Provision of an explanation for the inefficacy of immunotherapy in sporadic inclusion body myositis: Quantitative assessment of inflammation and β-amyloid in the muscle

Jana Zschüntzsch, Joachim Voss, Kim Creus, Stephan Sehmisch, Raghavan Pillai Raju, Marinos C. Dalakas, Jens Schmidt

Research output: Contribution to journalArticle

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Abstract

Objective In sporadic inclusion body myositis (IBM), inflammation and accumulation of β-amyloid-associated molecules cause muscle fiber damage. We undertook this study to determine why intravenous immunoglobulin (IVIG) and prednisone are not effective in sporadic IBM despite their effectiveness in other inflammatory myopathies. Methods Relevant inflammatory and degeneration- associated markers were assessed by quantitative polymerase chain reaction and immunohistochemistry in repeated muscle biopsy specimens from patients with sporadic IBM treated in a controlled study with IVIG and prednisone (n = 5) or with prednisone alone (n = 5). Functional effects were assessed in a muscle cell culture model. Results In muscle biopsy specimens, messenger RNA (mRNA) expression of the proinflammatory chemokines CXCL9, CCL3, and CCL4 and of the cytokines interferon-γ (IFNγ), transforming growth factor β, interleukin-10 (IL-10), and IL-1β was significantly reduced after treatment in both groups. No consistent changes were observed for tumor necrosis factor α, IL-6, inducible costimulator (ICOS), its ligand ICOSL, and perforin. Messenger RNA expression of the degeneration-associated molecule ubiquitin and the heat-shock protein αB-crystallin was also reduced, but no changes were noted for amyloid precursor protein (APP) or desmin. By immunohistochemistry, a significant down-modulation of chemokines was observed, but not of inducible nitric oxide (NO) synthase, nitrotyrosine, IL-1β, APP, and ubiquitin; β-amyloid was reduced in 6 of 10 patients. Pronounced staining of IgG was observed in the muscle after treatment with IVIG, indicating penetration of infused IgG into the muscle and a possible local effect. In muscle cells exposed to IFNγ plus IL-1β, IgG and/or prednisone down-regulated mRNA expression of IL-1β 2.5-fold. Accumulation of β-amyloid, overexpression of αB-crystallin, and cell death were prevented. In contrast, NO-associated cell stress remained unchanged. Conclusion IVIG and prednisone reduce some inflammatory and degenerative molecules in muscle of patients with sporadic IBM and in vitro, but do not sufficiently suppress myotoxic and cell stress mediators such as NO. The data provide an explanation for the resistance of sporadic IBM to immunotherapy and identify markers that may help to design novel treatment strategies.

Original languageEnglish (US)
Pages (from-to)4094-4103
Number of pages10
JournalArthritis and Rheumatism
Volume64
Issue number12
DOIs
StatePublished - Dec 1 2012

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Inclusion Body Myositis
Amyloid
Immunotherapy
Prednisone
Intravenous Immunoglobulins
Inflammation
Muscles
Interleukin-1
Crystallins
Immunoglobulin G
Ubiquitin
Muscle Cells
Messenger RNA
Interferons
Chemokine CXCL9
Nitric Oxide
Inducible T-Cell Co-Stimulator Protein
Immunohistochemistry
Chemokine CCL4
Chemokine CCL3

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

Cite this

Provision of an explanation for the inefficacy of immunotherapy in sporadic inclusion body myositis : Quantitative assessment of inflammation and β-amyloid in the muscle. / Zschüntzsch, Jana; Voss, Joachim; Creus, Kim; Sehmisch, Stephan; Raju, Raghavan Pillai; Dalakas, Marinos C.; Schmidt, Jens.

In: Arthritis and Rheumatism, Vol. 64, No. 12, 01.12.2012, p. 4094-4103.

Research output: Contribution to journalArticle

Zschüntzsch, Jana ; Voss, Joachim ; Creus, Kim ; Sehmisch, Stephan ; Raju, Raghavan Pillai ; Dalakas, Marinos C. ; Schmidt, Jens. / Provision of an explanation for the inefficacy of immunotherapy in sporadic inclusion body myositis : Quantitative assessment of inflammation and β-amyloid in the muscle. In: Arthritis and Rheumatism. 2012 ; Vol. 64, No. 12. pp. 4094-4103.
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abstract = "Objective In sporadic inclusion body myositis (IBM), inflammation and accumulation of β-amyloid-associated molecules cause muscle fiber damage. We undertook this study to determine why intravenous immunoglobulin (IVIG) and prednisone are not effective in sporadic IBM despite their effectiveness in other inflammatory myopathies. Methods Relevant inflammatory and degeneration- associated markers were assessed by quantitative polymerase chain reaction and immunohistochemistry in repeated muscle biopsy specimens from patients with sporadic IBM treated in a controlled study with IVIG and prednisone (n = 5) or with prednisone alone (n = 5). Functional effects were assessed in a muscle cell culture model. Results In muscle biopsy specimens, messenger RNA (mRNA) expression of the proinflammatory chemokines CXCL9, CCL3, and CCL4 and of the cytokines interferon-γ (IFNγ), transforming growth factor β, interleukin-10 (IL-10), and IL-1β was significantly reduced after treatment in both groups. No consistent changes were observed for tumor necrosis factor α, IL-6, inducible costimulator (ICOS), its ligand ICOSL, and perforin. Messenger RNA expression of the degeneration-associated molecule ubiquitin and the heat-shock protein αB-crystallin was also reduced, but no changes were noted for amyloid precursor protein (APP) or desmin. By immunohistochemistry, a significant down-modulation of chemokines was observed, but not of inducible nitric oxide (NO) synthase, nitrotyrosine, IL-1β, APP, and ubiquitin; β-amyloid was reduced in 6 of 10 patients. Pronounced staining of IgG was observed in the muscle after treatment with IVIG, indicating penetration of infused IgG into the muscle and a possible local effect. In muscle cells exposed to IFNγ plus IL-1β, IgG and/or prednisone down-regulated mRNA expression of IL-1β 2.5-fold. Accumulation of β-amyloid, overexpression of αB-crystallin, and cell death were prevented. In contrast, NO-associated cell stress remained unchanged. Conclusion IVIG and prednisone reduce some inflammatory and degenerative molecules in muscle of patients with sporadic IBM and in vitro, but do not sufficiently suppress myotoxic and cell stress mediators such as NO. The data provide an explanation for the resistance of sporadic IBM to immunotherapy and identify markers that may help to design novel treatment strategies.",
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AU - Voss, Joachim

