There are two main popular theories of pathogenesis for IBM; the autoimmune pathway and the degenerative pathway (Gang et al., 2014). This is shown by inflammatory T cells invading (non-vacuolated) fibres suggesting IMB is an autoimmune disease mediated by cytotoxic T cells, meanwhile, vacuolated cells are not being invaded suggesting it is a degenerative disease manifested by the vacuolated muscle fibres and deposits of amyloid-related proteins (Dalakas, 2005). The autoimmune theory is supported by the association of IMB with HLA 1+2 antigens which are linked with classic autoimmune diseases (Dalakas, 2005).
However this theory is unsupported by the failure of immunosuppressive drugs to work as a treatment, even though inflammation can be seen to be reduced the clinical symptoms remain (Gang et al., 2014), this lead many to support the degenerative pathway as the primary cause. One hypothesis suggests it is ‘overexpression of AbetaPP within the aging muscle fibres is an early upstream event causing a subsequent pathogenic cascade’ (Askanas and Engel, 2005). There are 6 degeneration-associated processes in IBM muscle fibres these include; the fore-mentioned protein aggregations, oxidative stress, ER stress, accumulation of lipoprotein and cholesterol, inhibition of the ‘ubiquitin-proteasome system and impaired autophagy-lysosome pathway (Gang et al., 2014). Mitochondrial changes have been said to be correlated with IBM progression, people who had higher levels of mitochondrial dysfunction were found to have more severe inflammation (Rygiel et al., 2015).
IBM is not an inherited disease however there are multiple genetic factors that have been associated with increased risk of IBM (Gang et al., 2014). ‘The strongest evidence for genetic susceptibility comes from studies of the major histocompatibility complex (MHC), where different combinations of alleles have been associated with IBM in different ethnic groups’ (Needham, Mastaglia and Garlepp, 2007).