Immunobiology of Inherited Muscular Dystrophies.

The immune response to acute muscle damage is important for normal repair. However, in chronic diseases such as many muscular dystrophies, the immune response can amplify pathology and play a major role in determining disease severity. Muscular dystrophies are inheritable diseases that vary tremendously in severity, but share the progressive loss of muscle mass and function that can be debilitating and lethal. Mutations in diverse genes cause muscular dystrophy, including genes that encode proteins that maintain membrane strength, participate in membrane repair, or are components of the extracellular matrix or the nuclear envelope. In this article, we explore the hypothesis that an important feature of many muscular dystrophies is an immune response adapted to acute, infrequent muscle damage that is misapplied in the context of chronic injury. We discuss the involvement of the immune system in the most common muscular dystrophy, Duchenne muscular dystrophy, and show that the immune system influences muscle death and fibrosis as disease progresses. We then present information on immune cell function in other muscular dystrophies and show that for many muscular dystrophies, release of cytosolic proteins into the extracellular space may provide an initial signal, leading to an immune response that is typically dominated by macrophages, neutrophils, helper T-lymphocytes, and cytotoxic T-lymphocytes. Although those features are similar in many muscular dystrophies, each muscular dystrophy shows distinguishing features in the magnitude and type of inflammatory response. These differences indicate that there are disease-specific immunomodulatory molecules that determine response to muscle cell damage caused by diverse genetic mutations. © 2018 American Physiological Society. Compr Physiol 8:1313-1356, 2018.

Which nonautoimmune myopathies are most frequently misdiagnosed as myositis?

PURPOSE OF REVIEW: To discuss the spectrum of nonautoimmune myopathies that may be misdiagnosed as autoimmune myopathy. RECENT FINDINGS: Inherited myopathies, such as dysferlinopathy, calpainopathy, and facioscapulohumeral dystrophy may be misdiagnosed as autoimmune myopathy, especially when they have inflammatory muscle biopsies. Inclusion body myositis is frequently misdiagnosed as polymyositis when rimmed vacuoles are absent on muscle biopsy, and a careful neuromuscular evaluation is not performed. Hypothyroid myopathy can be misdiagnosed as immune-mediated necrotizing myopathy if thyroid function tests, including a T4 level, are not obtained. Self-limited statin myopathy can be distinguished from statin-associated autoimmune myopathy because patients with the former do not have autoantibodies recognizing 3-hydroxy-3-methylglutaryl-coenzyme A reductase. SUMMARY: Autoimmune myopathies can usually be distinguished from nonautoimmune myopathies based on a combination of the patient history, neuromuscular exam, laboratory findings, and/or muscle biopsy features.

Chronic Myopathy Associated With Anti-Signal Recognition Particle Antibodies Can Be Misdiagnosed As Facioscapulohumeral Muscular Dystrophy.

OBJECTIVES: To report cases of chronic autoimmune necrotizing myopathy with anti-signal recognition particle antibodies (anti-SRP myopathy) initially misdiagnosed as muscular dystrophy, in particular, facioscapulohumeral muscular dystrophy (FSHD). METHODS: Medical records of patients with anti-SRP myopathy in our institution were retrospectively reviewed. RESULTS: All 6 patients were initially diagnosed with muscular dystrophy because of the long-term clinical course and lack of inflammation on biopsy; 5 were diagnosed with FSHD based on a winged scapula. However, the following features suggested an alternative diagnosis, leading to anti-SRP antibody measurement: (1) lack of family history, (2) lack of facial involvement and asymmetry, (3) prominent dysphagia, and (4) profuse spontaneous activities on needle electromyography. All patients showed improvement with immunomodulating therapy. CONCLUSIONS: Anti-SRP antibody measurement should be considered in patients diagnosed with FSHD if they present with diagnostic hallmarks of anti-SRP myopathy listed above, to avoid oversight of this potentially treatable disorder.

DUX4-induced gene expression is the major molecular signature in FSHD skeletal muscle.

