Elevated circulating levels of interferon-γ and interferon-γ-induced chemokines characterise patients with macrophage activation syndrome complicating systemic juvenile idiopathic arthritis

Claudia Bracaglia, Kathy de Graaf, Denise Pires Marafon, Florence Guilhot, Walter Ferlin, Giusi Prencipe, Ivan Caiello, Sergio Davì, Grant Schulert, Angelo Ravelli, Alexei A Grom, Cristina de Min, Fabrizio De Benedetti

Research output: Contribution to journalArticle

Abstract

OBJECTIVES: Interferon-γ (IFNγ) is the pivotal mediator in murine models of primary haemophagocytic lymphohistiocytosis (pHLH). Given the similarities between primary and secondary HLH (sec-HLH), including macrophage activation syndrome (MAS), we investigate the involvement of the IFNγ pathway in MAS by evaluating levels of IFNγ and of the induced chemokines, and their relation with laboratory parameters of MAS in systemic juvenile idiopathic arthritis (sJIA) patients with MAS and in a murine MAS model.

METHODS: The Luminex multiplexing assay was used to assess serum levels of interleukin (IL)-1β, IL-6, IFNγ and of the IFNγ-induced chemokines CXCL9, CXCL10 and CXCL11 in patients with sec-HLH (n=11) and in patients with sJIA (n=54), of whom 20 had active MAS at sampling. Expression of IFNγ-induced chemokines was assessed in IL-6 transgenic mice in which MAS is induced by TLR4 stimulation with lipopolysaccharide.

RESULTS: Levels of IFNγ and of IFNγ-induced chemokines were markedly elevated during active MAS and sec-HLH and were significantly higher in patients with MAS compared with active sJIA without MAS. Levels in patients with active sJIA without MAS were comparable to those of patients with clinically inactive sJIA. During MAS, ferritin and alanine transferase levels and neutrophil and platelet counts were significantly correlated with serum levels of IFNγ and CXCL9. In murine MAS, serum levels of ferritin were significantly correlated with mRNA levels of Cxcl9 in liver and spleen.

CONCLUSIONS: The high levels of IFNγ and of IFNγ-induced chemokines and their correlation with the severity of laboratory abnormalities of MAS suggest a pivotal role of IFNγ in MAS.

Original languageEnglish
Pages (from-to)166-172
Number of pages7
JournalAnnals of the Rheumatic Diseases
Volume76
Issue number1
DOIs
Publication statusPublished - Jan 2017

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Macrophage Activation Syndrome
Juvenile Arthritis
Macrophages
Chemokines
Interferons
Chemical activation
Ferritins
Chemokine CXCL11
Interleukin-6
Chemokine CXCL9
Serum
Chemokine CXCL10
Hemophagocytic Lymphohistiocytosis

Keywords

  • Adolescent
  • Animals
  • Arthritis, Juvenile
  • Biomarkers
  • Chemokines
  • Child
  • Child, Preschool
  • Disease Models, Animal
  • Female
  • Humans
  • Interferon-gamma
  • Interleukin-1beta
  • Interleukin-6
  • Macrophage Activation Syndrome
  • Male
  • Mice, Transgenic
  • Severity of Illness Index
  • Journal Article
  • Multicenter Study

Cite this

Elevated circulating levels of interferon-γ and interferon-γ-induced chemokines characterise patients with macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. / Bracaglia, Claudia; de Graaf, Kathy; Pires Marafon, Denise; Guilhot, Florence; Ferlin, Walter; Prencipe, Giusi; Caiello, Ivan; Davì, Sergio; Schulert, Grant; Ravelli, Angelo; Grom, Alexei A; de Min, Cristina; De Benedetti, Fabrizio.

In: Annals of the Rheumatic Diseases, Vol. 76, No. 1, 01.2017, p. 166-172.

Research output: Contribution to journalArticle

Bracaglia, Claudia ; de Graaf, Kathy ; Pires Marafon, Denise ; Guilhot, Florence ; Ferlin, Walter ; Prencipe, Giusi ; Caiello, Ivan ; Davì, Sergio ; Schulert, Grant ; Ravelli, Angelo ; Grom, Alexei A ; de Min, Cristina ; De Benedetti, Fabrizio. / Elevated circulating levels of interferon-γ and interferon-γ-induced chemokines characterise patients with macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. In: Annals of the Rheumatic Diseases. 2017 ; Vol. 76, No. 1. pp. 166-172.
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abstract = "OBJECTIVES: Interferon-γ (IFNγ) is the pivotal mediator in murine models of primary haemophagocytic lymphohistiocytosis (pHLH). Given the similarities between primary and secondary HLH (sec-HLH), including macrophage activation syndrome (MAS), we investigate the involvement of the IFNγ pathway in MAS by evaluating levels of IFNγ and of the induced chemokines, and their relation with laboratory parameters of MAS in systemic juvenile idiopathic arthritis (sJIA) patients with MAS and in a murine MAS model.METHODS: The Luminex multiplexing assay was used to assess serum levels of interleukin (IL)-1β, IL-6, IFNγ and of the IFNγ-induced chemokines CXCL9, CXCL10 and CXCL11 in patients with sec-HLH (n=11) and in patients with sJIA (n=54), of whom 20 had active MAS at sampling. Expression of IFNγ-induced chemokines was assessed in IL-6 transgenic mice in which MAS is induced by TLR4 stimulation with lipopolysaccharide.RESULTS: Levels of IFNγ and of IFNγ-induced chemokines were markedly elevated during active MAS and sec-HLH and were significantly higher in patients with MAS compared with active sJIA without MAS. Levels in patients with active sJIA without MAS were comparable to those of patients with clinically inactive sJIA. During MAS, ferritin and alanine transferase levels and neutrophil and platelet counts were significantly correlated with serum levels of IFNγ and CXCL9. In murine MAS, serum levels of ferritin were significantly correlated with mRNA levels of Cxcl9 in liver and spleen.CONCLUSIONS: The high levels of IFNγ and of IFNγ-induced chemokines and their correlation with the severity of laboratory abnormalities of MAS suggest a pivotal role of IFNγ in MAS.",
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author = "Claudia Bracaglia and {de Graaf}, Kathy and {Pires Marafon}, Denise and Florence Guilhot and Walter Ferlin and Giusi Prencipe and Ivan Caiello and Sergio Dav{\`i} and Grant Schulert and Angelo Ravelli and Grom, {Alexei A} and {de Min}, Cristina and {De Benedetti}, Fabrizio",
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T1 - Elevated circulating levels of interferon-γ and interferon-γ-induced chemokines characterise patients with macrophage activation syndrome complicating systemic juvenile idiopathic arthritis

