Contribution of Complement, Microangiopathy and Inflammation in Idiopathic Inflammatory Myopathies.

PURPOSE OF REVIEW: Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group characterized by muscle weakness and skin symptoms and are categorized into six subtypes: dermatomyositis (DM), polymyositis (PM), anti-synthetase syndrome (ASS), immune-mediated myopathy (IMNM), inclusion body myopathy (IBM), and overlap myositis. Myositis-specific autoantibodies were detected for the diagnosis and classification of IIM. This review highlights the pathogenic contributions of the complement system, microangiopathy, and inflammation in IIM. RECENT FINDINGS: Deposition of complement around capillaries and/or the sarcolemma was observed in muscle biopsy specimens from patients with DM, ASS, and IMNM, suggesting the pathomechanism of complement-dependent muscle and endothelial cell injury. A recent study using human muscle microvascular endothelial cells showed that Jo-1 antibodies from ASS induce complement-dependent cellular cytotoxicity in vitro. Based on both clinical and pathological observations, antibody- and complement-mediated microangiopathy may contribute to the development of DM and anti-Jo-1 ASS. Juvenile DM is characterized by the loss of capillaries, perivascular inflammation, and small-vessel angiopathies, which may be related to microinfarction and perifascicular atrophy. Several serum biomarkers that reflect the IFN1 signature and microangiopathy are elevated in patients with DM. The pathological observation of myxovirus resistance protein A (MxA), which suggests a type 1 interferon (IFN1) signature in DM, supports the diagnosis and further understanding of the pathomechanism of IIM. A recent report showed that an increase in triggering receptor expressed on myeloid cells (TREM-1) around perimysial blood vessels and muscles in patients with IIM plays a role in triggering inflammation and promoting the migration of inflammatory cells by secreting proinflammatory cytokines, such as tumor necrosis factor α. SUMMARY: The deposition of complement in muscles and capillaries is a characteristic feature of DM, ASS, and IMNM. Microangiopathy plays a pathogenic role in DM, possibly resulting in perifascicular atrophy. Further understanding of the detailed pathomechanism regarding complement, microangiopathy, and inflammation may lead to novel therapeutic approaches for IIM.

Jo-1 Antibodies From Myositis Induce Complement-Dependent Cytotoxicity and TREM-1 Upregulation in Muscle Endothelial Cells.

BACKGROUND AND OBJECTIVES: Muscle microangiopathy due to dysfunction of endothelial cells because of inflammation is a critical hallmark of dermatomyositis (DM); however, its pathomechanism remains unclear. The aim of this study was to evaluate the effect of immunogloblin G (IgG) from patients with idiopathic inflammatory myopathies (IIM) on muscle endothelial cells in vitro. METHODS: Using a high-content imaging system, we analyzed whether IgG purified from sera from patients with IIM (n = 15), disease controls (DCs: n = 7), and healthy controls (HCs: n = 7) can bind to muscle endothelial cells and induce complement-dependent cellular cytotoxicity. RESULTS: IgGs from Jo-1 antibody myositis could bind to muscle endothelial cells and caused complement-dependent cell cytotoxicity. RNA-seq demonstrated the upregulation of genes associated with tumor necrosis factor (TNF)-α, triggering receptor expressed on myeloid cells-1 (TREM-1), CD25, and mitochondria pathways after exposure to IgG from the Jo-1, signal recognition particle (SRP), and polymyositis (PM) groups. The high-content imaging system showed that TREM-1 expression in the Jo-1, SRP, and PM groups was increased in comparison with DCs and HCs and that the TNF-α expression in the Jo-1 group was higher in comparison with the SRP, PM, DC, and HC groups. The expression of TREM-1 was observed in biopsied capillaries and the muscle membrane from patients with Jo-1 and in biopsied muscle fiber and capillaries from patients with DM and SRP. The depletion of Jo-1 antibodies by IgG of patients with Jo-1 antibody myositis reduced the Jo-1 antibody-induced complement-dependent cellular cytotoxicity in muscle endothelial cells. DISCUSSION: Jo-1 antibodies from Jo-1 antibody myositis show complement-dependent cellular cytotoxicity in muscle endothelial cells. IgGs from patients with Jo-1, SRP, and DM increase the TREM-1 expression in endothelial cells and muscles.

