Neutralization of IFN-γ reverts clinical and laboratory features in a mouse model of macrophage activation syndrome

Prencipe, Giusi; Caiello, Ivan; Pascarella, Antonia; Grom, Alexei A.; Bracaglia, Claudia; Chatel, Laurence; Ferlin, Walter; Marasco, Emiliano; Strippoli, Raffaele; Min, Cristina de; Benedetti, Fabrizio

doi:10.1016/j.jaci.2017.07.021

Cited by 99 publications

(73 citation statements)

References 41 publications

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“…We hypothesize that the significant enrichment of inflammatory cytokines in the Vδ2 cases contributes to the increased risk of cytokine-driven symptoms. In particular, the significant upregulation of IFN-γ in Vδ2 lymphomas is consistent with emerging data suggesting a causal role for the cytokine in HLH and the potential therapeutic utility of IFN-γ blocking antibodies 52 .…”

Section: Discussionsupporting

confidence: 83%

Cellular origins and genetic landscape of cutaneous gamma delta T cell lymphomas

et al. 2020

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Primary cutaneous γδ T cell lymphomas (PCGDTLs) represent a heterogeneous group of uncommon but aggressive cancers. Herein, we perform genome-wide DNA, RNA, and T cell receptor (TCR) sequencing on 29 cutaneous γδ lymphomas. We find that PCGDTLs are not uniformly derived from Vδ2 cells. Instead, the cell-of-origin depends on the tissue compartment from which the lymphomas are derived. Lymphomas arising from the outer layer of skin are derived from Vδ1 cells, the predominant γδ cell in the epidermis and dermis. In contrast, panniculitic lymphomas arise from Vδ2 cells, the predominant γδ T cell in the fat. We also show that TCR chain usage is non-random, suggesting common antigens for Vδ1 and Vδ2 lymphomas respectively. In addition, Vδ1 and Vδ2 PCGDTLs harbor similar genomic landscapes with potentially targetable oncogenic mutations in the JAK/STAT, MAPK, MYC, and chromatin modification pathways. Collectively, these findings suggest a paradigm for classifying, staging, and treating these diseases.

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Section: Discussionsupporting

confidence: 83%

Cellular origins and genetic landscape of cutaneous gamma delta T cell lymphomas

et al. 2020

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“…Two potent chemokines, CXCL9 and CXCL10 that are markers of IFN-γ-stimulated classical M1 macrophages, were signi cantly reduced in our study subjects. This data is paradoxical to a previous report where LPS-induced elevation of serum CXCL9 and CXCL10 was reported in an LPS-induced ARDS model (38); however, neutralization of IFN-γ showed a marked decrease of plasma CXCL9 and CXCL10 levels (39), suggesting a relationship between stable IFN-γ levels and reduced levels of CXCL9 or CXCL10 in OT2D.…”

Section: M1 Macrophage Activation In Obese Type 2 Diabetescontrasting

confidence: 99%

Macrophage activation in obese type 2 diabetes: an enhanced risk for COVID-19 and Acute Respiratory Distress Syndrome?

Moin¹,

Sathyapalan

Diboun

et al. 2020

Preprint

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Objective Hyperactivation of the immune system through obesity and diabetes may enhance infection severity complicated by Acute Respiratory Distress Syndrome (ARDS), the hallmark of severe COVID-19 disease. Objectives: to determine the circulatory biomarkers for macrophage activation at baseline and after serum glucose normalization in obese type 2 diabetes (OT2D) subjects.Methods A case-controlled interventional pilot study in OT2D (n=23) and control subjects (n=23). Subjects underwent hyperinsulinemic clamp normalizing serum glucose. Plasma macrophage-related proteins were determined using Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement at baseline (control and OT2D subjects) and after 1-hour of insulin clamp (OT2D subjects only).Results. Basal M1 macrophage activation was characterized by elevated levels of M1 macrophage-specific surface proteins, CD80 and CD38, and cytokines or chemokines (CXCL1, CXCL5, RANTES) released by activated M1 macrophages. Two potent M1 macrophage activation markers CXCL9 and CXCL10 were decreased in OT2D. Activated M2 macrophages were characterized by elevated levels of plasma CD163, TFGβ-1, MMP7 and MMP9 in OT2D. Conventional mediators of both M1 and M2 macrophage activation markers (IFN-γ, IL-4, IL-13) were not altered. No changes were observed in plasma levels of M1/M2 macrophage activation markers in OT2D in response to acute normalization of glycemia.Conclusion In the basal state, macrophage activation markers are elevated, and these reflect the expression of circulatory cytokines, chemokines, growth factors and matrix metalloproteinases in obese individuals with type 2 diabetes, that were not changed by glucose normalisation. These differences may predispose the diabetic individuals to ARDS reflecting in increased COVID-19 disease severity.

