Reviews
The role of protein aggregation in the pathogenesis of inclusion body myositis.
A.M. Snedden1, K.A. Kellett2, J.B. Lilleker3, N.M. Hooper4, H. Chinoy5
- Centre for Musculoskeletal Research, Faculty of Biology, Medicine and Health, The University of Manchester, and Manchester Centre for Clinical Neurosciences, Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Manchester Academic Health Science Centre, Salford, UK. andrew.snedden@manchester.ac.uk
- Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, UK.
- Centre for Musculoskeletal Research, Faculty of Biology, Medicine and Health, The University of Manchester, and Manchester Centre for Clinical Neurosciences, Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Manchester Academic Health Science Centre, Salford, UK.
- Division of Neuro-science and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, and Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science Centre, Northern Care Alliance and University of Manchester, UK.
- Centre for Musculoskeletal Research, Faculty of Biology, Medicine and Health, The University of Manchester; National Institute for Health Research Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, The University of Manchester, and Department of Rheumatology, Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Manchester Academic Health Science Centre, Salford, UK.
CER15460
2022 Vol.40, N°2
PI 0414, PF 0424
Reviews
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PMID: 35225225 [PubMed]
Received: 04/01/2022
Accepted : 31/01/2022
In Press: 25/02/2022
Published: 25/02/2022
Abstract
Inclusion body myositis (IBM) is characterised by infiltration of CD8+ T-cells and signs of protein aggregation such as rimmed vacuoles and inclusion bodies. Aggregated proteins include those present in neurodegenerative diseases, and also those involved in protein homeostasis. The aim of this review is to discuss the pathological effects of protein aggregates and the process of aggregation following immune attack in IBM. Immune attack is likely to cause protein aggregation by impairing endoplasmic reticulum (ER) and mitochondrial function. Apoptotic and necrotic pathways are activated, possibly leading to nucleo-cytoplasmic coagulation. Overexpression of nuclear and ribosomal proteins in rimmed vacuoles suggests that the vacuoles develop from the collapse of myonuclei and the surrounding ER. Aggregated proteins can activate the NLR family pyrin domain containing 3 (NLRP3) inflammasome or provoke a humoral immune response. Heat shock proteins, ribosomal proteins and protein fragments may provoke interferon-gamma and cytotoxic T-cell responses in a similar manner to Mycobacterium tuberculosis antigens. Persistent provocation can lead to T-cell large granular lymphocytic leukaemia which is resistant to immunosuppression, and would explain the progression from polymyositis to IBM. Protein aggregates may impair the cellular machinery, and proteins may propagate along a myocyte in a prion-like manner. These pathological mechanisms may prevent myocyte regeneration following damage from eccentric muscle contraction, causing weakness and atrophy in a characteristic pattern. Further understanding of the mechanisms of protein aggregation in IBM may lead to additional therapies as well as novel muscle and blood biomarkers. Earlier diagnosis and treatment may result in improved outcomes when effective therapies are available.