AU - Bracaglia, Claudia

AU - de Graaf, Kathy

AU - Pires Marafon, Denise

AU - Guilhot, Florence

AU - Ferlin, Walter

AU - Prencipe, Giusi

AU - Caiello, Ivan

AU - Davì, Sergio

AU - Schulert, Grant

AU - Ravelli, Angelo

AU - Grom, Alexei A

AU - de Min, Cristina

AU - De Benedetti, Fabrizio

N1 - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

PY - 2017/1

Y1 - 2017/1

N2 - OBJECTIVES: Interferon-γ (IFNγ) is the pivotal mediator in murine models of primary haemophagocytic lymphohistiocytosis (pHLH). Given the similarities between primary and secondary HLH (sec-HLH), including macrophage activation syndrome (MAS), we investigate the involvement of the IFNγ pathway in MAS by evaluating levels of IFNγ and of the induced chemokines, and their relation with laboratory parameters of MAS in systemic juvenile idiopathic arthritis (sJIA) patients with MAS and in a murine MAS model.METHODS: The Luminex multiplexing assay was used to assess serum levels of interleukin (IL)-1β, IL-6, IFNγ and of the IFNγ-induced chemokines CXCL9, CXCL10 and CXCL11 in patients with sec-HLH (n=11) and in patients with sJIA (n=54), of whom 20 had active MAS at sampling. Expression of IFNγ-induced chemokines was assessed in IL-6 transgenic mice in which MAS is induced by TLR4 stimulation with lipopolysaccharide.RESULTS: Levels of IFNγ and of IFNγ-induced chemokines were markedly elevated during active MAS and sec-HLH and were significantly higher in patients with MAS compared with active sJIA without MAS. Levels in patients with active sJIA without MAS were comparable to those of patients with clinically inactive sJIA. During MAS, ferritin and alanine transferase levels and neutrophil and platelet counts were significantly correlated with serum levels of IFNγ and CXCL9. In murine MAS, serum levels of ferritin were significantly correlated with mRNA levels of Cxcl9 in liver and spleen.CONCLUSIONS: The high levels of IFNγ and of IFNγ-induced chemokines and their correlation with the severity of laboratory abnormalities of MAS suggest a pivotal role of IFNγ in MAS.

AB - OBJECTIVES: Interferon-γ (IFNγ) is the pivotal mediator in murine models of primary haemophagocytic lymphohistiocytosis (pHLH). Given the similarities between primary and secondary HLH (sec-HLH), including macrophage activation syndrome (MAS), we investigate the involvement of the IFNγ pathway in MAS by evaluating levels of IFNγ and of the induced chemokines, and their relation with laboratory parameters of MAS in systemic juvenile idiopathic arthritis (sJIA) patients with MAS and in a murine MAS model.METHODS: The Luminex multiplexing assay was used to assess serum levels of interleukin (IL)-1β, IL-6, IFNγ and of the IFNγ-induced chemokines CXCL9, CXCL10 and CXCL11 in patients with sec-HLH (n=11) and in patients with sJIA (n=54), of whom 20 had active MAS at sampling. Expression of IFNγ-induced chemokines was assessed in IL-6 transgenic mice in which MAS is induced by TLR4 stimulation with lipopolysaccharide.RESULTS: Levels of IFNγ and of IFNγ-induced chemokines were markedly elevated during active MAS and sec-HLH and were significantly higher in patients with MAS compared with active sJIA without MAS. Levels in patients with active sJIA without MAS were comparable to those of patients with clinically inactive sJIA. During MAS, ferritin and alanine transferase levels and neutrophil and platelet counts were significantly correlated with serum levels of IFNγ and CXCL9. In murine MAS, serum levels of ferritin were significantly correlated with mRNA levels of Cxcl9 in liver and spleen.CONCLUSIONS: The high levels of IFNγ and of IFNγ-induced chemokines and their correlation with the severity of laboratory abnormalities of MAS suggest a pivotal role of IFNγ in MAS.

KW - Adolescent

KW - Animals

KW - Arthritis, Juvenile

KW - Biomarkers

KW - Chemokines

KW - Child

KW - Child, Preschool

KW - Disease Models, Animal

KW - Female

KW - Humans

KW - Interferon-gamma

KW - Interleukin-1beta

KW - Interleukin-6

KW - Macrophage Activation Syndrome

KW - Male

KW - Mice, Transgenic

KW - Severity of Illness Index

KW - Journal Article

KW - Multicenter Study

U2 - 10.1136/annrheumdis-2015-209020

DO - 10.1136/annrheumdis-2015-209020

M3 - Article

C2 - 27296321

VL - 76

SP - 166

EP - 172

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

SN - 0003-4967

IS - 1

ER -