Identification of distinctive interferon gene signatures in different types of myositis

Iago Pinal-Fernandez, Maria Casal-Dominguez, Assia Derfoul, Katherine Pak, Paul Plotz, Frederick W. Miller, Jose C. Milisenda, Josep M. Grau-Junyent, Albert Selva-O'Callaghan, Julie Paik, Jemima Albayda, Lisa Christopher-Stine, Thomas Lloyd, Andrea Markl Corse, Andrew L. Mammen

Research output: Contribution to journalArticle

Abstract

OBJECTIVE: Activation of the type 1 interferon (IFN1) pathway is a prominent feature of dermatomyositis (DM) muscle and may play a role in the pathogenesis of this disease. However, the relevance of the IFN1 pathway in patients with other types of myositis such as the antisynthetase syndrome (AS), immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM) is largely unknown. Moreover, the activation of the type 2 interferon (IFN2) pathway has not been comprehensively explored in myositis. In this cross-sectional study, our objective was to determine whether IFN1 and IFN2 pathways are differentially activated in different types of myositis by performing RNA sequencing on muscle biopsy samples from 119 patients with DM, IMNM, AS, or IBM and on 20 normal muscle biopsies. METHODS: The expression of IFN1- and IFN2-inducible genes was compared between the different groups. RESULTS: The expression of IFN1-inducible genes was high in DM, moderate in AS, and low in IMNM and IBM. In contrast, the expression of IFN2-inducible genes was high in DM, IBM, and AS but low in IMNM. The expression of IFN-inducible genes correlated with the expression of genes associated with inflammation and muscle regeneration. Of note, ISG15 expression levels alone performed as well as composite scores relying on multiple genes to monitor activation of the IFN1 pathway in myositis muscle biopsies. CONCLUSIONS: IFN1 and IFN2 pathways are differentially activated in different forms of myositis. This observation may have therapeutic implications because immunosuppressive medications may preferentially target each of these pathways.

Original languageEnglish (US)
Pages (from-to)e1193-e1204
JournalNeurology
Volume93
Issue number12
DOIs
StatePublished - Sep 17 2019

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Myositis
Inclusion Body Myositis
Dermatomyositis
Interferons
Muscular Diseases
Muscles
Genes
Biopsy
RNA Sequence Analysis
Interferon Type I
Immunosuppressive Agents
Interferon-gamma
Regeneration
Cross-Sectional Studies
Inflammation
Gene Expression
Antisynthetase syndrome

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Pinal-Fernandez, I., Casal-Dominguez, M., Derfoul, A., Pak, K., Plotz, P., Miller, F. W., ... Mammen, A. L. (2019). Identification of distinctive interferon gene signatures in different types of myositis. Neurology, 93(12), e1193-e1204. https://doi.org/10.1212/WNL.0000000000008128

Identification of distinctive interferon gene signatures in different types of myositis. / Pinal-Fernandez, Iago; Casal-Dominguez, Maria; Derfoul, Assia; Pak, Katherine; Plotz, Paul; Miller, Frederick W.; Milisenda, Jose C.; Grau-Junyent, Josep M.; Selva-O'Callaghan, Albert; Paik, Julie; Albayda, Jemima; Christopher-Stine, Lisa; Lloyd, Thomas; Corse, Andrea Markl; Mammen, Andrew L.

In: Neurology, Vol. 93, No. 12, 17.09.2019, p. e1193-e1204.