[A Patient Developing Guillain-Barré Syndrome After Receiving the BNT162b2 COVID-19 mRNA Vaccine].

We report a 71-year-old woman who presented with paresthesia, progressive weakness, difficulty walking, diarrhea, and bladder dysfunction one week after she received the BNT162b2 COVID-19 vaccine. Her neurological signs and symptoms gradually worsened up to 27 days after onset, after which her weakness slowly improved without immunotherapy. Analysis of serial cerebrospinal fluid specimens showed gradually increasing protein levels. Results of a nerve conduction study suggested functional axonal disturbance. The clinical findings together with the monophasic clinical course were consistent with Guillain-Barré syndrome. Her previous history was negative for symptomatic infection. Serological and bacterial tests, including the presence of anti-glycolipid antibodies, were negative for prior infection. Few cases have been reported on the development of Guillain-Barré syndrome after the BNT162b2 vaccine. Our patient's syndrome was characterized by atypical proximal weakness of the dominant lower limb. (Received January 28, 2022; Accepted April 4, 2022; Published August 1, 2022).

[Peripheral Neuropathy and Myopathy Associated with COVID-19].

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated coronavirus disease (COVID-19) were reported to originate from Wuhan, China, in December 2019, spreading rapidly worldwide. With the emergence of this pandemic, an increasing number of cases of Guillain-Barré syndrome (GBS) have been reported following this infection. Most patients had a demyelinating subtype of GBS. The time interval between infectious and neuropathic symptoms, absence of cerebrospinal fluid pleocytosis, and negative polymerase chain reaction test result support a postinfectious mechanism. Skeletal muscle injury presents as muscle pain and elevated serum creatine kinase level in patients with COVID-19. Some patients developed several myopathic manifestations, including new-onset inflammatory myopathy. Muscle injury is caused by direct SARS-CoV-2 infection or through parainfectious mechanisms such as type I interferonopathy.

[Intravenous immunoglobulin-induced eczematous eruption in autoimmune neuromuscular diseases].

BACKGROUND: Intravenous immunoglobulin (IVIg) have been administrated for the long time in patients with several autoimmune neuromuscular diseases. Eczematous eruption has been described as IVIg-induced adverse effect. OBJECTIVE: The purpose of this study is to clarify the incidence and characteristic of IVIg-induced eczematous eruption in autoimmune neuromuscular disease. METHODS: We retrospectively collected the data from 92 patients with autoimmune neuromuscular diseases, including 35 patients with chronic inflammatory demyelinating polyneuropathy (CIDP), 8 patients with multifocal motor neuropathy (MMN), 25 patients with myositis, 15 patients with Guillain-Barré syndrome (GBS), and 9 patients with myasthenia gravis (MG), who have administrated IVIg in Yamaguchi University Hospital. RESULTS: There are 10 patients (6 CIDP/4 MMN), who had an eczematous skin reaction after IVIg infusion. The frequencies of IVIg-induced eczematous eruption were significantly higher in patients with multifocal acquired demyelinating sensory and motor (MADSAM) and MMN than in patients with GBS, myositis, and MG. In addition, corticosteroids or immunosuppressive drugs had been administrated before IVIg treatment more frequently in patients with myositis and MG than in those with MADSAM and MMN. CONCLUSION: MADSAM or MMN patients had more frequently IVIg-induced eczematous eruption than other autoimmune neuromuscular diseases. Pathophysiology of MADAM and MMN is considered to be cell-mediated immunity against the peripheral nerve and the accumulation of IgG in both epidermis and dermis of the hand after IVIg may induce the infiltration of inflammatory cells around the vessels in the skin, causing eczematous eruption in MADSAM and MMN.

A Japanese Patient with Hereditary Myopathy with Early Respiratory Failure Due to the p.P31732L Mutation of Titin.

