GRP78 antibodies damage the blood-brain barrier and relate to cerebellar degeneration in Lambert-Eaton myasthenic syndrome.

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease of the neuromuscular junction caused by autoantibodies binding to P/Q-type voltage-gated calcium channels. Breakdown of the blood-brain barrier and diffusion of cerebellar granule/Purkinje cell-reactive autoantibodies into the CNS are critical for the pathogenesis of paraneoplastic cerebellar degeneration (PCD) with Lambert-Eaton myasthenic syndrome. We recently found evidence that glucose-regulated protein 78 (GRP78) autoantibodies in the plasma of patients with neuromyelitis optica promote the CNS access of AQP4 autoantibodies. In the present study, we investigated whether the GRP78 autoantibodies in PCD-LEMS IgG boost the brain uptake of cerebellar cell-reactive antibodies across the blood-brain barrier and facilitate cerebellar dysfunction. We first evaluated the effects of purified IgG from PCD-LEMS or PCD patients on the blood-brain barrier function in human brain microvascular endothelial cells using a high content imaging system with nuclear factor κB p65 and intracellular adhesion molecule 1 (ICAM1) immunostaining. Next, we identified GRP78 autoantibodies causing blood-brain barrier permeability in PCD-LEMS IgG by co-immunoprecipitation and the living cell-based antibody binding assays. Exposure of brain microvascular endothelial cells to IgG from PCD-LEMS patients induced nuclear factor κB p65 nuclear translocation, ICAM1 upregulation, reduced claudin-5 expression, increased permeability and increased autocrine IL-1ß and IL-8 secretion; the IgG from patients with Lambert-Eaton myasthenic syndrome did not have these effects. We detected GRP78 autoantibodies in the IgG of LEMS-PCD (83.3%, n = 18), but observed fewer in patients with LEMS (6.6%, n = 15) and none were observed in the control subjects (n = 8). The depletion of GRP78 autoantibodies reduced the biological effect of LEMS-PCD IgG on brain microvascular endothelial cells. These findings suggest that GRP78 autoantibodies play a role beyond neuromyelitis optica and that they have direct implications in the phenotypic differences between PCD-LEMS and LEMS.

Blood-Nerve Barrier (BNB) Pathology in Diabetic Peripheral Neuropathy and In Vitro Human BNB Model.

In diabetic peripheral neuropathy (DPN), metabolic disorder by hyperglycemia progresses in peripheral nerves. In addition to the direct damage to peripheral neural axons, the homeostatic mechanism of peripheral nerves is disrupted by dysfunction of the blood-nerve barrier (BNB) and Schwann cells. The disruption of the BNB, which is a crucial factor in DPN development and exacerbation, causes axonal degeneration via various pathways. Although many reports revealed that hyperglycemia and other important factors, such as dyslipidemia-induced dysfunction of Schwann cells, contributed to DPN, the molecular mechanisms underlying BNB disruption have not been sufficiently elucidated, mainly because of the lack of in vitro studies owing to difficulties in establishing human cell lines from vascular endothelial cells and pericytes that form the BNB. We have developed, for the first time, temperature-sensitive immortalized cell lines of vascular endothelial cells and pericytes originating from the BNB of human sciatic nerves, and we have elucidated the disruption to the BNB mainly in response to advanced glycation end products in DPN. Recently, we succeeded in developing an in vitro BNB model to reflect the anatomical characteristics of the BNB using cell sheet engineering, and we established immortalized cell lines originating from the human BNB. In this article, we review the pathologic evidence of the pathology of DPN in terms of BNB disruption, and we introduce the current in vitro BNB models.

Increased IP-10 production by blood-nerve barrier in multifocal acquired demyelinating sensory and motor neuropathy and multifocal motor neuropathy.

