Immunotherapy reversed myopathy but not cardiomyopathy in a necrotizing autoimmune myopathy patient with positive anti-SRP and MDA-5 autoantibodies.

BACKGROUND: Necrotizing autoimmune myopathy (NAM) is pathologically characterized by myofiber necrosis and regeneration with paucity or absence of inflammatory cells in muscle biopsy. Two autoantibodies, namely anti-signal recognition particle (SRP)-antibodies and anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR)-antibodies, are typically specific with NAM. Anti-SRP-positive NAM can be associated with cardiomyopathy which responds well to immunotherapy. Here we reported an anti-SRP-antibody and anti-MDA5-antibody NAM patient who developed severe cardiomyopathy after gaining significant improvement of myopathy and subsequently accepted heart transplantation. CASE PRESENTATION: A NAM case with both positive anti-SRP and MDA-5 antibodies who gained significant improvement of the skeletal muscle weakness with immunotherapy, but 3 years later he developed severe dilated cardiomyopathy and at last received heart transplantation. Myocardial biopsy showed disarranged and atrophic myofibers, remarkable interstitial fibrosis without inflammatory infiltrates. Immunohistochemistry analysis revealed increased polyubiquitin-binding protein p62/SQSTM1 protein expression and the positive staining of cleaved-caspase 3 in a few cardiomyocytes. After the transplantation, the patient was symptom-free on oral prednisone (10 mg/day) and tacrolimus (2 mg/day). CONCLUSIONS: We described the first case of anti-SRP and anti-MAD5 positive NAM who had received heart transplantation because of cardiopathy. Though the myopathy had been clinically improved after immunotherapy, the cardiomyopathy remained progressive and lethal. The processes of dysfunctional autophagy and augmented apoptosis were putatively pathophysiological mechanisms underlying cardiac damage in anti-SRP and anti-MAD5 positive NAM.

Secondary cardiac involvement in anti-SRP-antibody-positive myopathy: an 87-year-old woman with heart failure symptoms as the first clinical presentation.

BACKGROUND: Necrotizing myopathy (NM) is defined by the dominant pathological feature of necrosis of muscle fibers without substantial lymphocytic inflammatory infiltration. Anti-signal recognition particle (SRP)-antibody-positive myopathy is related to NM. Anti-SRP-antibody-positive myopathy can comorbid with other disorders in some patients, however, comorbidity with malignant tumor and myopericarditis has still not been reported. CASE PRESENTATION: An 87-year-old woman with dyspnea on exertion and leg edema was referred to our hospital because of suspected heart failure and elevated serum creatine kinase level. Upon hospitalization, she developed muscle weakness predominantly in the proximal muscles. Muscle biopsy and immunological blood test led to the diagnosis of anti-SRP-antibody-positive myopathy. A colon carcinoma was also found and surgically removed. The muscle weakness remained despite the tumor resection and treatment with methylprednisolone. Cardiac screening revealed arrhythmia and diastolic dysfunction with pericardial effusion, which recovered with intravenous immunoglobulin (IVIg) treatment. CONCLUSIONS: We reported the first case of anti-SRP-positive myopathy comorbid with colon carcinoma and myopericarditis. This case is rare in the point that heart failure symptoms were the first clinical presentation. The underlying mechanism is still not clear, however, physicians should be carefully aware of the neoplasm and cardiac involvement in anti-SRP-antibody positive-myopathy patients and should consider farther evaluation and management.

Interleukin-33/suppression of tumorigenicity 2 (IL-33/ST2) axis in idiopathic inflammatory myopathies and its association with laboratory and clinical parameters: a pilot study.