Hereditary myopathy with early respiratory failure (HMERF) is caused by titin A-band mutations in exon 344 and is considered quite rare. Respiratory insufficiency can be the sole symptom in the disease course. We herein report the first Japanese HMERF patient with a p.P31732L mutation in titin. The patient manifested respiratory failure and mild weakness of the neck flexor muscle at 69 years old and showed fatty replacement of the bilateral semitendinosus muscles on muscle imaging. Our case indicates that HMERF with a heterozygous p.P31732L mutation should be included in the differential diagnosis of muscular diseases presenting with early respiratory failure.

[Neuropathy presenting conduction block in ANCA-negative eosinophilic granulomatosis with polyangiitis].

A 74-year-old woman with a history of asthma and allergic rhinitis rapidly developed multiple mononeuropathy. Although anti-neutrophil cytoplasmic antibodies were negative, the presence of eosinophilia and eosinophilic infiltrations in the sural nerve led to a diagnosis of eosinophilic granulomatosis with polyangiitis. A motor nerve conduction study on admission revealed conduction block, which promptly disappeared after initiating immunotherapy without findings suggestive for remyelination or axonal degeneration. This electrophysiological change distinct from that of Wallerian degeneration. A biopsy of the sural nerve showed many eosinophil infiltrations and degranulation of eosinophilic cationic protein within nerve fascicles, whereas findings of necrotizing vasculitis were absent. These findings suggest that a direct effect of eosinophilic cationic protein, rather than ischemic damage due to vasculitis, was the main mechanism of transient nerve conduction failure in this patient.

[Immunotherapy for Inflammatory Myopathies].

Inflammatory myopathies are heterogeneous disorders characterized by muscle inflammation. They are frequently accompanied by extra-muscular manifestations that affect the skin, lungs, heart, and joints. Owing to its low prevalence, wide phenotypic heterogeneity, and variable disease course, it is difficult to make clear recommendations for the treatment of inflammatory myopathies. Corticosteroids are administered as first-line treatment based on clinical experience rather than controlled trial findings. Empirically, addition of an immunosuppressive drug might offer a steroid-sparing effect or an additional benefit. Administration of intravenous immunoglobulins has been shown to be effective as second-line treatment. Recently, there has been a growing interest in assessing the potential of several biological agents in the treatment of inflammatory myopathies. There are multiple ongoing clinical trials that will lead to more treatment options for inflammatory myopathies.

Liquid-like droplet formation by tumor suppressor p53 induced by multivalent electrostatic interactions between two disordered domains.

Early in vivo studies demonstrated the involvement of a tumor-suppressing transcription factor, p53, into cellular droplets such as Cajal and promyelocytic leukemia protein bodies, suggesting that the liquid-liquid phase separation (LLPS) might be involved in the cellular functions of p53. To examine this possibility, we conducted extensive investigations on the droplet formation of p53 in vitro. First, p53 itself was found to form liquid-like droplets at neutral and slightly acidic pH and at low salt concentrations. Truncated p53 mutants modulated droplet formation, suggesting the importance of multivalent electrostatic interactions among the N-terminal and C-terminal domains. Second, FRET efficiency measurements for the dimer mutants of p53 revealed that distances between the core domains and between the C-terminal domains were modulated in an opposite manner within the droplets. Third, the molecular crowding agents were found to promote droplet formation, whereas ssDNA, dsDNA, and ATP, to suppress it. Finally, the p53 mutant mimicking posttranslational phosphorylation did not form the droplets. We conclude that p53 itself has a potential to form droplets that can be controlled by cellular molecules and by posttranslational modifications, suggesting that LLPS might be involved in p53 function.

GRP 78 antibodies are associated with clinical phenotype in neuromyelitis optica.

