Myeloperoxidase-specific Antineutrophil Cytoplasmic Antibody Research Articles

The effects of age and frailty on the risks of end-stage renal disease, death, and severe infection in older adults with antineutrophil cytoplasmic antibody-associated vasculitis: a retrospective cohort study

Frailty, a measure of biological age, might predict poor outcomes in older adults better than chronological age. We aimed to compare the effect of age and frailty on end-stage renal disease, death, and severe infection within 2 years of diagnosis in older adults with incident antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. This retrospective cohort study included individuals aged 65 years or older from the Mass General Brigham ANCA-associated vasculitis cohort in the USA who were treated between Jan 1, 2002, and Dec 31, 2019. Individuals with a diagnosis of eosinophilic granulomatosis with polyangiitis were excluded from the analysis. Baseline frailty was measured with a claims-based frailty index using data collected in the year before the date of treatment initiation in individuals with at least one health-care encounter before baseline; individuals who did not have an encounter within the 12 months before baseline were classified as pre-frail. Incidence rates of end-stage renal disease or death and severe infections (ie, infections leading to hospital admission or death) at 2 years were estimated, and multivariable analyses were performed to compare the association of age and frailty with these outcomes. Cumulative incidence rates and an additive interaction analysis were used to assess the interaction of age and frailty groupings. Of the 234 individuals included, 136 (58%) were women, 98 (42%) were men, 198 (85%) were White, and 198 (85%) were positive for myeloperoxidase-specific ANCA. Frailty was present in 25 (22%) of 116 individuals aged 65-74 years and 44 (37%) of 118 aged 75 years or older. In the multivariable analysis, an age of 75 years or older was associated with an increased risk of end-stage renal disease or death (hazard ratio [HR] 4·50 [95% CI 1·83-11·09]), however, frailty was not (1·08 [0·50-2·36]). Both an age of 75 years or older (HR 2·52 [95% CI 1·26-5·04]) and frailty (8·46 [3·95-18·14]) were independent risk factors for severe infections. The effect of frailty on the incidence of end-stage renal disease or death was greater in individuals aged 65-74 years (frail vs non-frail or pre-frail incidence rate 7·5 cases vs 2·0 cases per 100 person-years) than in those aged 75 years or older (13·5 cases vs 16·0 cases per 100 person-years). The effect of frailty on the incidence of serious infections varied by age, with large differences observed among both individuals aged 65-74 years (frail vs non-frail or pre-frail incidence rate 38·9 cases vs 0·8 cases per 100 person-years) and individuals aged 75 years or older (61·9 cases vs 12·3 cases per 100 person-years). Despite the observed differences between the age groups, the additive interaction terms were not statistically significant for either frailty and end-stage renal disease or death (p for interaction=0·276) or frailty and serious infections (p for interaction=0·650). Adults with ANCA-associated vasculitis aged 75 years or older had a higher incidence of end-stage renal disease, death, and severe infections within 2 years of diagnosis than adults aged 65-74 years. Frailty, an approximation of biological age, was a risk factor for severe infection. Assessment beyond chronological age could better inform management decisions in older adults with ANCA-associated vasculitis. National Institutes of Health and National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Characteristic changes in the mRNA expression profile of plasma exosomes from patients with MPO-ANCA-associated vasculitis and its possible correlations with pathogenesis

To explore the expression patterns and potential roles of mRNAs in exosomes from patients with myeloperoxidase-specific anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (MPO-AAV). Plasma exosomes were isolated from MPO-AAV patients and healthy controls (HCs) to screen for differential mRNA expression via exosomal mRNA sequencing. The differentially expressed mRNAs in exosomes from the 2 groups were comparatively explored by bioinformatics analysis. The six most differentially expressed mRNAs were selected and validated in larger groups of MPO-AAV patients and HCs by real-time quantitative polymerase chain reaction (RT‒qPCR). The relationships between these selected mRNAs and patient characteristics were statistically analyzed. Compared with HCs, a total of 1077 mRNAs in exosomes from MPO-AAV patients were found to be significantly upregulated, including DEPDC1B and TPST1, while NSUN4 and AK4 were significantly downregulated. Statistical analysis did not reveal any correlation between the six selected mRNAs and clinical indicators, including disease activity. GO enrichment analysis revealed that these differentially expressed genes participate in various enzyme activities, protein synthesis, etc. KEGG pathway analysis revealed that metabolic pathways, cell adhesion molecules, epithelial signaling, and mitogen-activated protein kinase (MAPK) signaling pathways were significantly enriched in the exosomal mRNAs. There were significant differences in the expression of exosomal mRNAs between MPO-AAV patients and HCs, which may be related to the occurrence and development of MPO-AAV. These findings provide clues for further investigations of MPO-AAV pathogenesis and the identification of new potential therapeutic targets.

