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Expression of apoptosis related proteins in normal and diseased muscle: A possible role for Bcl-2 in protection of striated muscle
Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Neurologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
University Hospital Örebro.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk immunologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk immunologi och transfusionsmedicin.
2009 (Engelska)Ingår i: NEUROMUSCULAR DISORDERS, ISSN 0960-8966, Vol. 19, nr 6, s. 412-417Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The unique absence of major histocompatibility complex class I antigen (MHC-I) expression in normal muscle is one possible mechanism protecting striated muscle. In order to define their possible involvement in protection of normal muscle. we investigated the expression of molecules involved in muscle fibre death and survival mechanisms (Bcl-2, Fas, Fas-ligand and TRAIL), focusing on disorders with possible involvement of cytotoxic T cells. We studied muscle biopsies from 20 healthy volunteers, from 10 patients affected by polymyositis and 10 by Duchenne muscular dystrophy. By using immunohistochemistry, Western blot and real-time PCR we detected a constitutional expression of Bcl-2 in healthy muscle, whereas the expression was weaker in disease processes. Fas-L and TRAIL were not detected in muscle fibres, and Fas only in muscle affected by disease. Our findings indicate that the major apoptotic protein Bcl-2 might have a hitherto unrecognized role in the protection of normal muscle.

Ort, förlag, år, upplaga, sidor
2009. Vol. 19, nr 6, s. 412-417
Nyckelord [en]
Inflammatory myopathy, Apoptosis, Bcl-2, TRAIL, Fas and Fas-L
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
URN: urn:nbn:se:liu:diva-19795DOI: 10.1016/j.nmd.2009.03.008OAI: oai:DiVA.org:liu-19795DiVA, id: diva2:228998
Tillgänglig från: 2009-08-10 Skapad: 2009-08-10 Senast uppdaterad: 2016-11-23
Ingår i avhandling
1. The Clinical and Pathological Spectrum of Idiopathic Inflammatory Myopathies: Implications for pathogenesis, classification and diagnosis
Öppna denna publikation i ny flik eller fönster >>The Clinical and Pathological Spectrum of Idiopathic Inflammatory Myopathies: Implications for pathogenesis, classification and diagnosis
2016 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Background: Idiopathic inflammatory myopathies (IIM) constitute a heterogeneous group of diseases with severe consequences for the life of affected patients. Dermatomyositis, polymyositis and inclusion body myositis (IBM) are the classical representatives of this group. The treatments given today often have limited effects, and are taken at the cost of side effects. Major obstacles in the search for more effective treatments are; (1) an incomplete understanding of the disease mechanisms, (2) difficulties to delineate homogeneous disease groups for clinical studies and (3) the sometimes challenging task to diagnose these diseases.

Aims: We addressed a number of “loose ends” in the areas of pathogenesis, classification and diagnosis; mechanisms of muscle fiber degeneration in IIM, with a focus of programmed cell death (apoptosis) and invasion of muscle  fibers by inflammatory cells (partial invasion); protecting and mediating factors present in muscle; the association of other diseases with IIM, in particular celiac disease ; the evaluation of two classification systems and laboratory methods for increased diagnostic performance.

The studies: We included 106 patients, diagnosed at the Neuromuscular unit in Linköping, Sweden, with pathological muscle findings consistent with IIM. The incidence in the county of Östergötland (during 5 years) was 7.3 per million/year (3 patients each year). Of 88 patients with confirmed IIM 4 (4.5 %) had celiac disease, 33 (38%) had an associated systemic inflammatory disease and 5 (5.7 %) had a malignancy. Ninety-nine patients were included for a comparison of two classification systems using criteria of the European Neuromuscle Centre (Amato/ENMC), and the widely used Bohan and Peter classification, both with the addition of IBM according to Griggs et al. Using the Amato/ENMC criteria the most prevalent diagnostic group after IBM (30%) was nonspecific myositis (23%), followed by polymyositis (20%) and dermatomyositis 17%). A substantial number of patients meeting Bohan and Peter (or Griggs) criteria were excluded by Amato/ENMC criteria, most (21/23) due to lack of detectable muscle weakness. Extended muscle sectioning increased the sensitivity of a muscle biopsy by 15 % and the specificity by 22%, and showed an overlap between disease groups. Muscle biopsies from patients with IIM and controls were used to investigate pathological findings considered specific for disease groups, and for the presence of programmed cell death (apoptosis) and disease protecting and mediating factors in muscle. The presence of apoptotic muscle fiber nuclei was detected in muscle with partial invasion (however not in the invaded fibers) in the presence of granzyme B and CD8+ cytotoxic T cells. The major apoptosis inhibiting protein Bcl-2 was shown to be constitutionally expressed in healthy muscle but weakened in IIM.

Conclusion: We present apoptosis as a possible disease mechanism in parallel with partial invasion of fibers. Furthermore, partial invasion may not be a suitable distinguishing feature in the pathogenesis, or for classification and diagnosis of IIM. We also introduce the anti-apoptotic Bcl-2 as a possible relevant muscle fiber protecting factor. A more extensive pathological work-up improves classification and diagnosis of IIM. The proposed Amato/ENMC creates a substantial portion of patients with non-specific or unclassified myositis. Associated diseases are common in IIM, and also include celiac disease.

Ort, förlag, år, upplaga, sidor
Linköping: Linköping University Electronic Press, 2016. s. 131
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1551
Nationell ämneskategori
Klinisk laboratoriemedicin Neurologi Reumatologi och inflammation Immunologi
Identifikatorer
urn:nbn:se:liu:diva-132768 (URN)10.3384/diss.diva-132768 (DOI)9789176856413 (ISBN)
Disputation
2016-12-19, Berzeliussalen, Campus US, Linköping, 13:00 (Svenska)
Opponent
Handledare
Tillgänglig från: 2016-11-23 Skapad: 2016-11-23 Senast uppdaterad: 2017-05-02Bibliografiskt granskad

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Danielsson, OlofNilsson, CathrineErnerudh, Jan

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NeurologiHälsouniversitetetExperimentell patologiKlinisk immunologiKlinisk immunologi och transfusionsmedicin
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