Idiopathic inflammatory myopathies (IIM) are rare connective tissue diseases, which can lead to internal organ involvement. IL-33/ST2 pathway is involved in the pathogenesis of numerous diseases including autoimmune disorders. IL-33 fulfils cardioprotective function, while soluble ST2 (sST2) is a decoy receptor that reduces protective impact of IL-33. The aim of the study was to evaluate the concentrations of sST2 and IL-33 in sera of patients with IIM and evaluate its associations with the clinical course of the disease. Patients with IIM as well as age- and sex-matched healthy controls were recruited. Concentrations of sST2 and IL-33 were assessed with ELISA in sera of both patients and controls. Patients were asked to fill in the questionnaires concerning clinical symptoms and physical functioning. Concentrations of sST2 and IL-33 were correlated with the results of laboratory tests and clinical symptoms. Concentrations of sST2 were significantly higher in IIM group than in healthy subjects (median sST2 in IIM 26.51 vs in healthy controls 21.39; p = 0.03). In the majority of patients, IL-33 concentrations did not exceed the detection limit. Anti-SRP-positive patients presented significantly higher concentrations of sST2 as compared to anti-SRP-negative patients (p = 0.04). In patients with anti-Ro52 antibodies, sST2 concentrations were significantly lower than in anti-Ro52-negative patients (p = 0.02). Concentrations of sST2 correlated with the degree of disability evaluated with Health Assessment Questionnaire. sST2 is increased in patients with IIM and its concentration correlates with the degree of disability. In patients with anti-SRP antibodies, levels of sST2 are exceptionally high.

In vivo pathogenicity of IgG from patients with anti-SRP or anti-HMGCR autoantibodies in immune-mediated necrotising myopathy.

OBJECTIVES: In autoimmunity, autoantibodies (aAb) may be simple biomarkers of disease or true pathogenic effectors. A form of idiopathic inflammatory myopathy associated with anti-signal recognition particle (SRP) or anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) aAb has been individualised and is referred to as immune-mediated necrotising myopathy (IMNM). The level of aAb correlates with IMNM activity and disease may respond to immunosuppression, suggesting that they are pathogenic. We aimed to evaluate the pathogenicity of IgG from patients with anti-SRP or anti-HMGCR aAb in vivo by developing the first mouse model of IMNM. METHODS: IgG from patients suffering from anti-SRP or anti-HMGCR associated IMNM were passively transferred to wild-type, Rag2-/- or complement C3-/- mice. Muscle deficiency was evaluated by muscle strength on electrostimulation and grip test. Histological analyses were performed after haematoxylin/eosin staining or by immunofluorescence or immunohistochemistry analysis. Antibody levels were quantified by addressable laser bead assay (ALBIA). RESULTS: Passive transfer of IgG from patients suffering from IMNM to C57BL/6 or Rag2-/- mice provoked muscle deficiency. Pathogenicity of aAb was reduced in C3-/- mice while increased by supplementation with human complement. Breakage of tolerance by active immunisation with SRP or HMGCR provoked disease. CONCLUSION: This study demonstrates that patient-derived anti-SRP+ and anti-HMGCR+ IgG are pathogenic towards muscle in vivo through a complement-mediated mechanism, definitively establishing the autoimmune character of IMNM. These data support the use of plasma exchanges and argue for evaluating complement-targeting therapies in IMNM.

Benign acute viral myositis in African migrants: A clinical, serological, and pathological study.

BACKGROUND: Several viruses have been described as causes of acquired inflammatory myopathies; however, the mechanisms by which they cause muscle disease are still unclear. The aim of this study was to describe the laboratory features of benign acute myositis in a small case series. METHODS: A detailed pathological and serological analysis was performed in five African migrants who developed an acute viral myositis complicated by rhabdomyolysis. RESULTS: Muscle biopsies clearly documented an inflammatory myopathy with histological features similar to polymyositis including CD8+ T cells surrounding and invading nonnecrotic muscle fibers, CD68+ macrophages and major histocompatibility complex class I antigen upregulation. In addition, positivity for myositis-specific antibodies (MSA), in particular anti-aminoacyl tRNA synthetases, was found in the serum of two patients. CONCLUSIONS: Our study demonstrated that T-cell mediated injury occurs in muscle of patients with acute viral myositis, and that MSA may be present in the serum of these patients.

