Deep Analysis of the Peripheral Immune System in IBD Reveals New Insight in Disease Subtyping and Response to Monotherapy or Combination Therapy

Kosoy, Roman; Kim‐Schulze, Seunghee; Rahman, Adeeb; Friedman, Joshua R.; Huang, Ruiqi; Peters, Lauren; Amir, El-ad David; Perrigoue, Jacqueline; Stojmirović, Aleksandar; Song, Won‐Min; Hao, Ke; Ungaro, Ryan C.; Mehandru, Saurabh; Cho, Judy H.; Dubinsky, Marla; Curran, Mark; Brodmerkel, Carrie; Schadt, Eric E.; Sands, Bruce E.; Colombel, Jean–Frédéric; Kasarskis, Andrew; Argmann, Carmen; Suárez‐Fariñas, Mayte

doi:10.1016/j.jcmgh.2021.03.012

Cited by 23 publications

(26 citation statements)

References 43 publications

(45 reference statements)

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“…We curated transcriptome datasets (blood or biopsy) from four separate IBD cohorts and using the same gene sets as in the discovery MSCCR cohort, we generated MISs and associated them with available clinical information. Figure 4A shows significantly higher bMIS levels in biopsies taken at week 0 from adult patients with UC during two phase 3 trials of VDZ (GEMINI I and LTS) or prior to IFX therapy,13 as compared with non-IBD control individuals. Furthermore, a significantly higher bMIS was observed in the patients with UC with Mayo endo score of 3 versus 2, supporting that bMIS levels also correlate with levels of disease activity.…”

Section: Resultsmentioning

confidence: 99%

“…The MSCCR is a cross-sectional cohort consisting of patients with IBD and controls prospectively recruited during their endoscopy visit from December 2013 to September 2016 13. Paired blood and biopsy RNA sequencing (RNA-seq) data were generated at the time of clinical, histological and endoscopic assessments (figure 1A).…”

Section: Methodsmentioning

confidence: 99%

“…We also derived a circulating MIS (cirMIS) of gut inflammation using blood RNA transcriptomic data to develop a less invasive blood test of disease activity. Both bMIS and cirMIS were developed using the Mount Sinai Crohn’s and Colitis Registry (MSCCR), a discovery cohort with ~1200 patients with IBD and controls 13. As histological, endoscopic and clinical assessments were available on the same patient cohort, cross-comparisons of newly derived molecular with clinical scores could be performed.…”

Section: Introductionmentioning

confidence: 99%

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Biopsy and blood-based molecular biomarker of inflammation in IBD

Argmann

Hou

Ungaro

et al. 2022

Gut

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ObjectiveIBD therapies and treatments are evolving to deeper levels of remission. Molecular measures of disease may augment current endpoints including the potential for less invasive assessments.DesignTranscriptome analysis on 712 endoscopically defined inflamed (Inf) and 1778 non-inflamed (Non-Inf) intestinal biopsies (n=498 Crohn’s disease, n=421 UC and 243 controls) in the Mount Sinai Crohn’s and Colitis Registry were used to identify genes differentially expressed between Inf and Non-Inf biopsies and to generate a molecular inflammation score (bMIS) via gene set variance analysis. A circulating MIS (cirMIS) score, reflecting intestinal molecular inflammation, was generated using blood transcriptome data. bMIS/cirMIS was validated as indicators of intestinal inflammation in four independent IBD cohorts.ResultsbMIS/cirMIS was strongly associated with clinical, endoscopic and histological disease activity indices. Patients with the same histologic score of inflammation had variable bMIS scores, indicating that bMIS describes a deeper range of inflammation. In available clinical trial data sets, both scores were responsive to IBD treatment. Despite similar baseline endoscopic and histologic activity, UC patients with lower baseline bMIS levels were more likely treatment responders compared with those with higher levels. Finally, among patients with UC in endoscopic and histologic remission, those with lower bMIS levels were less likely to have a disease flare over time.ConclusionTranscriptionally based scores provide an alternative objective and deeper quantification of intestinal inflammation, which could augment current clinical assessments used for disease monitoring and have potential for predicting therapeutic response and patients at higher risk of disease flares.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Biopsy and blood-based molecular biomarker of inflammation in IBD

Argmann

Hou

Ungaro

et al. 2022

Gut

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“…Future research should include newly diagnosed patients or prediagnostic samples (with the latter being hard to collect) to assess how CD4 T cells at baseline or before diagnosis are altered. This could be pre-onset changes as shown by presence of an IBD-like microbiome in healthy co-twins at risk of developing IBD, 51 the influence of (previous) administered medication as shown in the blood of IBD patients, 52 or the effect of previous flares. The fact that CD patients with an ileocecal resection often experience relapses at the anastomosis 53 suggests that the gut mucosa of CD patients exhibits (pre-existent) changes, although the occurrence of relapses could also be (partly) caused by non-immune cell related factors.…”