OBJECTIVE: Dysfunction of the blood-nerve barrier (BNB) plays important roles in chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). The aim of the present study was to identify the candidate cytokines/chemokines that cause the breakdown of the BNB using sera from patients with CIDP and MMN. METHODS: We determined the levels of 27 cytokines and chemokines in human peripheral nerve microvascular endothelial cells (PnMECs) after exposure to sera obtained from patients with CIDP variants (typical CIDP and multifocal acquired demyelinating sensory and motor neuropathy [MADSAM]), MMN and amyotrophic lateral sclerosis (ALS), and healthy controls (HC), using a multiplexed fluorescent bead-based immunoassay system. RESULTS: The induced protein (IP)10 level in the cells in both the MADSAM and MMN groups was markedly increased in comparison with the typical CIDP, ALS and HC groups. The other cytokines, including granulocyte colony-stimulating factor,vascular endothelial growth factor (VEGF) and interleukin-7, were also significantly upregulated in the MADSAM group. The increase of IP-10 produced by PnMECs was correlated with the presence of conduction block in both the MADSAM and MMN groups. CONCLUSION: The autocrine secretion of IP-10 induced by patient sera in PnMECs was markedly upregulated in both the MADSAM and MMN groups. The overproduction of IP-10 by PnMECs leads to the focal breakdown of the BNB and may help to mediate the transfer of pathogenic T cells across the BNB, thereby resulting in the appearance of conduction block in electrophysiological studies of patients with MADSAM and MMN.

Establishment of a new conditionally immortalized human skeletal muscle microvascular endothelial cell line.

In skeletal muscle, the capillaries have tight junctions (TJs) that are structurally similar to those in the blood-brain barrier (BBB) and blood-nerve barrier (BNB). Although many findings have been clarified in the territory of BBB and BNB, few have so far examined the TJs of capillaries in the skeletal muscle. In addition, no in vitro human skeletal muscle microvasculature models have been reported thus far. We newly established a new human skeletal muscle microvascular endothelial cell (HSMMEC) line. HSMMECs were isolated from human skeletal muscle and were infected with retroviruses harboring temperature-sensitive SV40 T antigen and telomerase genes. This cell line, termed TSM15, showed a spindle fiber-shaped morphology, an immunoreactivity to anti-factor VIII and anti-VE-cadherin antibodies, and a temperature-sensitive growth. TSM15 cells grew stably for more than 40 passages when they were cultured at 33°C, thereby retaining their spindle fiber-shaped morphology and contact inhibition at confluence. The cells expressed tight junctional molecules such as claudin-5, occludin, and zonula occludens-1, as well as transporters such as a glucose transporter 1. The transendothelial electrical resistance of TSM15 was as high as those of the human brain microvascular endothelial cell line. This novel cell line might facilitate the analyses of the pathophysiology of inflammatory myopathy, such as dermatomyositis, and can improve our understanding of the physiological and biochemical properties of the microvasculature in human skeletal muscle.

Identification of galectin-3 as a possible antibody target for secondary progressive multiple sclerosis.

BACKGROUND: Recent studies have revealed that the disruption of the blood-brain barrier (BBB) might contribute to the induction of neurodegeneration in the progressive stage of multiple sclerosis (MS). OBJECTIVE: We investigated a potential target for the serum auto-antibodies responsible for the BBB impairment in patients with secondary progressive MS (SPMS). METHODS: We identified undetermined target antigens in human brain microvascular endothelial cells (BMECs) that reacted with auto-antibodies in sera from SPMS patients using a proteomic approach. In addition, we examined how the identified auto-antibodies compromise the BBB integrity. RESULTS: We found that 10 of 11 SPMS sera had auto-antibodies against galectin-3, although the patients with other neurological diseases did not have these antibodies. Downregulation of galectin-3 led to elevated intercellular adhesion molecule-1 (ICAM-1) and phospho-nuclear factor-kappa (NFκ) B p65 expression in the BMECs. Exposure to SPMS patients' sera also increased the protein levels of ICAM-1 and phospho-NFκB p65 in BMECs, but these effects induced by anti-galectin-3 immunoreactivity were canceled by the downregulation of galectin-3. CONCLUSION: Galectin-3 is a possible immunological target molecule of the pathogenic auto-antibodies and contributes to the persistent BBB breakdown in patients with SPMS. These antibodies may also serve as a novel biomarker for SPMS.

