Sporadic inclusion body myositis (IBM) is the commonest acquired myopathy in individuals aged over 50 years. Currently, diagnosis is based largely upon specific muscle biopsy findings, though these are thought to lack sensitivity. More recently, many abnormal protein aggregates have been described in IBM and some have been proposed as diagnostic markers. However, their diagnostic utility is untested and how they relate to the pathogenesis is uncertain. The clinical characteristics, pathological findings and disease course in 67 patients with histopathologically diagnosed and clinically diagnosed IBM were compared and revealed that patients with IBM have a characteristic pattern of weakness at presentation that is independent of the pathological findings. Current diagnostic pathological features are more common in older patients and therefore may be linked to disease duration. The pathology of IBM and the diagnostic utility of protein aggregates in IBM were studied in six clinicopathologically typical cases of IBM. Protein aggregates immunoreactive for p62, TDP-43, myotilin, α B-crystallin and ubiquitin were more abundant than the current diagnostic pathological features. The diagnostic potential of these pathological features was then assessed in pathologically typical and atypical IBM and controls. This revealed that staining for p62, MHC Class I, CD8 positive lymphocytes and mitochondrial abnormalities could support the diagnosis and should be included in diagnostic criteria for IBM. Laser microdissection and label-free mass spectrometry were used to validate the histological findings. The presence of nuclear and aggresomal proteins in rimmed vacuoles indicated that they are derived from myonuclei. Increased protein synthesis and ER stress suggest that abnormal protein aggregates may be the result of abnormal protein production. In conclusion, this thesis emphasises that a diagnosis of IBM can be confidently made on clinical grounds, with a supportive muscle biopsy. The histological and proteomic findings reveal that there is a spectrum of pathological features most likely associated with the disease duration and that adherence to the current pathological based diagnostic criteria may have led to some erroneous conclusions about the pathogenesis of this enigmatic disease.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:618541 |
| Date | January 2014 |
| Creators | Brady, Stefen |
| Contributors | Hilton-Jones, David; Holton, Janice; Squier, Waney |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:bf7b9891-3cc1-46c5-bf96-3423a0087b6f |
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