BACKGROUND: We previously reported the association between blood-brain barrier (BBB) dysfunction and glucose-regulated protein 78 (GRP 78) autoantibodies in neuromyelitis optica (NMO). OBJECTIVE: We clarify whether the BBB-endothelial cell activation induced by immunoglobulin G (IgG) is associated with the clinical phenotype, disease activity, and markers of BBB disruption. METHODS: We purified serum IgG from 24 serum samples from patients with NMO spectrum disorder (NMOSD), who were positive for anti-AQP4 antibodies (longitudinally extensive transverse myelitis [LETM], n = 14; optic neuritis [ON], n = 6; other phenotype, n = 4) and nine healthy controls. IgG was exposed to human brain microvascular endothelial cells (TY10) and the number of nuclear NF-κB p65-positive cells, as a marker of endothelial cell activation, was analyzed using a high-content imaging system. Change in BBB permeability was also measured. The presence of GRP78 autoantibodies was detected by Western blotting. RESULTS: In the LETM group, IgG significantly induced the nuclear translocation of NF-κB p65 in comparison to the ON and healthy control groups. A significant correlation was observed between the number of NF-κB nuclear-positive cells and clinical markers of BBB disruption, including Gd enhancement in spinal MRI and the cerebrospinal fluid/serum albumin ratio. This effect was significantly reduced at the remission phase in the individual NMOSD patients. Furthermore, GRP78 antibody positivity was associated with the LETM phenotype and disease severity in NMOSD patients. CONCLUSION: Endothelial cell activation was associated with the LETM phenotype, clinical markers of BBB disruption and disease activity. These observations may explain the phenotypic differences between the NMOSD subtypes, LETM, and isolated ON.

[A case of Hashimoto's encephalopathy successfully treated with cyclophosphamide pulse therapy].

Hashimoto's encephalopathy has been described as an autoimmune disorder which demonstrates favorable response to corticosteroid therapy. However, steroid-resistant cases which require additional treatment are frequently reported, and there is no consensus how such cases should be treated. We present a 69 years-old man, who progressed cognitive dysfunction in the past three months. Anti-thyroid and anti-NH2 terminal of alpha-enolase antibodies were positive. Because initial corticosteroid therapy was ineffective, cyclophosphamide (CPA) pulse therapy was added, and his cognitive function was immediately improved. He had no relapse after tapering dose of corticosteroid for three years. CPA pulse therapy should be considered for steroid-resistant Hashimoto's encephalopathy.

[Treatment for central nervous system vasculitis].

Central nervous system (CNS) vasculitis is classified into two categories based on whether it is primary or secondary. Primary CNS vasculitis is rare disorder of unknown cause that is restricted to the brain and spinal cord. Currently, there are no randomized clinical trials for treatment of primary CNS vasculitis. Therefore, treatment regimens for primary CNS vasculitis have been derived from therapeutic strategies used in other kinds of vasculitis. Early detection is important because corticosteroid treatment with or without cyclophosphamide can often prevent serious outcomes and may result in a favorable response. However, because some patients are intolerant or respond poorly to combination therapy, development of novel treatment options is eagerly awaited. Several immunosuppressive agents such as mycophenolate mofetil, tumor necrosis factor-α blockers, and rituximab could be options for refractory patients.

[Primary central nervous system post-transplant lymphoproliferative disorders].

The post-transplant lymphoproliferative disorders (PTLD) are a heterogeneous disease entity of lymphoid and plasmacytic proliferations that can occur after solid organ and bone marrow/stem cell transplantation. PTLD sometimes involves the central nervous system (CNS), but primary occurrence in central nervous system (PCNS-PTLD) is rare. The Epstein-Barr virus (EBV) plays a causative role, and up to 90% of the tumors are associated with this virus. Diagnosing PCNS-PTLD is often challenging based solely on computed tomography, magnetic resonance imaging, and physical findings; therefore, direct biopsy of the lesion is usually necessary to make a definitive diagnosis. The optimal therapy for PCNS-PTLD remains unknown. Dose reduction or discontinuation of immunosuppressive agents is effective for approximately half of PTLD patients, but not for most patients with PCNS-PTLD. It has been noted that CNS involvement is a poor prognostic factor, but early diagnosis and initiation of chemotherapy or radiotherapy seem critical for maximizing the likelihood of a favorable outcome.