Aetiology
Idiopathic inflammatory myopathies (IIMs) are thought to have an autoimmune aetiology with a dysfunctional adaptive immune response suggested by evidence of cell-mediated myocytoxicity, a high prevalence of autoantibodies, and overexpression of major histocompatibility complex (MHC) I and II molecules on the muscle sarcolemma.[15][16][17][18]
Although the exact triggering factors and the relative contributions of various components of the immune system to IIM pathogenesis remains largely unknown, interactions between environmental and genetic factors are implicated in provoking autoimmunity.[1][15] For instance, the presence of the HLA-DRB1*03:01 allele in combination with smoking has been reported to significantly increase the risk of interstitial lung disease and polymyositis.[19]
However, the pathology of inclusion body myositis appears to involve non-immunological processes, including degenerative components and features of inappropriate intracellular protein accumulation and mitochondrial dysfunction.[15][18]
Therefore, factors associated with the aetiology of IIMs may include infectious, environmental, genetic, and immunological factors.
Infectious factors:
Non-infectious environmental factors:
Statins have been associated with a spectrum of muscle toxicity ranging from myaliga to immune-mediated necrotising myopathy and rhabdomyolysis.[28][29]
Other drugs: immune-checkpoint inhibitors, antiretrovirals, hydroxycarbamide, gemfibrozil, carbimazole (possible increased risk in people of Asian ethnicity), penicillamine.[1][30][31][32][33][34][35][36]
Vaccinations: SARS-CoV-2 (predominantly reported after mRNA vaccine administration), influenza (reported following pandemic H1N1 vaccination and seasonal trivalent vaccinations), hepatitis B (unclear if autoimmune complications are attributable to other components such as yeast proteins, aluminium adjuvant, neomycin).[37][38][39]
Substance use: smoking has been associated with an increased risk of polymyositis in white people, leading to an increased risk of developing interstitial lung disease compared with people who have never smoked.[34] Antisynthetase antibodies were more prevalent in white smokers compared with non-smokers, regardless of the duration of tobacco exposure.[19][34][40]
Ultraviolet light: there is some evidence to suggest that UV radiation intensity is the strongest contributor to the relative proportion of dermatomyositis and is strongly related to the proportion of anti-Mi2 autoantibodies.[41] Conversely, in subsequent studies this correlation was not found when comparing the capital cities of the Australian states, with latitudes ranging from Hobart (42.9°S) to Darwin (12.5°S), or when examining the north-south gradient of IIM incidence within Sweden.[42][43]
Other environmental factors: silicone breast implants, graft-versus-host disease, chimerism (associated with juvenile dermatomyositis), silica (describe in association with overlap myositis with systemic sclerosis), certain mushrooms/red yeast rice/Pu-erh tea/Bacopa (linked to statin-naive anti-HMGCR immune-mediated necrotising myopathy).[1][41][44][45][46][47][48] Environmental factors such as latitude, living in urban areas and living close to waterfront have also been suggested to be associated with IIM.[34]
Genetic factors: specific human leukocyte antigen (HLA) subtypes are believed to confer increased risk of development of IIMs.[49] Of note, the 8.1 ancestral haplotype alleles HLA-DRB1*03:01 and HLA-B*08:01 are most strongly associated with IIM.[1][50] Other associations to note are:[50][51][52]
HLA-DRB1*03:01 with polymyositis and juvenile dermatomyositis
HLA-B*08:01 with adult dermatomyositis
HLA-DRB1*03:01, HLA-DRB1*01:01, and HLA-DRB1*13:01 with sporadic inclusion body myositis
HLA-DRB1*03:01 and HLA-B*08:01 with anti-Jo1 positivity
HLA-DQB1*02:01 with anti-PM/Scl positivity
HLA-DRB1*03:01 with anti-cN1A positivity
HLA-DQB1*02:02 with anti-TIF1gamma positivity in adult dermatomyositis
HLA-DQB1*02:01 with anti-TIF1gamma positivity in juvenile dermatomyositis
HLA-DRB1*11:01 with anti-HMGCR positivity
Genetic factors - non-HLA genes: the non-HLA genes associations described in IIM include:[50][53][54][55][56]
STAT4 and PTPN22 which interact with T-cell signalling
TRAF6 and UBE2L3 which interact with B-cell signalling
NAB1 with polymyositis
CCR5 and novel associated variants of SDK2 and LINC00924 with sporadic inclusion body myositis
WDFY4 gene with anti-MDA5 positivity in Japanese and with anti-MDA5 disease in Chinese
Immunological factors: various myositis-specific and/or myositis-associated autoantibodies (MSAs/MAAs) have been found in up to 70% of patients with IIMs.[6]
Pathophysiology
The exact cascade of mechanisms leading to the occurrence of different IIM subtypes remain largely unknown.[57] IIM is believed to be caused by a dysregulation in innate immune function and the autoimmune response differs depending on the IIM-subtype. The bulk of research regarding the innate immune system in IIMs pertains to dermatomyositis and much remains unknown about exactly how these processes interrelate or differ between IIM-subtypes.[15]
Each subtype has been associated with a distinct clinical phenotype, and often myositis-specific and/or myositis-associated autoantibodies (MSAs/MAAs).[1][2][6][58]
MSAs and MAAs associated with the IIM-subtypes[1][2][6][58]
In addition to the above, the following autoantibodies have been described but not formally ascribed as an MSA or MAA for diagnosing or classifying IIM-subtypes:[1][57]
Presence of anti-Sp4 and anti-CCAR in anti-TIF1gamma dermatomyositis patients have been described to ameliorate cancer risk.
