Causes
The causes of sIBM are currently unknown, though it is likely that it results from the interaction of a number of factors, both genetic and environmental. The understanding of sIBM is slowly maturing and evolving.
Currently, there are two major theories about how sIBM is caused:
1) Some researchers (e.g., Dalakas) advocate the theory that the inflammation-immune reaction, caused by an unknown trigger – likely an undiscovered virus or an autoimmune disorder, is the primary, proximal cause of sIBM and that the degeneration of muscle fibres and protein abnormalities are secondary features.
Despite the arguments "in favor of an adaptive immune response in s-IBM, a purely autoimmune hypothesis for s-IBM is untenable because of the disease's resistance to most immunotherapy."
2) Some researchers (e.g., Engel and Askanas) advocate the theory that sIBM is a degenerative disorder related to aging of the muscle fibres and that abnormal, potentially pathogenic protein accumulations in myofibers play a key causative role in s-IBM (apparently before the immune system comes into play). This theory emphasizes the abnormal intracellular accumulation of many proteins, protein aggregation and misfolding, proteosome inhibition, and endoplasmic reticulum (ER) stress.
A recent review by Greenberg (2009) discusses the "limitations in the beta-amyloid-mediated theory of IBM myofiber injury,"
Dalakas (2006) said: "we can say that two processes, one autoimmune and the other degenerative, occur in the muscle cells in parallel."
Dalakas (2006) suggested that a chain of events causes IBM—some sort of virus, likely a retrovirus, triggers the cloning of T cells. These T cells appear to be driven by specific antigens to invade muscle fibers. In people with sIBM, the muscle cells display “flags” telling the immune system that they are infected or damaged (the muscles ubiquitously express MHC class I antigens) and this immune process leads to the death of muscle cells. The chronic stimulation of these antigens also causes stress inside the muscle cell in the endoplasmic reticulum (ER) and this ER stress may be enough to cause a self-sustaining T cell response (even after a virus has dissipated). In addition, this ER stress may cause the misfolding of protein. The ER is in charge of processing and folding molecules carrying antigens. In IBM, muscle fibers are overloaded with these major histocompatibility complex (MHC) molecules that carry the antigen protein pieces, leading to more ER stress and more protein misfolding.
A self-sustaining T cell response would make sIBM a type of autoimmune disorder. One confusing aspect is that medications that lower the immune response do not improve sIBM symptoms, as would be expected in the case of an autoimmune disorder.
When studied carefully, it has not been impossible to detect an ongoing viral infection in the muscles. One theory is that a chronic viral infection might be the initial triggering factor setting IBM in motion. There have been a handful of IBM cases—about 15 or so—that have shown clear evidence of a virus called HTLV-1. This is a complex virus that can cause leukemia, but in most cases it lies dormant and people end up being lifelong carriers of the virus. It is too early to say that this is the particular virus directly involved in causing IBM. The Dalakas article says that the best evidence points towards a connection with some type of retrovirus and that a retroviral infection combined with immune recognition of the retrovirus is enough to trigger the inflammation process.
As mentioned above, in the past, some researchers have suggested that it is the protein changes that are primary and that precede or trigger the abnormal immune response. From an article by Askanas and Engel: "Two hypotheses predominate regarding the key pathogenic mechanisms involved in s-IBM: an amyloid-beta-related degenerative process and an immune dysregulation. Ultimately, both may be considered important, and their possible interrelationship may be clarified. An intriguing feature is the accumulation within s-IBM muscle fibers of amyloid-beta (Ab), phosphorylated tau protein, and at least 20 other proteins that are also accumulated in the brain of Alzheimer's disease patients. In the s-IBM muscle fibers, there is evidence of misfolding of proteins, pathologic proteinaceous inclusions including aggresomes, abnormalities of the two protein-disposal systems involving the ubiquitin proteasome pathway and the lysosomes, mitochondrial dysfunctions, and oxidative stress. The pronounced T-cell inflammation can be striking, and it is characterized by activated, antigen-driven, cytotoxic CD8+ T-cells.
- amyloid protein
- The hypothesis that beta amyloid protein is key to IBM has been supported in a mouse model using an Aβ vaccine that was found to be effective against inclusion body myositis in mouse models. Although this vaccine is likely not safe for human use, it still shows that attacking Aβ has efficacy in mice against IBM.
- Following up on earlier leads, the Greenberg group report finding that the protein TDP-43 is a very prominent and highly sensitive and specific feature of IBM. This protein is normally found within the nucleus but in IBM is found in the cytoplasm of the cell. This important advance should help develop a new screening technique for IBM and may provide clues in terms of a therapeutic approach
Read more about this topic: Inclusion Body Myositis