Inflammatory cell trafficking across the blood-brain barrier: chemokine regulation and in vitro models.

The blood-brain barrier (BBB) is the brain-specific capillary barrier that is critical for preventing toxic substances from entering the central nervous system (CNS). In contrast to vessels of peripheral organs, the BBB limits the exchange of inflammatory cells and mediators under physiological and pathological conditions. Clarifying these limitations and the role of chemokines in regulating the BBB would provide new insights into neuroprotective strategies in neuroinflammatory diseases. Because there is a paucity of in vitro BBB models, however, some mechanistic aspects of transmigration across the BBB still remain largely unknown. In this review, we summarize current knowledge of BBB cellular components, the multistep process of inflammatory cells crossing the BBB, functions of CNS-derived chemokines, and in vitro BBB models for transmigration, with a particular focus on new and recent findings.

[Peripheral Neuropathy in Eosinophilic Granulomatosis with Polyangiitis].

Eosinophilic granulomatosis with polyangiitis (EGPA) is an antineutrophil cytoplasmic autoantibody-associated vasculitis secondary to inflammation of the small vessels. EGPA-induced neuropathy develops in approximately 90% of patients with peripheral blood eosinophilia and may lead to serious complications of the peripheral nervous system, necessitating emergency therapeutic intervention.

Physician awareness and understanding of chronic inflammatory demyelinating polyradiculoneuropathy in Japan: a web-based study.

OBJECTIVES: To investigate potential knowledge gaps between neurologists and non-specialists and identify challenges in the current management of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), with a focus on 'early diagnosis' and 'appropriate treatment' for CIDP. DESIGN: A non-interventional, cross-sectional, web-based quantitative survey of physicians working in healthcare clinics or hospitals in Japan. SETTING: Participants were recruited from the Nikkei Business Publications panel from 18 August to 14 September 2022. PARTICIPANTS: Responses from 360 physicians (120 each of internists, orthopaedists and neurologists) were collected. OUTCOME MEASURES: Responses relating to a CIDP hypothetical case and current understanding were assessed to determine awareness, collaboration preferences and diagnosis and treatment decisions. RESULTS: Understanding of CIDP was 90.8% among neurologists, 10.8% among orthopaedists and 13.3% among internists; >80% of orthopaedists and internists answered that neurologists are preferable for treatment. Diagnostic assessment using a hypothetical case showed 95.0% of neurologists, 74.2% of orthopaedists and 72.5% of internists suspected CIDP. Among orthopaedists and internists suspecting CIDP, >70% considered referring to neurology, while ~10% considered continuing treatment without a referral. Among neurologists, 69.4% chose intravenous immunoglobulin (IVIg) as first-line treatment and determined effectiveness to be ≤3 months. CONCLUSIONS: Orthopaedists and internists had lower CIDP awareness compared with neurologists, which may lead to inadequate referrals to neurology. Evaluation of IVIg effectiveness for maintenance therapy occurred earlier than the guideline recommendations (6-12 months), risking premature discontinuation. Improving CIDP knowledge among orthopaedists and internists is critical for better diagnosis and collaboration with neurologists. Neurologists should consider slow and careful evaluation of IVIg maintenance therapy. TRIAL REGISTRATION NUMBER: UMIN000048516.

[Mechanism of Synthesis and Effect of Autoantibodies: Implications for Therapy].

The detailed mechanisms of autoantibody synthesis are different in each disease; however, the dysfunction of immune tolerance is attracting interest as the common mechanism in many autoantibody-associated diseases. Autoantibodies must pass through various physiological barriers, such as the blood-brain barrier, to approach their antigen in the central nervous system. The direct effects of autoantibodies on their antigens vary among antibodies. Exploring the detailed mechanism of synthesis and effect of autoantibodies would provide a more radical and effective therapeutic strategy.