Anti-FHL1 has been reported in seronegative IIM and systemic sclerosis patients and could be considered as an MAA.
Anti-mitochondrial autoantibodies (AMA) may be found in a small percentage of adults with dermatomyositis, polymyositis, and sporadic inclusion body myositis. In these AMA positive patients, Raynaud’s phenomenon, dysphagia, cardiomyopathy, and more severe IIM disease were reported.
Dermatomyositis
In dermatomyositis, the primary antigen target consists of components of the vascular endothelium of the larger endomysial blood vessels.[27][59][60] Activation of complement leads to the deposition of a membranolytic attack complex on the endomysial microvasculature. This results in capillary necrosis, microinfarction, inflammation, endofascicular hypoperfusion, and, finally, perifascicular atrophy.[61][62] This is most prominent at the periphery of the fascicles where the capillary network is less dense.[61] Lymphocytic cells infiltrate the perimysial and perivascular regions of affected muscles, supporting the humoral-mediated process in the pathogenesis of dermatomyositis.[61] See Dermatomyositis.
Polymyositis and inclusion body myositis
In polymyositis and inclusion body myositis, there is evidence of antigen-directed and major histocompatibility complex-1 (MHC-1)-restricted cytotoxicity mediated by CD8+ T cells.[61] In polymyositis, immunological synapses form between CD8+ T cells and MHC-1 expressed on muscle fibres.[61] In polymyositis and sporadic inclusion body myositis, inducible costimulator (ICOS) ligand expressed on muscle fibres interacts with ICOS receptors located on the autoinvasive T cells. This facilitates clonal expansion and the co-stimulation of memory T cells.[61] A programmed death ligand that mediates the inhibition of T-cell activation is also expressed in muscle fibres.[61] These findings suggest that:
The muscle fibres behave as antigen-presenting cells
There is a balance of inflammatory stimuli within the immunological synapse of muscle/CD8+ cells, to protect the muscle from excessive immune aggression.[61]
Adhesion to muscle fibres by activated T cells is facilitated by cytokines, chemokines, and adhesion molecules.[61][62][63][64]
Inclusion body myositis has another histological hallmark, the presence of autophagic 'rimmed' vacuoles containing basophilic granules, and intracellular Congo-red-positive beta-amyloid deposits.[65]
These vacuoles are not a specific feature of sporadic inclusion body myositis, and may be seen in a variety of non-inflammatory myopathic processes. A number of other degeneration-associated intracellular molecules have been found, including tau, presenilin, alpha-synuclein, ubiquitin, and apolipoprotein.[65]
The interplay between inflammation and degeneration that occur in inclusion body myositis is not well understood.[15][66]
Some believe the primary pathological event is inflammatory with secondary protein dysfunction; others conceptualise the disease as a degenerative process with inflammation occurring in response to accumulating β-amyloid molecules.[66][65]
Role of interferons
Type I interferon signature has been found to be upregulated in dermatomyositis and polymyositis, but not sporadic inclusion body myositis.[67] The likely sources of the interferon-α/β in dermatomyositis are the CD4+ plasmacytoid dendritic cells (which can be activated by diverse factors) and possibly immature or regenerating muscle cells.[68] The proteins and cytokines induced by interferon-α/β have deleterious effects on muscle. Interferons also induce aberrant expression of MHC I on muscle sarcolemma, which would allow muscle autoantigen presentation to the CD8+ T cells, and may also have direct negative effects on muscle independent of inflammation.
Other triggers for upregulation of MHC-I expression are TNFα, high mobility group box protein 1 (HMGB1), IL-1, other cytokines, viral infection, denervation, and mechanical muscle injury.[69]
Of note, HMGB1 can induce a wide range of pro-inflammatory and regenerative effects once in the extracellular space.[70] It may also play a role in activation and dysregulation of autophagy within regenerating muscle cells and acting directly on muscle via toll-like-receptor 4 to negatively affect muscle function.[70][71] Activation of the inflammasome pathways may also play a role in these conditions.
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