AU - Creus, Kim

AU - Sehmisch, Stephan

AU - Raju, Raghavan Pillai

AU - Dalakas, Marinos C.

AU - Schmidt, Jens

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N2 - Objective In sporadic inclusion body myositis (IBM), inflammation and accumulation of β-amyloid-associated molecules cause muscle fiber damage. We undertook this study to determine why intravenous immunoglobulin (IVIG) and prednisone are not effective in sporadic IBM despite their effectiveness in other inflammatory myopathies. Methods Relevant inflammatory and degeneration- associated markers were assessed by quantitative polymerase chain reaction and immunohistochemistry in repeated muscle biopsy specimens from patients with sporadic IBM treated in a controlled study with IVIG and prednisone (n = 5) or with prednisone alone (n = 5). Functional effects were assessed in a muscle cell culture model. Results In muscle biopsy specimens, messenger RNA (mRNA) expression of the proinflammatory chemokines CXCL9, CCL3, and CCL4 and of the cytokines interferon-γ (IFNγ), transforming growth factor β, interleukin-10 (IL-10), and IL-1β was significantly reduced after treatment in both groups. No consistent changes were observed for tumor necrosis factor α, IL-6, inducible costimulator (ICOS), its ligand ICOSL, and perforin. Messenger RNA expression of the degeneration-associated molecule ubiquitin and the heat-shock protein αB-crystallin was also reduced, but no changes were noted for amyloid precursor protein (APP) or desmin. By immunohistochemistry, a significant down-modulation of chemokines was observed, but not of inducible nitric oxide (NO) synthase, nitrotyrosine, IL-1β, APP, and ubiquitin; β-amyloid was reduced in 6 of 10 patients. Pronounced staining of IgG was observed in the muscle after treatment with IVIG, indicating penetration of infused IgG into the muscle and a possible local effect. In muscle cells exposed to IFNγ plus IL-1β, IgG and/or prednisone down-regulated mRNA expression of IL-1β 2.5-fold. Accumulation of β-amyloid, overexpression of αB-crystallin, and cell death were prevented. In contrast, NO-associated cell stress remained unchanged. Conclusion IVIG and prednisone reduce some inflammatory and degenerative molecules in muscle of patients with sporadic IBM and in vitro, but do not sufficiently suppress myotoxic and cell stress mediators such as NO. The data provide an explanation for the resistance of sporadic IBM to immunotherapy and identify markers that may help to design novel treatment strategies.

AB - Objective In sporadic inclusion body myositis (IBM), inflammation and accumulation of β-amyloid-associated molecules cause muscle fiber damage. We undertook this study to determine why intravenous immunoglobulin (IVIG) and prednisone are not effective in sporadic IBM despite their effectiveness in other inflammatory myopathies. Methods Relevant inflammatory and degeneration- associated markers were assessed by quantitative polymerase chain reaction and immunohistochemistry in repeated muscle biopsy specimens from patients with sporadic IBM treated in a controlled study with IVIG and prednisone (n = 5) or with prednisone alone (n = 5). Functional effects were assessed in a muscle cell culture model. Results In muscle biopsy specimens, messenger RNA (mRNA) expression of the proinflammatory chemokines CXCL9, CCL3, and CCL4 and of the cytokines interferon-γ (IFNγ), transforming growth factor β, interleukin-10 (IL-10), and IL-1β was significantly reduced after treatment in both groups. No consistent changes were observed for tumor necrosis factor α, IL-6, inducible costimulator (ICOS), its ligand ICOSL, and perforin. Messenger RNA expression of the degeneration-associated molecule ubiquitin and the heat-shock protein αB-crystallin was also reduced, but no changes were noted for amyloid precursor protein (APP) or desmin. By immunohistochemistry, a significant down-modulation of chemokines was observed, but not of inducible nitric oxide (NO) synthase, nitrotyrosine, IL-1β, APP, and ubiquitin; β-amyloid was reduced in 6 of 10 patients. Pronounced staining of IgG was observed in the muscle after treatment with IVIG, indicating penetration of infused IgG into the muscle and a possible local effect. In muscle cells exposed to IFNγ plus IL-1β, IgG and/or prednisone down-regulated mRNA expression of IL-1β 2.5-fold. Accumulation of β-amyloid, overexpression of αB-crystallin, and cell death were prevented. In contrast, NO-associated cell stress remained unchanged. Conclusion IVIG and prednisone reduce some inflammatory and degenerative molecules in muscle of patients with sporadic IBM and in vitro, but do not sufficiently suppress myotoxic and cell stress mediators such as NO. The data provide an explanation for the resistance of sporadic IBM to immunotherapy and identify markers that may help to design novel treatment strategies.

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