementioning

confidence: 99%

“…A combination of mass cytometry and machine learning detected a pro‐inflammatory monocyte signature in pediatric and adult systemic lupus erythematosus (SLE) patients which was reverted upon blockade of interferon (IFN)/JAK pathway in an in‐vitro setting . Likewise, an enhanced responsiveness to IFN‐γ has been identified in T‐helper and classical monocytes of polyarticular juvenile idiopathic arthritis , encouraging the use of Jak inhibitors for the treatment of autoimmune disease entities with an increased IFN signature.…”

Section: Identification Of Molecular Signatures and Disease‐associatementioning

confidence: 99%

“…The generation of scientific data from the integrated analysis of biological samples from different cohorts allows a detailed analysis of the different markers measured by HDcyto. The data obtained can then be integrated with clinical metadata such as age, sex, disease‐scores, routine serology screens, and therapy plans, thus providing a valuable contribution for bridging cutting‐edge technologies to tailored medicine .…”

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confidence: 99%

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The end of omics? High dimensional single cell analysis in precision medicine

et al. 2019

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High-dimensional single-cell (HDcyto) technologies, such as mass cytometry (CyTOF) and flow cytometry, are the key techniques that hold a great promise for deciphering complex biological processes. During the last decade, we witnessed an exponential increase of novel HDcyto technologies that are able to deliver an in-depth profiling in different settings, such as various autoimmune diseases and cancer. The concurrent advance of custom data-mining algorithms has provided a rich substrate for the development of novel tools in translational medicine research. HDcyto technologies have been successfully used to investigate cellular cues driving pathophysiological conditions, and to identify disease-specific signatures that may serve as diagnostic biomarkers or therapeutic targets. These technologies now also offer the possibility to describe a complete cellular environment, providing unanticipated insights into human biology. In this review, we present an update on the current cutting-edge HDcyto technologies and their applications, which are going to be fundamental in providing further insights into human immunology and pathophysiology of various diseases. Importantly, we further provide an overview of the main algorithms currently available for data mining, together with the conceptual workflow for high-dimensional cytometric data handling and analysis. Overall, this review aims to be a handy overview for immunologists on how to design, develop and read HDcyto data.Keywords: bioinformatic tools r diagnostic biomarkers r flow cytometry r mass cytometry (CyTOF) r single cell analysisIn recent years, we witnessed an exponential growth in highdimensional (HD) technologies, which resulted in a wide range of medical [1][2][3][4][5][6][7][8][9][10][11] and biological [12][13][14] applications. HD cytometers such as mass cytometry (Cytometry by time of flight, CyTOF) and flow cytometry (hereafter termed HDcyto) can detect more than 40 parameters (with the promise for detection of up to 100 parameters) with single-cell resolution. The data produced by HDcyto techniques together with appropriate computational methods of analysis have initiated a new era for translational medicine, enabling the unsupervised discovery of new cell pop-

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Spondyloarthritis mass cytometry immuno-monitoring: a proof of concept study in the tight-control and treat-to target TiCoSpA trial

et al. 2023

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Objective Mass cytometry (MC) immunoprofiling allows high-parameter phenotyping of immune cells. We set to investigate the potential of MC immuno-monitoring of axial spondyloarthritis (axSpA) patients enrolled in the Tight Control SpondyloArthritis (TiCoSpA) trial. Methods Fresh, longitudinal PBMCs samples (baseline, 24, and 48 weeks) from 9 early, untreated axSpA patients and 7 HLA-B27+ controls were analyzed using a 35-marker panel. Data were subjected to HSNE dimension reduction and Gaussian mean shift clustering (Cytosplore), followed by Cytofast analysis. Linear discriminant analyzer (LDA), based on initial HSNE clustering, was applied onto week 24 and 48 samples. Results Unsupervised analysis yielded a clear separation of baseline patients and controls including a significant difference in 9 T cell, B cell, and monocyte clusters (cl), indicating disrupted immune homeostasis. Decrease in disease activity (ASDAS score; median 1.7, range 0.6–3.2) from baseline to week 48 matched significant changes over time in five clusters: cl10 CD4 Tnai cells median 4.7 to 0.02%, cl37 CD4 Tem cells median 0.13 to 8.28%, cl8 CD4 Tcm cells median 3.2 to 0.02%, cl39 B cells median 0.12 to 2.56%, and cl5 CD38+ B cells median 2.52 to 0.64% (all p<0.05). Conclusions Our results showed that a decrease in disease activity in axSpA coincided with normalization of peripheral T- and B-cell frequency abnormalities. This proof of concept study shows the value of MC immuno-monitoring in clinical trials and longitudinal studies in axSpA. MC immunophenotyping on a larger, multi-center scale is likely to provide crucial new insights in the effect of anti-inflammatory treatment and thereby the pathogenesis of inflammatory rheumatic diseases. Key Points• Longitudinal immuno-monitoring of axSpA patients through mass cytometry indicates that normalization of immune cell compartments coincides with decrease in disease activity.• Our proof of concept study confirms the value of immune-monitoring utilizing mass cytometry.

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Identification of enhanced IFN-γ signaling in polyarticular juvenile idiopathic arthritis with mass cytometry

Cited by 21 publications

References 39 publications

Differential Accumulation and Activation of Monocyte and Dendritic Cell Subsets in Inflamed Synovial Fluid Discriminates Between Juvenile Idiopathic Arthritis and Septic Arthritis

Differential Accumulation and Activation of Monocyte and Dendritic Cell Subsets in Inflamed Synovial Fluid Discriminates Between Juvenile Idiopathic Arthritis and Septic Arthritis

The end of omics? High dimensional single cell analysis in precision medicine

Spondyloarthritis mass cytometry immuno-monitoring: a proof of concept study in the tight-control and treat-to target TiCoSpA trial

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