JAK inhibitor improves type I interferon induced damage: proof of concept in dermatomyositis

被引：175

作者：

Ladislau, Leandro ^{[1
,2
]}

Suarez-Calvet, Xavier ^{[1
,3
,4
,5
]}

Toquet, Segolene ^{[1
]}

Landon-Cardinal, Oceane ^{[1
]}

Amelin, Damien ^{[1
]}

Depp, Marine ^{[6
,7
]}

Rodero, Mathieu P. ^{[6
,7
]}

Hathazi, Denisa ^{[8
]}

Duffy, Darragh ^{[9
,10
]}

Bondet, Vincent ^{[9
,10
]}

Preusse, Corinna ^{[11
]}

Bienvenu, Boris ^{[12
]}

Rozenberg, Flore ^{[13
]}

Roos, Andreas ^{[8
,14
]}

Benjamim, Claudia F. ^{[2
]}

Gallardo, Eduard ^{[3
,4
,5
]}

Illa, Isabel ^{[3
,4
,5
]}

Mouly, Vincent ^{[1
]}

Stenzel, Werner ^{[11
]}

Butler-Browne, Gillian ^{[1
]}

Benveniste, Olivier ^{[1
]}

Allenbach, Yves ^{[1
]}

机构：

[1] Sorbonne Univ, Pitie Salpetriere Hosp, INSERM,Assoc Inst Myol,Ctr Res Myol,AP HP, Dept Internal Med & Clin Immunol,DHU I2B,UMRS 974, F-75013 Paris, France

[2] Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, Rio De Janeiro, Brazil

[3] Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Neuromuscular Dis Unit, Neurol, Barcelona, Spain

[4] Inst Recerca St Pau, Barcelona, Spain

[5] Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid, Spain

[6] Univ Sorbonne Paris Cite, Inst Imagine, Lab Neurogenet & Neuroinflammat, INSERM,UMR1163, F-75015 Paris, France

[7] Univ Sorbonne Paris Cite, Inst Imagine, Univ Paris Descartes, F-75015 Paris, France

[8] Leibniz Inst Analyt Wissensch ISAS EV, Biomed Res Dept, Tissue Omics Grp, Otto Hahn Str 6b, D-44227 Dortmund, Germany

[9] Inst Pasteur, INSERM, UMR 1223, Paris, France

[10] Inst Pasteur, Lab Dendrit Cell Immunobiol, Paris, France

[11] Charite, Dept Neuropathol, Berlin, Germany

[12] St Joseph Hosp, Dept Internal Med, Marseille, France

[13] Paris Descartes Univ, Hop Cochin, Dept Virol, Paris, France

[14] Int Ctr Life, John Walton Muscular Dystrophy Res Ctr, Inst Med Genet, Cent Pkwy, Newcastle Upon Tyne, Tyne & Wear, England

来源：

BRAIN | 2018年 / 141卷

关键词：

dermatomyositis; type I interferon; JAK inhibitor; autoimmune diseases; INDUCIBLE GENE-EXPRESSION; ENDOTHELIAL GROWTH-FACTOR; IDIOPATHIC INFLAMMATORY MYOPATHIES; SKELETAL-MUSCLE REGENERATION; INCLUSION-BODY MYOSITIS; DISEASE-ACTIVITY; CUTANEOUS DERMATOMYOSITIS; JUVENILE DERMATOMYOSITIS; ADULT DERMATOMYOSITIS; AUTOIMMUNE MYOPATHIES;

D O I：

10.1093/brain/awy105

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Dermatomyositis is an acquired auto-immune disease characterized by skin lesions and muscle-specific pathological features such as perifascicular muscle fibre atrophy and vasculopathy. Dermatomyositis patients display an upregulation of type I interferon-inducible genes in muscle fibres, endothelial cells, skin and peripheral blood. However, the effect of type I interferon on muscle tissue has not yet been determined. Our aim was to study the pathogenicity of type I interferon in vitro and to evaluate the efficacy of the type I interferon pathway blockade for therapeutic purposes. The activation of type I interferon in differentiating myoblasts abolished myotube formation with reduced myogenin expression while in differentiated myotubes, we observed a reduction in surface area and an upregulation of atrophy-associated genes. In vitro endothelial cells exposure to type I interferon disrupted vascular network organization. All the pathogenic effects observed in vitro were abolished by ruxolitinib. Finally, four refractory dermatomyositis patients were treated with ruxolitinib and improvement ensued in skin lesions, muscle weakness and a reduced serum type I interferon levels and interferon-inducbile genes scores. We propose JAK inhibition as a mechanism-based treatment for dermatomyositis, a finding that is relevant for the design of future clinical trials targeting dermatomyositis.

引用

页码：1609 / 1621

页数：13

共 71 条

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