Lead Encephalopathy in a 73-year-old Man Manifesting as Acute Disturbance of Consciousness with a Unique Magnetic Resonance Imaging Appearance.

A 73-year-old man was admitted with Cheyne-Stokes respiration and progressive disturbance of consciousness over the course of a month. Cranial magnetic resonance imaging revealed signs suggestive of angioedema in the posterior limb of the internal capsule, external capsule, and subcortical white matter. Acute lead encephalopathy was diagnosed based on abnormally high plasma lead levels. After methylprednisolone pulse therapy followed by chelation therapy, the patient fully recovered. In this case, the angioedema with a distinctive magnetic resonance imaging appearance was attributed to the cytotoxic effects of lead on the nervous system, which responded well to methylprednisolone pulse therapy.

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.

Autocrine TNF-α Increases Penetration of Myelin-Associated Glycoprotein Antibodies Across the Blood-Nerve Barrier in Anti-MAG Neuropathy.

BACKGROUND AND OBJECTIVES: Deposition of myelin-associated glycoprotein (MAG) immunoglobulin M (IgM) antibodies in the sural nerve is a key feature in anti-MAG neuropathy. Whether the blood-nerve barrier (BNB) is disrupted in anti-MAG neuropathy remains elusive.We aimed to evaluate the effect of sera from anti-MAG neuropathy at the molecular level using our in vitro human BNB model and observe the change of BNB endothelial cells in the sural nerve of anti-MAG neuropathy. METHODS: Diluted sera from patients with anti-MAG neuropathy (n = 16), monoclonal gammopathies of undetermined significance (MGUS) neuropathy (n = 7), amyotrophic lateral sclerosis (ALS, n = 10), and healthy controls (HCs, n = 10) incubated with human BNB endothelial cells to identify the key molecule of BNB activation using RNA-seq and a high-content imaging system, and exposed with a BNB coculture model to evaluate small molecule/IgG/IgM/anti-MAG antibody permeability. RESULTS: RNA-seq and the high-content imaging system showed the significant upregulation of tumor necrosis factor (TNF-α) and nuclear factor-kappa B (NF-κB) in BNB endothelial cells after exposure to sera from patients with anti-MAG neuropathy, whereas the serum TNF-α concentration was not changed among the MAG/MGUS/ALS/HC groups. Sera from patients with anti-MAG neuropathy did not increase 10-kDa dextran or IgG permeability but enhanced IgM and anti-MAG antibody permeability. Sural nerve biopsy specimens from patients with anti-MAG neuropathy showed higher TNF-α expression levels in BNB endothelial cells and preservation of the structural integrity of the tight junctions and the presence of more vesicles in BNB endothelial cells. Neutralization of TNF-α reduces IgM/anti-MAG antibody permeability. DISCUSSION: Sera from individuals with anti-MAG neuropathy increased transcellular IgM/anti-MAG antibody permeability via autocrine TNF-α secretion and NF-κB signaling in the BNB.

LONRF2 is a protein quality control ubiquitin ligase whose deficiency causes late-onset neurological deficits.

Protein misfolding is a major factor of neurodegenerative diseases. Post-mitotic neurons are highly susceptible to protein aggregates that are not diluted by mitosis. Therefore, post-mitotic cells may have a specific protein quality control system. Here, we show that LONRF2 is a bona fide protein quality control ubiquitin ligase induced in post-mitotic senescent cells. Under unperturbed conditions, LONRF2 is predominantly expressed in neurons. LONRF2 binds and ubiquitylates abnormally structured TDP-43 and hnRNP M1 and artificially misfolded proteins. Lonrf2-/- mice exhibit age-dependent TDP-43-mediated motor neuron (MN) degeneration and cerebellar ataxia. Mouse induced pluripotent stem cell-derived MNs lacking LONRF2 showed reduced survival, shortening of neurites and accumulation of pTDP-43 and G3BP1 after long-term culture. The shortening of neurites in MNs from patients with amyotrophic lateral sclerosis is rescued by ectopic expression of LONRF2. Our findings reveal that LONRF2 is a protein quality control ligase whose loss may contribute to MN degeneration and motor deficits.