Pathogenic role of anti-signal recognition protein and anti-3-Hydroxy-3-methylglutaryl-CoA reductase antibodies in necrotizing myopathies: Myofiber atrophy and impairment of muscle regeneration in necrotizing autoimmune myopathies.

OBJECTIVE: Immune-mediated necrotizing myopathies (IMNM) may be associated with either anti-signal recognition protein (SRP) or anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) antibodies (Abs), and the titer of these Abs is correlated with disease activity. We investigated whether anti-SRP and anti-HMGCR Abs could be involved in muscle damage. METHODS: Muscle biopsies of patients were analyzed for atrophy and regeneration by measuring fiber size and by performing immunostaining of neonatal myosin heavy chain. To further understand the role of the Abs in the pathology, we performed muscle cell coculture with the Abs. Atrophy and regeneration were evaluated based on the myotube surface area as well as gene and cytokine profiles. RESULTS: In muscle biopsies of patients with anti-SRP+ and anti-HMGCR+ Abs, a large number of small fibers corresponding to both atrophic and regenerating fibers were observed. In vitro, anti-SRP and anti-HMGCR Abs induced muscle fiber atrophy and increased the transcription of MAFbx and TRIM63. In addition, the muscle fiber atrophy was associated with high levels of inflammatory cytokines: tumor necrosis factor, interleukin (IL)-6, and reactive oxygen species. In the presence of anti-SRP or anti-HMGCR Abs, mechanisms involved in muscle regeneration were also impaired due to a defect of myoblast fusion. This defect was associated with a decreased production of IL-4 and IL-13. The addition of IL-4 and/or IL-13 totally rescued fusion capacity. INTERPRETATION: These data show that molecular mechanisms of atrophy and regeneration are affected and contribute to loss of muscle function occurring in IMNM. This emphasizes the potential interest of targeted therapies addressing these mechanisms. Ann Neurol 2017;81:538-548.

Potential Pathogenic Role of Anti-Signal Recognition Protein and Anti-3-hydroxy-3-methylglutaryl-CoA Reductase Antibodies in Immune-Mediated Necrotizing Myopathies.

PURPOSE OF REVIEW: This review provides an overview of the potential pathogenic roles of anti-SRP and anti-HMGCR in IMNM over the past 5 years. RECENT FINDINGS: Idiopathic inflammatory myopathies (IIM) are a group of acquired autoimmune disorders that mainly affect the skeletal muscle tissue. Classification criteria of IIM are comprised of polymyositis, dermatomyositis, inclusion body myositis and immune-mediated necrotizing myopathies. One important hallmark of autoimmune diseases is the detection of autoantibodies in patient sera. The anti-SRP (signal recognition particle) and anti-HMGCR (3-hydroxy-3-methylglutaryl coenzyme A reductase) antibodies are specifically associated with IMNM patients, and their detection has been described as related to disease severity. The muscles of IMNM patients are characterized by necrosis, atrophy and regenerating fibres with sparse inflammatory infiltrates. Although an important correlation between autoantibody titres, creatine kinase levels and disease progression/severity has been described in the last few years, the potential pathogenic roles of these autoantibodies have only recently been described.

Thigh muscle MRI in immune-mediated necrotising myopathy: extensive oedema, early muscle damage and role of anti-SRP autoantibodies as a marker of severity.