Facioscapulohumeral dystrophy (FSHD) is caused by decreased epigenetic repression of the D4Z4 macrosatellite array and recent studies have shown that this results in the expression of low levels of the DUX4 mRNA in skeletal muscle. Several other mechanisms have been suggested for FSHD pathophysiology and it remains unknown whether DUX4 expression can account for most of the molecular changes seen in FSHD. Since DUX4 is a transcription factor, we used RNA-seq to measure gene expression in muscle cells transduced with DUX4, and in muscle cells and biopsies from control and FSHD individuals. We show that DUX4 target gene expression is the major molecular signature in FSHD muscle together with a gene expression signature consistent with an immune cell infiltration. In addition, one unaffected individual without a known FSHD-causing mutation showed the expression of DUX4 target genes. This individual has a sibling with FSHD and also without a known FSHD-causing mutation, suggesting the presence of an unidentified modifier locus for DUX4 expression and FSHD. These findings demonstrate that the expression of DUX4 accounts for the majority of the gene expression changes in FSHD skeletal muscle together with an immune cell infiltration.

DUX4 activates germline genes, retroelements, and immune mediators: implications for facioscapulohumeral dystrophy.

Facioscapulohumeral dystrophy (FSHD) is one of the most common inherited muscular dystrophies. The causative gene remains controversial and the mechanism of pathophysiology unknown. Here we identify genes associated with germline and early stem cell development as targets of the DUX4 transcription factor, a leading candidate gene for FSHD. The genes regulated by DUX4 are reliably detected in FSHD muscle but not in controls, providing direct support for the model that misexpression of DUX4 is a causal factor for FSHD. Additionally, we show that DUX4 binds and activates LTR elements from a class of MaLR endogenous primate retrotransposons and suppresses the innate immune response to viral infection, at least in part through the activation of DEFB103, a human defensin that can inhibit muscle differentiation. These findings suggest specific mechanisms of FSHD pathology and identify candidate biomarkers for disease diagnosis and progression.

Acetylcholine receptor antibodies in patients with genetic myopathies: clinical and biological significance.

We report two patients with facioscapulohumeral muscular dystrophy (FSHD) presenting with atypical clinical features. Both were found to have antibodies to acetylcholine receptor (AChR-abs) and improved with immunosuppression. AChR-abs have also been reported in patients with other genetic myopathies and it is unlikely that the association is coincidental. There is increasing evidence that muscle fibre degeneration can cause innate immune responses (autoinflammation) that may lead to the breaking of immune tolerance and the generation of autoantibodies to muscle proteins. We compare and contrast this process with the pathogenesis of archetypical myasthenia gravis.

CD8(+) T cells in facioscapulohumeral muscular dystrophy patients with inflammatory features at muscle MRI.

Facioscapulohumeral muscular dystrophy (FSHD) is an inherited disease, and although strongly suggested, a contribution of inflammation to its pathogenesis has never been demonstrated. In FSHD patients, we found by immunohistochemistry inflammatory infiltrates mainly composed by CD8(+) T cells in muscles showing hyperintensity features on T2-weighted short tau inversion recovery magnetic resonance imaging (T2-STIR-MRI) sequences. Therefore, we evaluated the presence of circulating activated immune cells and the production of cytokines in patients with or without muscles showing hyperintensity features on T2-STIR-MRI sequences and from controls. FSHD patients displaying hyperintensity features in one or more muscles showed higher CD8(+)pSTAT1(+), CD8(+)T-bet(+) T cells and CD14(+)pSTAT1(+), CD14(+)T-bet(+) cells percentages and IL12p40, IFNγ and TNFα levels than patients without muscles displaying hyperintense features and controls. Moreover, the percentages of CD8(+)pSTAT1(+), CD8(+)T-bet(+) and CD14(+)pSTAT1(+) cells correlated with the proportion of muscles displaying hyperintensity features at T2-STIR sequences. These data indicate that circulating activated immune cells, mainly CD8(+) T cells, may favour FSHD progression by promoting active phases of muscle inflammation.