Plasma-induced signatures reveal an extracellular milieu possessing an immunoregulatory bias in treatment-naive paediatric inflammatory bowel disease

Bhaskar Gurram, N. H. Salzman, M. L. Kaldunski, S. Jia, B. U.K. Li, M. Stephens, M. R. Sood, M. J. Hessner

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

The inflammatory state associated with Crohn's disease (CD) and ulcerative colitis (UC) remains incompletely defined. To understand more clearly the extracellular milieu associated with inflammatory bowel disease (IBD), we employed a bioassay whereby plasma of treatment naive paediatric IBD patients (n = 22 CD, n = 15 UC) and unrelated healthy controls (uHC, n = 10) were used to induce transcriptional responses in a healthy leucocyte population. After culture, gene expression was measured comprehensively with microarrays and analysed. Relative to uHC, plasma of CD and UC patients induced distinct responses consisting, respectively, of 985 and 895 regulated transcripts [|log2 ratio| ≥ 0·5 (1·4-fold); false discovery rates (FDR) ≤ 0·01]. The CD:uHC and UC:uHC signatures shared a non-random, commonly regulated, intersection of 656 transcripts (χ2 = P < 0·001) and were highly correlative [Pearson's correlation coefficient = 0·96, 95% confidence interval (CI) = 0.96, 0.97]. Despite sharing common genetic susceptibility loci, the IBD signature correlated negatively with that driven by plasma of type 1 diabetes (T1D) patients (Pearson's correlation coefficient = -0·51). Ontological analyses revealed the presence of an immunoregulatory plasma milieu in IBD, as transcripts for cytokines/chemokines, receptors and signalling molecules consistent with immune activation were under-expressed relative to uHC and T1D plasma. Multiplex enzyme-linked immunosorbent assay (ELISA) and receptor blockade studies confirmed transforming growth factor (TGF)-β and interleukin (IL)-10 as contributors to the IBD signature. Analysis of CD patient signatures detected a subset of transcripts associated with responsiveness to 6-mercaptopurine treatment. Through plasma-induced signature analysis, we have defined a unique, partially TGF-β/IL-10-dependent immunoregulatory signature associated with IBD that may prove useful in predicting therapeutic responsiveness.

Original languageEnglish (US)
Pages (from-to)36-49
Number of pages14
JournalClinical and Experimental Immunology
Volume184
Issue number1
DOIs
StatePublished - Apr 1 2016

Fingerprint

Inflammatory Bowel Diseases
Crohn Disease
Pediatrics
Ulcerative Colitis
Transforming Growth Factors
Type 1 Diabetes Mellitus
Interleukin-10
Therapeutics
6-Mercaptopurine
Cytokine Receptors
Genetic Loci
Chemokine Receptors
Genetic Predisposition to Disease
Biological Assay
Leukocytes
Enzyme-Linked Immunosorbent Assay
Confidence Intervals
Gene Expression
Population

Keywords

  • Crohn's disease
  • Gene expression profiling
  • Inflammatory bowel disease
  • Microarray
  • Ulcerative colitis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Plasma-induced signatures reveal an extracellular milieu possessing an immunoregulatory bias in treatment-naive paediatric inflammatory bowel disease. / Gurram, Bhaskar; Salzman, N. H.; Kaldunski, M. L.; Jia, S.; Li, B. U.K.; Stephens, M.; Sood, M. R.; Hessner, M. J.

In: Clinical and Experimental Immunology, Vol. 184, No. 1, 01.04.2016, p. 36-49.

Research output: Contribution to journalArticle

Gurram, Bhaskar ; Salzman, N. H. ; Kaldunski, M. L. ; Jia, S. ; Li, B. U.K. ; Stephens, M. ; Sood, M. R. ; Hessner, M. J. / Plasma-induced signatures reveal an extracellular milieu possessing an immunoregulatory bias in treatment-naive paediatric inflammatory bowel disease. In: Clinical and Experimental Immunology. 2016 ; Vol. 184, No. 1. pp. 36-49.
@article{024196d8ec954baca56bd0d75e0de57f,
title = "Plasma-induced signatures reveal an extracellular milieu possessing an immunoregulatory bias in treatment-naive paediatric inflammatory bowel disease",
abstract = "The inflammatory state associated with Crohn's disease (CD) and ulcerative colitis (UC) remains incompletely defined. To understand more clearly the extracellular milieu associated with inflammatory bowel disease (IBD), we employed a bioassay whereby plasma of treatment naive paediatric IBD patients (n = 22 CD, n = 15 UC) and unrelated healthy controls (uHC, n = 10) were used to induce transcriptional responses in a healthy leucocyte population. After culture, gene expression was measured comprehensively with microarrays and analysed. Relative to uHC, plasma of CD and UC patients induced distinct responses consisting, respectively, of 985 and 895 regulated transcripts [|log2 ratio| ≥ 0·5 (1·4-fold); false discovery rates (FDR) ≤ 0·01]. The CD:uHC and UC:uHC signatures shared a non-random, commonly regulated, intersection of 656 transcripts (χ2 = P < 0·001) and were highly correlative [Pearson's correlation coefficient = 0·96, 95{\%} confidence interval (CI) = 0.96, 0.97]. Despite sharing common genetic susceptibility loci, the IBD signature correlated negatively with that driven by plasma of type 1 diabetes (T1D) patients (Pearson's correlation coefficient = -0·51). Ontological analyses revealed the presence of an immunoregulatory plasma milieu in IBD, as transcripts for cytokines/chemokines, receptors and signalling molecules consistent with immune activation were under-expressed relative to uHC and T1D plasma. Multiplex enzyme-linked immunosorbent assay (ELISA) and receptor blockade studies confirmed transforming growth factor (TGF)-β and interleukin (IL)-10 as contributors to the IBD signature. Analysis of CD patient signatures detected a subset of transcripts associated with responsiveness to 6-mercaptopurine treatment. Through plasma-induced signature analysis, we have defined a unique, partially TGF-β/IL-10-dependent immunoregulatory signature associated with IBD that may prove useful in predicting therapeutic responsiveness.",
keywords = "Crohn's disease, Gene expression profiling, Inflammatory bowel disease, Microarray, Ulcerative colitis",
author = "Bhaskar Gurram and Salzman, {N. H.} and Kaldunski, {M. L.} and S. Jia and Li, {B. U.K.} and M. Stephens and Sood, {M. R.} and Hessner, {M. J.}",
year = "2016",
month = "4",
day = "1",
doi = "10.1111/cei.12753",
language = "English (US)",
volume = "184",
pages = "36--49",
journal = "Clinical and Experimental Immunology",
issn = "0009-9104",
publisher = "Wiley-Blackwell",
number = "1",