OBJECTIVES: The aims of this study were to define the pattern of muscle involvement in patients with immune-mediated necrotising myopathy (IMNM) relative to those with other inflammatory myopathies and to compare patients with IMNM with different autoantibodies. METHODS: All Johns Hopkins Myositis Longitudinal Cohort subjects with a thigh MRI (tMRI) who fulfilled criteria for IMNM, dermatomyositis (DM), polymyositis (PM), inclusion body myositis (IBM) or clinically amyopathic DM (CADM) were included in the study. Muscles were assessed for intramuscular and fascial oedema, atrophy and fatty replacement. Disease subgroups were compared using univariate and multivariate analyses. Patients with IMNM with anti-signal recognition particle (SRP) autoantibodies were compared with those with IMNM with anti-HMG-CoA reductase (HMGCR) autoantibodies. RESULTS: The study included 666 subjects (101 IMNM, 176 PM, 219 DM, 17 CADM and 153 IBM). Compared with DM or PM, IMNM was characterised by a higher proportion of thigh muscles with oedema, atrophy and fatty replacement (p<0.01). Patients with IMNM with anti-SRP had more atrophy (19%, p=0.003) and fatty replacement (18%, p=0.04) than those with anti-HMGCR. In IMNM, muscle abnormalities were especially common in the lateral rotator and gluteal groups. Fascial involvement was most widespread in DM. Fatty replacement of muscle tissue began early during the course of disease in IMNM and the other groups. An optimal combination of tMRI features had only a 55% positive predictive value for diagnosing IMNM. CONCLUSIONS: Compared with patients with DM or PM, IMNM is characterised by more widespread muscle involvement. Anti-SRP-positive patients have more severe muscle involvement than anti-HMGCR-positive patients.

Necrotising myopathy associated with anti-signal recognition particle (anti-SRP) antibody.

OBJECTIVES: Prompted by the few studies available in the literature, we analysed patients with necrotising myopathy associated with anti-signal recognition particle (anti-SRP). METHODS: We conducted a retrospective, single-centre cohort study involving 14 patients with anti-SRP antibody followed between 2001 and 2016. RESULTS: Patients had a mean age at disease onset of 40.7 years and were predominantly female and of white ethnicity. At disease onset, all patients had limb muscle weakness with median serum of creatine phosphokinase level of 8080U/L, 64.3% had constitutional symptoms, 50% dysphagia, 42.9% myalgia, 21.4% and 14.3% pulmonary and articular involvement, respectively. There were no cases of cutaneous, neurological or cardiac involvements. Notably, 21.4% of patients had previous exposure to statins. Moreover, with the exception of one patient, all received methylprednisolone pulse therapy and/or human intravenous immunoglobulin (IVIg), as well as prednisone and different immunosuppressive drugs or rituximab. Relapse occurred in 64.3% of the cases. However, most patients had significant recovery of muscle strength, with half no longer using glucocorticoids and the remainder on a weaning regimen with low dose prednisone. CONCLUSIONS: Unlike the cases described in the literature, there was a high frequency of extra-muscular symptoms in the patients studied. Moreover, one fifth of patients had previous exposure to statin use. There was a high relapse rates, but with good clinical and laboratory recovery, especially with pulse therapy regimen of methylprednisolone and/or IVIg.

[Clinical features and therapeutic response of our anti-SRP positive patients with myositis]. / Anti-SRP-pozitív myositises betegeink klinikai sajátosságai és terápiára adott válaszuk.

INTRODUCTION: Idiopathic inflammatory myopathies are a group of clinically heterogeneous diseases, which have been classified by myositis specific antibodies recently. The anti-SRP positive subset of this group is characterized by more severe clinical prognosis than other myositis specific antibody positive types. AIM: Our goal was to compare 16 anti-SRP positive patients in the Division of Clinical Immunology, Department of Internal Medicine, University of Debrecen with 16 antibody negative ones. METHOD: Muscle strength validated in both groups by the manual muscle test proved to be significantly decreased both before and after therapy (χ2 = 0.006 and 0.019) in the anti-SRP positive group. RESULTS: Muscle-specific inflammatory laboratory parameters showed significant difference only in case of LDH-levels after therapy. Both groups showed good clinical response to first line steroid treatment, yet the significantly higher rate of second line administration suggests worse therapeutic response of the antibody positive group. CONCLUSION: Based on these facts we determined poor clinical prognosis and therapeutic response of the anti-SRP positive group. Orv Hetil. 2017; 158(35): 1382-1389.

Spectrum of immune-mediated necrotizing myopathies and their treatments.