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“…They also found that high serum IFNγ levels were correlated over time with decreased muscle strength in juvenile DM and adult DM patients, suggesting a correlation between IFNγ and muscle inflammation. It should be pointed out that measurement of blood levels of IFNγ may be unreliable and may not reflect tissue production as shown in other diseases in both animals and humans . Our data showed marked overproduction of IFNγ in the muscle and an association of IFNγ with disease severity at the time of biopsy.…”

Section: Discussionmentioning

confidence: 51%

Muscle Expression of Type I and Type II Interferons Is Increased in Juvenile Dermatomyositis and Related to Clinical and Histologic Features

Moneta

Marafon

Marasco

et al. 2019

Arthritis & Rheumatology

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Objective. To evaluate the expression of type I interferon (IFNα/β)-and type II IFN (IFNγ)-inducible genes in muscle biopsy specimens from patients with juvenile dermatomyositis (DM) and to correlate their expression levels with histologic and clinical features.Methods. Expression levels of IFN-inducible genes and proinflammatory cytokines were assessed by quantitative polymerase chain reaction in muscle biopsy specimens from patients with juvenile DM (n = 39), patients with Duchenne's muscular dystrophy (DMD), and healthy controls. Muscle biopsy sections were stained and scored for severity of histopathologic features. The charts of patients with juvenile DM were reviewed for clinical features at the time of sampling and long-term outcomes.Results. Muscle expression levels of IFNα/β-inducible genes (type I IFN score), IFNγ, IFNγ-inducible genes (type II IFN score), and tumor necrosis factor (TNF) were significantly higher in juvenile DM patients not receiving glucocorticoid therapy before muscle biopsy (n = 27) compared to DMD patients (n = 24) (type I IFN score, P < 0.0001; type II IFN score, P < 0.001; TNF, P < 0.05) and healthy controls (n = 4) (type I IFN score, P < 0.01; type II IFN score, P < 0.01; TNF, P < 0.05). Immunofluorescence staining of muscle biopsy sections from untreated juvenile DM patients showed increased immunoreactivity for IFNγ and HLA class II molecules compared to controls. Type I and type II IFN scores were correlated with typical histopathologic features of juvenile DM muscle biopsy samples, such as infiltration of endomysial CD3+ cells (type I IFN score, r = 0.68; type II IFN score, r = 0.63), perimysial CD3+ cells (type I IFN score, r = 0.59; type II IFN score, r = 0.66), CD68+ cells (type II IFN score, r = 0.46), and perifascicular atrophy (type I IFN score, r = 0.61; type II IFN score, r = 0.77). Juvenile DM patients with a high type I IFN score, a high type II IFN score, and high TNF expression levels showed more severe disease activity at biopsy (P < 0.05). In addition, juvenile DM patients with a high type II IFN score at biopsy reached clinically inactive disease significantly later than patients with low type II IFN score (log rank chi-square value 13.53, P < 0.001).Conclusion. The increased expression of IFN-inducible genes in the muscle in juvenile DM patients and their association with histologic and clinical features further support a pathogenic role for both type I and type II IFNs in juvenile DM.

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Neutralization of IFN-γ reverts clinical and laboratory features in a mouse model of macrophage activation syndrome

Abstract: These results provide evidence for a pathogenic role of IFN-γ in the setting of MAS.

Cited by 99 publications

References 41 publications

Cellular origins and genetic landscape of cutaneous gamma delta T cell lymphomas

Cellular origins and genetic landscape of cutaneous gamma delta T cell lymphomas

Macrophage activation in obese type 2 diabetes: an enhanced risk for COVID-19 and Acute Respiratory Distress Syndrome?

Muscle Expression of Type I and Type II Interferons Is Increased in Juvenile Dermatomyositis and Related to Clinical and Histologic Features

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