Section: Discussionmentioning

confidence: 99%

Compartment-driven imprinting of intestinal CD4 (regulatory) T cells in inflammatory bowel disease and homeostasis

Lutter

Linde

Brand

et al. 2022

Preprint

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Objective: The mucosal immune system is implicated in the etiology and progression of inflammatory bowel diseases. The lamina propria and epithelium of the gut mucosa constitute two separate compartments, containing distinct T cell populations. Human CD4 T cell programming and regulation of lamina propria and epithelium CD4 T cells, especially during inflammation, remains incompletely understood. Design: We performed imaging mass cytometry, flow cytometry, bulk and single-cell RNA-sequencing to profile ileal lamina propria and intraepithelial CD4 T cells (CD4CD8αα, regulatory T cells (Tregs), CD69- and CD69high Trm T cells) in controls and Crohn's disease (CD) patients (paired non-inflamed and inflamed). Results: Inflammation results in alterations of the CD4 T cell population with a pronounced increase in Tregs and migrating/infiltrating cells. On a transcriptional level, inflammation within the epithelium induced T cell activation, increased IFNγ; responses and effector Treg differentiation. Conversely, few transcriptional changes within the lamina propria were observed. Key regulators including the chromatin remodelers ARID4B and SATB1 were found to drive compartment-specific transcriptional programming of CD4 T(reg) cells. Conclusion: Inflammation in CD patients primarily induces changes within the epithelium and not the lamina propria. Additionally, there is compartment-specific CD4 T cell imprinting, driven by shared regulators, upon translocation from the lamina propria to the epithelium. The main consequence of epithelial translocation, irrespective of inflammation, seems to be an overall dampening of broad (pro-inflammatory) responses and tight regulation of lifespan. These data suggest differential regulation of the lamina propria and epithelium, with a specific regulatory role in the inflamed epithelium.

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“…Data were collected from all incoming blood samples to the UFDI from 2014-2018, hence the lack of age-matching between clinical subgroups based on clinical status. Importantly, participants were generally healthy with no reported infection or malignancy at time of blood draw, and sample collection preceded the coronavirus disease 2019 (COVID- 19) pandemic. Deidentified demographic and clinical information are presented in Table 1.…”

Section: Methodsmentioning

confidence: 99%

Human immune phenotyping reveals accelerated aging in type 1 diabetes

Shapiro

Dong

Perry

et al. 2023

Preprint

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The composition of immune cells in peripheral blood is dramatically remodeled throughout the human lifespan, as environmental exposures shape the proportion and phenotype of cellular subsets. These dynamic shifts complicate efforts to identify disease-associated immune signatures in type 1 diabetes (T1D), which is variable in age of onset and rate of beta-cell decline. Herein, we conducted standardized flow cytometric immune profiling on peripheral blood from a cross-sectional cohort of T1D participants (n=240), their first-degree relatives (REL, n=310), those at increased risk with two or more islet autoantibodies (RSK, n=24), and autoantibody negative healthy controls (CTR, n=252). We constructed an immune-age predictive model in healthy subjects and developed an interactive data visualization portal (ImmScape; https://ufdiabetes.shinyapps.io/ImmScape/). When applied to the T1D cohort, this model revealed accelerated immune aging (p<0.001) as well as phenotypic signatures of disease after age correction. Of 192 investigated flow cytometry and complete blood count readouts, 46 were significantly associated with age only, 25 with T1D only, and 23 with both age and T1D. Phenotypes associated with T1D after age-correction were predictive of T1D status (AUROC=82.3%). Phenotypes associated with accelerated aging in T1D included increased CXCR3+ and PD-1+ frequencies in naive and memory T cell subsets, despite reduced PD-1 expression levels (mean fluorescence intensity) on memory T cells. Additionally, quantitative trait locus analysis linked an increase in HLA-DR expression on monocytes with the T1D-associated HLA-DR4/DQ8 genotype, regardless of clinical group. Our findings demonstrate advanced immune aging in T1D and highlight disease-associated phenotypes for biomarker monitoring and therapeutic interventions.

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Deep Analysis of the Peripheral Immune System in IBD Reveals New Insight in Disease Subtyping and Response to Monotherapy or Combination Therapy

Cited by 23 publications

References 43 publications

Biopsy and blood-based molecular biomarker of inflammation in IBD

Biopsy and blood-based molecular biomarker of inflammation in IBD

Compartment-driven imprinting of intestinal CD4 (regulatory) T cells in inflammatory bowel disease and homeostasis

Human immune phenotyping reveals accelerated aging in type 1 diabetes

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