The significances of peripheral neutrophils CD(55) and myeloperoxidase expression in patients with myeloperoxidase-specific anti-neutrophil cytoplasmic antibody associated vasculitis

Objective: To investigate the expression of CD(55) and myeloperoxidase (MPO) on neutrophils in patients with MPO-specific anti-neutrophil cytoplasmic antibody associated vasculitis(MPO-AAV), and analyze the relationship between the expression and clinical manifestation. Methods: Forty untreated patients with active MPO-AAV (patient group) and 30 healthy volunteers (control group) were enrolled in this study. The CD(55) on neutrophils and both membrane and cytoplasmic MPO were detected by flow cytometry. Serum fragment-from the activated complement factor B(Ba) and MPO were measured by ELISA. The clinical activity of vasculitis was valued by Birmingham vasculitis activity score-version 3(BVAS-V3). The significance of laboratory data was evaluated by Spearman correlation test and multivariate linear regression analysis. Results: (1)The mean fluorescence intensity(MFI) of CD(55) expressed on neutrophils was significantly higher than that in control group[4 068.6±2 306.0 vs 2 999.5±1 504.9, P=0.033]. Similar results of serum MPO and Ba in patient group were found compared to controls [500.0(381.0, 612.7) IU/L vs 286.9(225.5, 329.1) IU/L, P<0.001; 35.2(25.2, 79.5) ng/L vs 18.0(15.0, 28.0) ng/L, P<0.001], respectively. However, MIF of cytoplasmic MPO in patients was significantly lower than that of control group(1 577.1±1 175.9 vs 3 105.3±2 323.0, P=0.003) . (2) In patient group, cytoplasmic intensity of MPO was negatively associated with the serum levels of MPO(r=-0.710, P<0.001) and Ba (r=-0.589, P=0.001). Moreover, serum MPO was positively associated with serum Ba(r=0.691, P<0.001). Membrane intensity of CD(55) on neutrophils was positively correlated with patient age (r=0.514, P=0.001), C reactive protein (r=0.376, P=0.018), peripheral neutrophils count (r=0.485, P=0.001) and BVAS-V3 (r=0.484, P=0.002), whereas negative correlation between membrane CD(55) and disease duration was seen (r=-0.403, P=0.01). (3) The result of multiple linear regression analysis showed there was statistically significant positive correlation between MFI of CD(55) expressed on neutrophils and BVAS-V3 (β=0.001, P=0.027). Conclusions: In MPO-AAV, CD(55) expression on neutrophils is markedly enhanced, which is one of the independent risk factors related to disease activity. It might protect neutrophils from attacking AAV, CD(55) expression on neutrophils is markedly enhanced, which is one of the independent risk factors related to disease activity. It might protect neutrophils from attacking by complement alternative pathway. Activated neutrophils release more MPO and lysosome to intensify the inflammation reaction and aggravate the disease. Thus CD(55) might become a new potential target for the treatment of this disease in the future.

Transient Cerebral Ischemic Attack and Delirium Heralding the Vasculitic Phase of Eosinophilic Granulomatosis With Polyangiitis (Churg-Strauss Syndrome)

Eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as Churg-Strauss syndrome, is a rare systemic vasculitis characterized by a prodromic history of allergic asthma and sinusitis for many years, followed by an eosinophilic phase and a vasculitic phase. Central nervous system (CNS) involvement associated with EGPA is very rare, in particular as first sign of the vasculitic phase. We describe a patient with transient cerebral ischemic attack and delirium heralding the vasculitic phase of EGPA. We report a case of EGPA (Churg-Strauss syndrome) in a 76-year-old Italian woman with acute neurologic and neuropsychiatric symptoms and history of asthma and sinusitis. She was admitted in stroke unit with acutely developing aphasia, ataxia and delirium without acute lesions on neuroimaging. When she was transferred in neurorehabilitation unit, an anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis was suspected on the basis of anamnesis, facies (saddle nose) and presence of systemic inflammation. She was finally diagnosed with EGPA because of the presence of subclinical demyelinating polyneuropathy, interstitial pulmonary disease and increased myeloperoxidase-specific ANCA (MPO-ANCA). The patient’s neurologic symptoms were, therefore, attributed to a vasculitic process, and they improved with steroid treatment. CNS involvement associated with EGPA is very rare and, in this case it represented the first sign of systemic vasculitis after many years of prodromic phase, and it should be considered in patients with acute cerebrovascular disease associated with systemic inflammation or eosinophilia and anamnestic asthma or sinusitis. J Med Cases. 2015;6(11):501-504 doi: https://doi.org/10.14740/jmc2300w

Clinical Outcomes of Patients with Dual Positivity for Proteinase 3 and Myeloperoxidase Specific Antineutrophil Cytoplasmic Antibodies