PURPOSE OF REVIEW: This review aims to describe the spectrum of clinical, histological, and serological features in patients with immune-mediated necrotizing myopathies (IMNMs). RECENT FINDINGS: Autoantibodies recognizing the signal recognition particle (SRP) or 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) define two unique subtypes of necrotizing myositis patient with distinct clinical features. For example, the major histocompatibility class II human leukocyte antigen allele DRB111:01 is a strong immunogenetic risk factor for developing anti-HMGCR autoantibodies whereas B5001 and DQA10104 are over-represented in patients with anti-SRP autoantibodies. Furthermore, statin exposure is a risk factor only for anti-HMGCR autoantibodies. And while skeletal muscle involvement is predominant in most patients with both autoantibodies, lung involvement appears in ∼20% of anti-SRP-positive patients but is more rare in anti-HMGCR-positive patients. Of note, ∼20% of anti-SRP and anti-HMGCR positive patients have significant lymphocytic infiltrates on muscle biopsy and thus would not be formally categorized as having IMNM; aside from this, these patients are clinically indistinguishable from other patients with the same autoantibody profile. SUMMARY: Anti-SRP and anti-HMGCR autoantibodies define unique populations of IMNM patients. It may be more appropriate to subtype myositis patients based on these autoantibodies than on their muscle biopsy features.

Signal recognition particle immunoglobulin g detected incidentally associates with autoimmune myopathy.

INTRODUCTION: Paraneoplastic autoantibody screening of 150,000 patient sera by tissue-based immunofluorescence incidentally revealed 170 with unsuspected signal recognition particle (SRP) immunoglobulin G (IgG), which is a recognized biomarker of autoimmune myopathy. Of the 77 patients with available information, 54 had myopathy. We describe the clinical/laboratory associations. METHODS: Distinctive cytoplasm-binding IgG (mouse tissue substrate) prompted western blot, enzyme-linked immunoassay, and immunoprecipitation analyses. Available histories were reviewed. RESULTS: The immunostaining pattern resembled rough endoplasmic reticulum, and mimicked Purkinje-cell cytoplasmic antibody type 1 IgG/anti-Yo. Immunoblotting revealed ribonucleoprotein reactivity. Recombinant antigens confirmed the following: SRP54 IgG specificity alone (17); SRP72 IgG specificity alone (3); both (32); or neither (2). Coexisting neural autoantibodies were identified in 28% (low titer). Electromyography revealed myopathy with fibrillation potentials; 78% of biopsies had active necrotizing myopathy with minimal inflammation, and 17% had inflammatory myopathy. Immunotherapy responsiveness was typically slow and incomplete, and relapses were frequent on withdrawal. Histologically confirmed cancers (17%) were primarily breast and hematologic, with some others. CONCLUSIONS: Autoimmune necrotizing SRP myopathy, both idiopathic and paraneoplastic, is underdiagnosed in neurological practice. Serological screening aids early diagnosis. Cancer surveillance and appropriate immunosuppressant therapy may improve outcome. Muscle Nerve 53: 925-932, 2016.

Expression of anti-SRP19 antibody in muscle tissues from patients with autoimmune necrotizing myopathy.

This study aimed to investigate the role of anti-SRP19 antibody in muscle tissues of patients with autoimmune necrotizing myopathy. Immunohistochemistry staining was used to determine the expression of anti-SRP19 antibodies in muscle tissues of autoimmune necrotizing myopathy patients. Results demonstrated that anti-SRP19 antibody was expressed in 71.4% (20/28) of muscle tissue specimens from patients with autoimmune necrotizing myopathy. Anti-SRP19 antibody expression was mainly localized in cytoplasm of necrotic muscle fibers surrounding the small blood vessels and interstitial cells. There were no significant differences in the age, course of disease, muscle, and creatine kinase levels between patients with positive or negative expression of anti-SRP19 antibodies. The expression levels of anti-SRP19, serum anti-nuclear antibodies, as well as anti-Ro-52, anti- SSA, anti-Sm, and anti-Jo-1 antibodies were not significantly different among groups. This study demonstrates that anti-SRP19 antibody is highly expressed in muscle tissues of patients with autoimmune necrotizing myopathy, and suggests that this protein may be involved in the origin and progression of the disease.