Research output: Contribution to journalArticle

Pinal-Fernandez, I, Casal-Dominguez, M, Derfoul, A, Pak, K, Plotz, P, Miller, FW, Milisenda, JC, Grau-Junyent, JM, Selva-O'Callaghan, A, Paik, J, Albayda, J, Christopher-Stine, L, Lloyd, T, Corse, AM & Mammen, AL 2019, 'Identification of distinctive interferon gene signatures in different types of myositis', Neurology, vol. 93, no. 12, pp. e1193-e1204. https://doi.org/10.1212/WNL.0000000000008128
Pinal-Fernandez I, Casal-Dominguez M, Derfoul A, Pak K, Plotz P, Miller FW et al. Identification of distinctive interferon gene signatures in different types of myositis. Neurology. 2019 Sep 17;93(12):e1193-e1204. https://doi.org/10.1212/WNL.0000000000008128
Pinal-Fernandez, Iago ; Casal-Dominguez, Maria ; Derfoul, Assia ; Pak, Katherine ; Plotz, Paul ; Miller, Frederick W. ; Milisenda, Jose C. ; Grau-Junyent, Josep M. ; Selva-O'Callaghan, Albert ; Paik, Julie ; Albayda, Jemima ; Christopher-Stine, Lisa ; Lloyd, Thomas ; Corse, Andrea Markl ; Mammen, Andrew L. / Identification of distinctive interferon gene signatures in different types of myositis. In: Neurology. 2019 ; Vol. 93, No. 12. pp. e1193-e1204.
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AU - Pinal-Fernandez, Iago

AU - Casal-Dominguez, Maria

AU - Derfoul, Assia

AU - Pak, Katherine

AU - Plotz, Paul

AU - Miller, Frederick W.

AU - Milisenda, Jose C.

AU - Grau-Junyent, Josep M.

AU - Selva-O'Callaghan, Albert

AU - Paik, Julie

AU - Albayda, Jemima

AU - Christopher-Stine, Lisa

AU - Lloyd, Thomas

AU - Corse, Andrea Markl

AU - Mammen, Andrew L.

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N2 - OBJECTIVE: Activation of the type 1 interferon (IFN1) pathway is a prominent feature of dermatomyositis (DM) muscle and may play a role in the pathogenesis of this disease. However, the relevance of the IFN1 pathway in patients with other types of myositis such as the antisynthetase syndrome (AS), immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM) is largely unknown. Moreover, the activation of the type 2 interferon (IFN2) pathway has not been comprehensively explored in myositis. In this cross-sectional study, our objective was to determine whether IFN1 and IFN2 pathways are differentially activated in different types of myositis by performing RNA sequencing on muscle biopsy samples from 119 patients with DM, IMNM, AS, or IBM and on 20 normal muscle biopsies. METHODS: The expression of IFN1- and IFN2-inducible genes was compared between the different groups. RESULTS: The expression of IFN1-inducible genes was high in DM, moderate in AS, and low in IMNM and IBM. In contrast, the expression of IFN2-inducible genes was high in DM, IBM, and AS but low in IMNM. The expression of IFN-inducible genes correlated with the expression of genes associated with inflammation and muscle regeneration. Of note, ISG15 expression levels alone performed as well as composite scores relying on multiple genes to monitor activation of the IFN1 pathway in myositis muscle biopsies. CONCLUSIONS: IFN1 and IFN2 pathways are differentially activated in different forms of myositis. This observation may have therapeutic implications because immunosuppressive medications may preferentially target each of these pathways.

AB - OBJECTIVE: Activation of the type 1 interferon (IFN1) pathway is a prominent feature of dermatomyositis (DM) muscle and may play a role in the pathogenesis of this disease. However, the relevance of the IFN1 pathway in patients with other types of myositis such as the antisynthetase syndrome (AS), immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM) is largely unknown. Moreover, the activation of the type 2 interferon (IFN2) pathway has not been comprehensively explored in myositis. In this cross-sectional study, our objective was to determine whether IFN1 and IFN2 pathways are differentially activated in different types of myositis by performing RNA sequencing on muscle biopsy samples from 119 patients with DM, IMNM, AS, or IBM and on 20 normal muscle biopsies. METHODS: The expression of IFN1- and IFN2-inducible genes was compared between the different groups. RESULTS: The expression of IFN1-inducible genes was high in DM, moderate in AS, and low in IMNM and IBM. In contrast, the expression of IFN2-inducible genes was high in DM, IBM, and AS but low in IMNM. The expression of IFN-inducible genes correlated with the expression of genes associated with inflammation and muscle regeneration. Of note, ISG15 expression levels alone performed as well as composite scores relying on multiple genes to monitor activation of the IFN1 pathway in myositis muscle biopsies. CONCLUSIONS: IFN1 and IFN2 pathways are differentially activated in different forms of myositis. This observation may have therapeutic implications because immunosuppressive medications may preferentially target each of these pathways.

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