Editing Inclusion body myositis (section)

==Causes==
The cause of IBM is unknown. IBM likely results from the interaction of a number of genetic and environmental factors.<ref name="General Information About IBM">{{cite web|title=Inclusion Body Myositis (IBM)|url=http://ibmmyositis.com/aboutibm1old.htm|access-date=7 May 2017|archive-date=16 October 2018|archive-url=https://web.archive.org/web/20181016125546/http://ibmmyositis.com/aboutibm1old.htm|url-status=dead}}</ref>

There are two major theories about how sIBM is caused. One hypothesis suggests that the inflammation-immune reaction, caused by an unknown trigger&nbsp;– likely an undiscovered virus or an autoimmune disorder – is the primary cause of sIBM and that the degeneration of muscle fibers and protein abnormalities are secondary features.<ref name="pmid16932602">{{cite journal |author=Dalakas MC |title=Sporadic inclusion body myositis--diagnosis, pathogenesis and therapeutic strategies |journal=Nat Clin Pract Neurol |volume=2 |issue=8 |pages=437–447 |year=2006 |pmid=16932602 |doi=10.1038/ncpneuro0261|s2cid=7462545 |url=https://zenodo.org/record/1233387 }}</ref> Despite the arguments "in favor of an adaptive immune response in sIBM, a purely autoimmune hypothesis for sIBM is untenable because of the disease's resistance to most immunotherapy."<ref>{{EMedicine|article|1172746|Inclusion Body Myositis}}</ref>

The second school of thought advocates the theory that sIBM is a degenerative disorder related to aging of the muscle fibers and that abnormal, potentially pathogenic protein accumulations in myofibrils play a key causative role in sIBM (apparently before the immune system comes into play). This hypothesis emphasizes the abnormal intracellular accumulation of many proteins, protein aggregation and misfolding, [[proteosome]] inhibition, and [[endoplasmic reticulum]] (ER) stress.<ref name="pmid16432144"/>

One review discusses the "limitations in the beta-amyloid-mediated theory of IBM myofiber injury."<ref name="pmid19080758">{{cite journal |author=Greenberg SA. |title=Inclusion body myositis: review of recent literature |journal=Curr Neurol Neurosci Rep |volume=9 |issue=1 |pages=83–89 |year=2009 |pmid=19080758 |doi=10.1007/s11910-009-0013-x |s2cid=16391053 }}</ref>

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 [[antigen]]s 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.<ref name="pmid16932602"/>

A self-sustaining T cell response would make sIBM a type of autoimmune disorder. When studied carefully, it has not been possible 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 – approximately 15 – that have shown clear evidence of a virus called [[HTLV-1]]. The HTLV-1 virus can cause [[leukemia]], but in most cases lies dormant and most people end up being lifelong carriers of the virus. One review 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.<ref name="pmid16932602"/>
* [[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.<ref>{{cite journal |title=Immunization with amyloid-β attenuates inclusion body myositis-like myopathology and motor impairment in a transgenic mouse model |vauthors=Kitazawa M, Vasilevko V, Cribbs DH, LaFerla FM |journal=The Journal of Neuroscience |date=13 May 2009 |volume=29 |issue=19 |pages=6132–41 |quote=Inclusion body myositis...features include T-cell mediated inflammatory infiltrates and aberrant accumulations of proteins, including amyloid-β (Aβ), tau, ubiquitinated proteins, apolipoprotein E, and β-synuclein in skeletal muscle. ... active immunization markedly reduces intracellular Aβ deposits and attenuates the motor impairment compared with untreated mice...Aβ oligomers contribute to the myopathy process as they were significantly reduced in the affected skeletal muscle from immunized mice. In addition, the anti-Aβ antibodies produced in the immunized mice blocked the toxicity of the Aβ oligomers in vitro, providing a possible key mechanism for functional recovery. |doi=10.1523/JNEUROSCI.1150-09.2009 |pmid=19439591 |pmc=3049190}}</ref>
* 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<ref>{{cite journal |title=Sarcoplasmic redistribution of nuclear TDP-43 in inclusion body myositis |author=Salajegheh, M, Pinkus, JL, Taylor, JP, Amato, AA, Nazareno, R, Baloh, RH, Greenberg, SA. |journal=Muscle Nerve |year=2009 |volume=40 |issue=1 |pages=19–31 |doi=10.1002/mus.21386 |pmid=19533646 |pmc=2700211}}</ref>

===Genetics===
sIBM is not inherited and is not passed on to the children of IBM patients. There are genetic features that do not directly cause IBM but that appear to predispose a person to getting IBM&nbsp;– having this particular combination of genes increases one's susceptibility to getting IBM. Some 67% of IBM patients have a particular combination of [[human leukocyte antigen]] genes in a section of the 8.1 ancestral haplotype in the center of the MHC class II region. sIBM is not passed on from generation to generation, although the susceptibility region of genes may be.<ref name="pmid16932602"/>

There are also several rare forms of hereditary inclusion body myopathy that are linked to specific genetic defects and that are passed on from generation to generation. Since these forms do not show features of muscle inflammation, they are classified as myopathies rather than forms of myositis. Because they do not display inflammation as a primary symptom, they may in fact be similar, but different diseases to sporadic inclusion body myositis. There are several different types, each inherited in different ways. See [[hereditary inclusion body myopathy]].<ref>{{Cite web |title=Inclusion body myopathy 2: MedlinePlus Genetics |url=https://medlineplus.gov/genetics/condition/inclusion-body-myopathy-2/ |access-date=2022-11-18 |website=medlineplus.gov |language=en}}</ref>

A 2007 review concluded there is no indication that the genes responsible for the familial or hereditary conditions are involved in sIBM.<ref name="pmid17366591">{{cite journal |vauthors=Needham M, Mastaglia FL, Garlepp MJ |title=Genetics of inclusion-body myositis |journal=Muscle Nerve |volume=35 |issue=5 |pages=549–561 |year=2007 |pmid=17366591 |doi=10.1002/mus.20766|s2cid=23665612 }}</ref>