Magnetic resonance imaging changes of thigh muscles in myopathy with antibodies to signal recognition particle.

OBJECTIVE: The aim of this study was to evaluate muscle MRI changes and the role of MRI in monitoring therapy in patients with myopathy associated with antibodies to signal recognition particle (anti-SRP myopathy). METHODS: We identified 12 patients with anti-SRP myopathy [6 females and 6 males; mean age of onset 38.5 years (s.d. 12.4), mean duration 22.8 months (s.d. 20.6). The main symptoms were proximal limb muscle weakness. Mean serum creatine kinase levels were moderately increased. Muscle biopsies revealed necrotizing myopathy in all patients, with obvious connective tissue proliferation in five patients and a single focus of lymphocytic infiltration in the endomysium in one. The myositis disease activity assessment (MYOACT) visual analogue scales scores were assessed. Muscle MRI was performed through the thighs. All patients were treated with corticosteroids and other immunosuppressive drugs. RESULTS: MRI revealed fatty infiltration and oedema in the thigh muscles of all 12 patients. Prominent fatty infiltration was present in 4 of the 12 patients. The hamstrings and adductor magnus were the most severely infiltrated and the quadriceps femoris the least. Obvious oedema was observed in 10 of the 12 patients, the most severely affected muscles being the vastus lateralis, rectus femoris, biceps femoris and adductor magnus, with relative sparing of the vastus intermedius. The degree of oedema was not correlated with creatine kinase levels or MYOACT scores. The four patients with striking fatty infiltration were refractory to therapy. CONCLUSION: MRI of the thigh muscles shows a distinct pattern of oedema and fatty infiltration and can be used to monitor the treatment of patients with anti-SRP myopathy.

Anti-signal recognition particle autoantibody ELISA validation and clinical associations.

OBJECTIVE: The aim of this study was to develop and validate a quantitative anti-signal recognition particle (SRP) autoantibody serum ELISA in patients with myositis and longitudinal association with myositis disease activity. METHODS: We developed a serum ELISA using recombinant purified full-length human SRP coated on ELISA plates and a secondary antibody that bound human IgG to detect anti-SRP binding. Protein immunoprecipitation was used as the gold standard for the presence of anti-SRP. Serum samples from three groups were analysed: SRP(+) myositis subjects by immunoprecipitation, SRP(-) myositis subjects by immunoprecipitation and non-myositis controls. The ELISA's sensitivity, specificity, positive predictive value and negative predictive value were evaluated. Percentage agreement and test-retest reliability were assessed. Serial samples from seven SRP immunoprecipitation-positive subjects were also tested, along with serum muscle enzymes and manual muscle testing. RESULTS: Using immunoprecipitation, we identified 26 SRP(+) myositis patients and 77 SRP(-) controls (including 38 patients with necrotizing myopathy). Non-myositis control patients included SLE (n = 4) and SSc (n = 7) patients. Anti-SRP positivity by ELISA showed strong agreement (97.1%) with immunoprecipitation (κ = 0.94). The sensitivity, specificity, positive predictive value, and negative predictive value of the anti-SRP ELISA were 88, 100, 100 and 96, respectively. The area under the curve was 0.94, and test-retest reliability was strong (r = 0.91, P < 0.001). Serial samples showed that anti-SRP levels paralleled changes in muscle enzymes and manual muscle testing. CONCLUSION: We developed a quantitative ELISA for detecting serum anti-SRP autoantibodies and validated the assay in myositis. Longitudinal assessment of SRP levels by ELISA may be a useful biomarker for disease activity.

Serum levels of anti-SRP54 antibodies reflect disease activity of necrotizing myopathy in a child treated effectively with combinatorial methylprednisolone pulses and plasma exchanges followed by intravenous cyclophosphamide.