}

TY - JOUR

T1 - Plasma-induced signatures reveal an extracellular milieu possessing an immunoregulatory bias in treatment-naive paediatric inflammatory bowel disease

AU - Gurram, Bhaskar

AU - Salzman, N. H.

AU - Kaldunski, M. L.

AU - Jia, S.

AU - Li, B. U.K.

AU - Stephens, M.

AU - Sood, M. R.

AU - Hessner, M. J.

PY - 2016/4/1

Y1 - 2016/4/1

N2 - The inflammatory state associated with Crohn's disease (CD) and ulcerative colitis (UC) remains incompletely defined. To understand more clearly the extracellular milieu associated with inflammatory bowel disease (IBD), we employed a bioassay whereby plasma of treatment naive paediatric IBD patients (n = 22 CD, n = 15 UC) and unrelated healthy controls (uHC, n = 10) were used to induce transcriptional responses in a healthy leucocyte population. After culture, gene expression was measured comprehensively with microarrays and analysed. Relative to uHC, plasma of CD and UC patients induced distinct responses consisting, respectively, of 985 and 895 regulated transcripts [|log2 ratio| ≥ 0·5 (1·4-fold); false discovery rates (FDR) ≤ 0·01]. The CD:uHC and UC:uHC signatures shared a non-random, commonly regulated, intersection of 656 transcripts (χ2 = P < 0·001) and were highly correlative [Pearson's correlation coefficient = 0·96, 95% confidence interval (CI) = 0.96, 0.97]. Despite sharing common genetic susceptibility loci, the IBD signature correlated negatively with that driven by plasma of type 1 diabetes (T1D) patients (Pearson's correlation coefficient = -0·51). Ontological analyses revealed the presence of an immunoregulatory plasma milieu in IBD, as transcripts for cytokines/chemokines, receptors and signalling molecules consistent with immune activation were under-expressed relative to uHC and T1D plasma. Multiplex enzyme-linked immunosorbent assay (ELISA) and receptor blockade studies confirmed transforming growth factor (TGF)-β and interleukin (IL)-10 as contributors to the IBD signature. Analysis of CD patient signatures detected a subset of transcripts associated with responsiveness to 6-mercaptopurine treatment. Through plasma-induced signature analysis, we have defined a unique, partially TGF-β/IL-10-dependent immunoregulatory signature associated with IBD that may prove useful in predicting therapeutic responsiveness.

AB - The inflammatory state associated with Crohn's disease (CD) and ulcerative colitis (UC) remains incompletely defined. To understand more clearly the extracellular milieu associated with inflammatory bowel disease (IBD), we employed a bioassay whereby plasma of treatment naive paediatric IBD patients (n = 22 CD, n = 15 UC) and unrelated healthy controls (uHC, n = 10) were used to induce transcriptional responses in a healthy leucocyte population. After culture, gene expression was measured comprehensively with microarrays and analysed. Relative to uHC, plasma of CD and UC patients induced distinct responses consisting, respectively, of 985 and 895 regulated transcripts [|log2 ratio| ≥ 0·5 (1·4-fold); false discovery rates (FDR) ≤ 0·01]. The CD:uHC and UC:uHC signatures shared a non-random, commonly regulated, intersection of 656 transcripts (χ2 = P < 0·001) and were highly correlative [Pearson's correlation coefficient = 0·96, 95% confidence interval (CI) = 0.96, 0.97]. Despite sharing common genetic susceptibility loci, the IBD signature correlated negatively with that driven by plasma of type 1 diabetes (T1D) patients (Pearson's correlation coefficient = -0·51). Ontological analyses revealed the presence of an immunoregulatory plasma milieu in IBD, as transcripts for cytokines/chemokines, receptors and signalling molecules consistent with immune activation were under-expressed relative to uHC and T1D plasma. Multiplex enzyme-linked immunosorbent assay (ELISA) and receptor blockade studies confirmed transforming growth factor (TGF)-β and interleukin (IL)-10 as contributors to the IBD signature. Analysis of CD patient signatures detected a subset of transcripts associated with responsiveness to 6-mercaptopurine treatment. Through plasma-induced signature analysis, we have defined a unique, partially TGF-β/IL-10-dependent immunoregulatory signature associated with IBD that may prove useful in predicting therapeutic responsiveness.

KW - Crohn's disease

KW - Gene expression profiling

KW - Inflammatory bowel disease

KW - Microarray

KW - Ulcerative colitis

UR - http://www.scopus.com/inward/record.url?scp=84960311190&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84960311190&partnerID=8YFLogxK

U2 - 10.1111/cei.12753

DO - 10.1111/cei.12753

M3 - Article

VL - 184

SP - 36

EP - 49

JO - Clinical and Experimental Immunology

JF - Clinical and Experimental Immunology

SN - 0009-9104

IS - 1

ER -