Intracellular colocalization of HAP1/STBs with steroid hormone receptors and its enhancement by a proteasome inhibitor.

The stigmoid body (STB) is a cytoplasmic inclusion containing huntingtin-associated protein 1 (HAP1), and HAP1/STB formation is induced by transfection of the HAP1 gene into cultured cells. In the present study, we examined the intracellular colocalization of HAP1/STBs with steroid hormone receptors (SHRs), including the androgen receptor (AR), estrogen receptor, glucocorticoid receptor (GR), and mineralocorticoid receptor, in COS-7 cells cotransfected with HAP1 and each receptor. We found that C-terminal ligand-binding domains of all SHRs had potential for colocalization with HAP1/STBs, whereas only AR and GR were clearly colocalized with HAP1/STBs when each full-length SHR was coexpressed with HAP1. In addition, it appeared that HAP1/STBs did not disrupt GR and AR functions because the receptors on HAP1/STBs maintained nuclear translocation activity in response to their specific ligands. When the cells were treated with a proteasome inhibitor, GR and AR localized outside HAP1/STBs translocated into the nucleus, whereas the receptors colocalized with HAP1/STBs persisted in their colocalization even after treatment with their ligands. Therefore, HAP1/STBs may be involved in cytoplasmic modifications of the nuclear translocation of GR and AR in a ubiquitin-proteasome system.

[Steroids-Resistant EGPA-Induced Neuropathy with Acute Disease Progression: How to Select Remission-Induction/Maintenance Therapy Based on The Characteristics].

Recently, given the availability of mepolizumab as a novel treatment for eosinophilic polyangiitis granulomatosis (EGPA), several studies on remission-induction/maintenance therapies are in progress. However, there is little evidence regarding the treatment of EGPA neuropathy. In this article, we clarify the characteristics of steroid-resistant EGPA neuropathy by presenting actual cases and explaining the selection of remission-induction/maintenance therapies based on the characteristics.

An In Vitro Model of the Blood-Brain Barrier to Study Alzheimer's Disease: The Role of ß-Amyloid and Its Influence on PBMC Infiltration.

The blood-brain barrier (BBB) is a highly specialized structure, constituted by endothelial cells that together with astrocytes and pericytes provide a functional interface between the central nervous system and the periphery. Several pathological conditions may affect its functions, and lately BBB involvement in the pathogenesis of Alzheimer's disease has been demonstrated. Both endothelial cells and astrocytes can be differentially affected during the course of the disease. In vitro BBB models present a powerful tool in evaluating the effects that ß-amyloid (Aß), or other pathogenic stimuli, play on the BBB at cellular level. In vitro BBB models derived from human cell sources are rare and not easily implemented. We generated two conditionally immortalized human cell lines, brain microvascular endothelial cells (TY10), and astrocytes (hAST), that, when co-cultured under appropriate conditions, exhibit BBB-like characteristics. This model allowed us to evaluate the transmigration of peripheral blood mononuclear cells (PBMCs) through the in vitro barrier exposed to Aß and the role played by astrocytes in the modulation of this phenomenon. We describe here the methodology used in our lab to set up our in vitro model of the BBB and to carry out a PBMC transmigration assay.

Spinal cord sarcoidosis in Japan: utility of cerebrospinal fluid examination and nerve conduction study for diagnosis and prognosis prediction.

