Elevated circulating levels of interferon-γ and interferon-γ-induced chemokines characterise patients with macrophage activation syndrome complicating systemic juvenile idiopathic arthritis.
OBJECTIVE
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.
Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy.
Claudia
C
Bracaglia
Novimmmune SA, Plan-les-Ouates, Geneva, Switzerland.
Kathy
K
de Graaf
Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy.
Denise
D
Pires Marafon
Novimmmune SA, Plan-les-Ouates, Geneva, Switzerland.
Florence
F
Guilhot
Novimmmune SA, Plan-les-Ouates, Geneva, Switzerland.
Walter
W
Ferlin
Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy.
Giusi
G
Prencipe
Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy.
Ivan
I
Caiello
University of Genoa, Istituto Giannina Gaslini, Genoa, Italy.
Sergio
S
Davì
Division of Pediatric Rheumatology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Grant
G
Schulert
University of Genoa, Istituto Giannina Gaslini, Genoa, Italy.
Angelo
A
Ravelli
Division of Pediatric Rheumatology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Alexei A
AA
Grom
Novimmmune SA, Plan-les-Ouates, Geneva, Switzerland.
Cristina
C
de Min
Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy.
Fabrizio
F
De Benedetti
D000293:Adolescent; D000818:Animals; D001171:Arthritis, Juvenile / Q000150:complications* / Q000276:immunology; D015415:Biomarkers / Q000097:blood; D018925:Chemokines / Q000097:blood*; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000097:blood* / Q000276:immunology; D053583:Interleukin-1beta / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D055501:Macrophage Activation Syndrome / Q000209:etiology* / Q000276:immunology; D008297:Male; D008822:Mice, Transgenic; D012720:Severity of Illness Index
D015415:Biomarkers; D018925:Chemokines; D053583:Interleukin-1beta; D015850:Interleukin-6; D007371:Interferon-gamma
Chemokines; Cytokines; Inflammation; Juvenile Idiopathic Arthritis