We describe the effectiveness of combinatorial therapy with plasma exchanges and methylprednisolone pulses followed by intravenous cyclophosphamide in a young girl with anti-signal recognition particle 54 (SRP54) antibody-associated myopathy. We also use a newly described quantitative assay to demonstrate the close association between the titers of anti-SRP54 antibodies and disease activity. This is the first report of a pediatric patient indicating that the serum levels of anti-SRP54 antibodies are also beneficial for monitoring the disease activity of progressive necrotizing myopathy.

[Anti-signal recognition particle autoantibody positive myopathy]. / Szignálfelismerorészecske-ellenes autoantitest-pozitív myopathia.

Idiopathic inflammatory myopathies are systemic, autoimmune diseases characterized by proximal symmetrical muscle weakness. We review the myositis-associated and myositis-specific autoantibodies, among them the anti-SRP autoantibody. Among those autoimmune myopathy cases, that are associated with autoantibodies, we can detect anti-SRP autoantibody positive myositis cases. We describe the role of signal recognition particle, its structure and role in protein biosynthesis. We review how necrotizing autoimmune myopathy is identified, and the differences from classical polymyositis. The anti-SRP titer correlates with disease activity. We present some cases to show how the disease appears in childhood and also some rare cases from the literature. Finally we present a case to draw attention to the importance of this disease.

[Immune-Mediated Necrotizing Myopathy].

Immune-mediated necrotizing myopathy (IMNM) is a form of autoimmune myositis characterized by the presence of necrotic and regenerating process as a major finding in the muscle. Anti-SRP and anti-HMGCR have been identified as IMNM-specific autoantibodies. Patients with this disease often present with severe muscle weakness and markedly elevated serum creatine kinase (CK) levels. Differentiation from muscular dystrophy is challenging in certain cases. When patients meet the condition "subacute onset", "hyperCKemia over 1000 IU/L", and "clinical diagnosis of muscular dystrophy lacking molecular diagnosis", the possibility of IMNM should be considered. Autoantibody measurement, including of anti-SRP and HMGCR antibodies, is recommended. Treatment with corticosteroid in combination with immunosuppressants, intravenous immunoglobulin, and rituximab can be performed.

SRP54 of black carp negatively regulates MDA5-mediated antiviral innate immunity.

Signal Recognition Particle 54 kDa (SRP54) is a subunit of the signal recognition particle (SRP), a cytoplasmic ribonucleoprotein complex guiding the transportation of newly synthesized proteins from polyribosomes to endoplasmic reticulum. In mammals, it has been reported to regulate the RLR signaling pathway negatively by impairing the association between MAVS and MDA5/RIG-I. However, the role of SRP54 in teleost antiviral innate immune response remains obscure. In this study, the SRP54 homolog of black carp (bcSRP54) has been cloned, and its function in antiviral innate immunity has been elucidated. The CDS of bcSRP54 gene consists of 1515 nucleotides and encodes 504 amino acids. Immunofluorescence (IF) showed that bcSRP54 was mainly distributed in the cytoplasm. Overexpressed bcSRP54 significantly reduced bcMDA5-mediated transcription of interferon (IFN) promoter in reporter assay. Co-expression of bcSRP54 and bcMDA5 significantly suppressed bcMDA5-mediated IFN signaling and antiviral activity, while bcSRP54 knockdown increased the antiviral ability of host cells. In addition, the results of the immunofluorescence staining demonstrated the subcellular overlapping between bcSRP54 and bcMDA5, and the co-immunoprecipitation (co-IP) experiment identified their association. Furthermore, the over-expression of bcSRP54 did not influence the protein expression and ubiquitination modification level of bcMDA5, however, hindered the binding of bcMDA5 to bcMAVS. In summary, our results conclude that bcSRP54 targets bcMDA5 and inhibits the interaction between bcMDA5 and bcMAVS, thereby negatively regulating antiviral innate immunity, which provides insight into how teleost SRP54 regulates IFN signaling.