Spinal cord sarcoidosis (SCS) is rare, and its diagnosis is challenging. We examined clinical, laboratory, and imaging features in patients with SCS to obtain useful clues for diagnosis and prognosis. Eleven consecutive patients (four males, seven females) at a single Japanese institution were investigated. Median age at onset was 66 years old. The most frequent site affected, other than the nervous system, was the respiratory system. While histological confirmation of non-caseating granulomas was often found there, no patient had respiratory symptoms. Peripheral nerve involvement was detected in 64% of patients. Soluble IL-2 receptor (sIL-2R) levels in serum and cerebrospinal fluid (CSF) were elevated in 64% and 45% of patients, respectively, and this finding was more common than elevation of angiotensin-converting enzyme (ACE). 18F-fluorodeoxyglucose (FDG) positron emission tomography showed abnormally high uptake in spinal lesions of all examined patients. Although corticosteroids were administrated to all patients, and immuno-suppressants were prescribed to six (55%), the modified Rankin Scale was unchanged or worsened in four (36%) patients during the follow-up period. Neurological exacerbation of myelopathy was seen in four (36%) patients. Complete response rate was only seen in 9%. High levels of cell count, protein, ACE, and sIL-2R in CSF were significantly more frequent in patients with a marked improvement after immunotherapy than in the other patients. These results suggest that high serum and CSF sIL-2R, high uptake of FDG, and peripheral nerve involvement are indicative of SCS. Given that SCS is commonly intractable, CSF abnormalities may predict efficacy of immunotherapies.

[Clinical and long-term characteristics of the subtypes of chronic inflammatory demyelinating polyneuropathy].

OBJECTIVE: To clarify the clinical and long-term characteristic of each subtype of chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: We evaluated data from 30 consecutive CIDP patients who met the criteria proposed by the European Federation of Neurological Societies and the Peripheral Nerve Society. RESULTS: Patients were classified as having typical CIDP (t-|CIDP) (10/30, 33%), multifocal acquired demyelinating sensory and motor (MADSAM) (12/30, 40%), DADS (4/30, 13%), sensory CIDP (3/30, 10%) or motor CIDP (1/30, 3%). Nerve conduction studies showed more prolonged distal motor latencies/F-wave latencies and slower motor nerve conduction in the typical CIDP group than in the MADSAM group. Intravenous immunoglobulin (IVIg) was effective in 80% (8/10) of t-|CIDP, 100% (12/12) of MADSAM, 100% (4/4) of DADS, and 100% (3/3) of sensory CIDP cases. Maintenance therapy with immunoglobulin was administered in patients with t-|CIDP (5/10, 50%), MADSAM (9/12, 75%), DADS (1/4, 25%), and sensory CIDP (2/3, 67%). There were no patients with CIDP, in whom CIDP subtype was transformed from the initial diagnosis during five years of follow-up. DISCUSSION: Percentage of MADSAM was the most common phenotype in our cohort of CIDP patients, and IVIg/immunoglobulin maintenance was effective for MADSAM as well as t-|CIDP in contrast to findings from the previous reports.

[An 11 year old woman with myelin-oligodendrocyte glycoprotein antibody showing various phenotypes of central nervous system disorders in one year].

An 11-year-old woman with myelin-oligodendrocyte glycoprotein (MOG) antibody developed cortical encephalitis twice, followed by acute disseminated encephalomyelitis (ADEM) and optic neuritis in one year. Although optic neuritis was refractory after corticosteroid therapy, plasma exchange was effective and complete remission was achieved. We considered that episodes of cortical encephalitis, ADEM and optic neuritis occurred in the present patient can be included in MOG IgG-associated disorders. Also, we recommend plasma exchange for refractory MOG IgG-associated optic neuritis, even in pediatric patient.

Glomerulonephritis and Interstitial Nephritis Originating from Vasculitis of the Interlobular Arteries of the Kidney in a Patient with Eosinophilic Granulomatosis with Polyangiitis.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a type of antineutrophil cytoplasmic antibody-associated vasculitis. Patients often present with peripheral neuropathy and purpura, suggesting impairment of small vessels, especially capillaries. However, medium-sized vessels and small vessels with a vascular diameter larger than that of capillaries may also be impaired, causing atypical findings. We report a case of EGPA treated with corticosteroids, cyclophosphamide, and mepolizumab. Renal biopsy revealed vasculitis of the interlobular arteries as the cause of glomerulonephritis and interstitial nephritis. This case suggests the importance of considering vessels upstream of capillaries dominant EGPA as a differential diagnosis in patients with eosinophilia.