Objective: Granulomatous polyangiitis patients generally have ANCA targeting Proteinase 3 (PR3), while microscopic polyangiitis and eosinophilic granulomatous polyangiitis patients generally have ANCA targeting myeloperoxidase (MPO). Patients positive for both PR3-ANCA and MPO-ANCA are uncommon and any diagnostic value of this situation has not been well described. The aim of this study was to determine whether there were any patterns of clinical presentations or outcomes of patients who tested positive for both PR3-ANCA and MPO-ANCA. Methods: A retrospective clinical audit was carried out. A list of patients who had tested positive for both PR3- ANCA and MPO-ANCA was obtained from ACT Pathology from 2003-2013. Medical records were then used to determine their clinical outcomes. Results: 3 of the 15 study patients were found to have ANCA-associated vasculitis (AAV), two with MPA and the other EGPA along with a non-AAV autoimmune disease. 1 patient had drug-induced vasculitis and 4 had a non-AAV autoimmune disease. An additional three patients had a non-AVV autoimmune disease, but one concurrently had a malignancy while the other two had recurrent infections. Two patients had a malignancy, another one only had recurrent infections, and the remaining patient was lost to follow up with an undiagnosed inflammatory condition Conclusion: Pathology results showing dual positivity for PR3-ANCA and MPO-ANCA in itself does not appear to indicate any particular pattern of clinical outcome and so cannot be used to draw any clinical conclusions at the time of presentation. The 3 cases of AAV demonstrated MPO-predominance which fitted with their final diagnosis.

Correlation of interleukin‐6 and monocyte chemotactic protein‐1 concentrations with crescent formation and myeloperoxidase‐specific anti‐neutrophil cytoplasmic antibody titer in SCG/Kj mice by treatment with anti‐interleukin‐6 receptor antibody or mizoribine

Myeloperoxidase-specific anti-neutrophil cytoplasmic antibody (MPO-ANCA) is associated with rapidly progressive glomerulonephritis (RPGN) and glomerular crescent formation. Pathogenic factors in RPGN were analyzed by using SCG/Kj mice, which spontaneously develop MPO-ANCA-associated RPGN. The serum concentration of soluble IL-6R was determined by using ELISA and those of another 23 cytokines and chemokines by Bio-Plex analysis. Sections of frozen kidney tissue were examined by fluorescence microscopy and the CD3(+) B220(+) T cell subset in the spleen determined by a flow cytometry. Concentrations of IL-6 and monocyte chemotactic protein-1 were significantly correlated with the percentages of crescent formation. Anti-IL-6R antibody, which has been effective in patients with rheumatoid arthritis, was administered to SCG/Kj mice to elucidate the role of IL-6 in the development of RPGN. MPO-ANCA titers decreased after administration of anti-IL-6R antibody, but not titers of mizoribine, which is effective in Kawasaki disease model mice. These results suggest that IL-6-mediated signaling is involved in the production of MPO-ANCA.

Monitoring with serum SP-A, SP-D, and KL-6 in a patient with interstitial pneumonia complicated with ANCA-associated glomerulonephritis.

A 69-year-old woman was admitted to hospital, complaining of fatigue and dry cough. Her renal function deteriorated rapidly, and the laboratory findings showed elevated myeloperoxidase-specific anti-neutrophil cytoplasmic antibody (ANCA). Renal biopsy examination revealed crescentic glomerulonephritis (pauci-immune type), and linear opacities and a honeycomb appearance in both lower lobes was evident on the chest computed tomography scan. The patient was diagnosed as having ANCA-associated glomerulonephritis complicated with mild interstitial pneumonia (IP). Treatment with methylprednisolone pulse therapy improved both her renal function and IP, but her lung lesions worsened during the course of tapering the prednisolone doses. After careful observation, her IP improved gradually without specific treatment. Worsening or improvement of her lung lesions was accompanied by changes in the serological markers of IP, namely, surfactant protein-A, surfactant protein-D, and KL-6. We found that monitoring these markers was helpful in diagnosing and managing IP in our patient with ANCA-associated vasculitis.

Combined membranous nephropathy and crescentic glomerulonephritis with concurrent anti-glomerular basement membrane antibody and myeloperoxidase-specific anti-neutrophil cytoplasmic antibody.

We report a case of a 71-year-old man with rapidly progressive nephritic syndrome and dual positivity for anti-glomerular basement membrane antibody and myeloperoxidase-specific anti-neutrophil cytoplasmic antibody. Renal biopsy revealed crescentic, mainly cellular, glomerulonephritis with granulomatous lesions, and advanced membranous changes. Membranous nephropathy had apparently existed for an extended period before the development of crescentic glomerulonephritis. In some studies reporting the simultaneous occurrence of both diseases, membranous nephropathy might be followed by crescentic glomerulonephritis, presumably from a histological point of view. Although we cannot prove a causal relationship between the two diseases, we caution that precise observations, especially histological, are necessary in similar cases.

Biliary hamartomas (von Meyenburg complex) complicated with microscopic polyangiitis

Vasculitis syndrome accompanied by multiple liver lesions is uncommon. Biliary hamartomas, also called von Meyenburg complexes (VMCs), are small benign liver malformations that pathologically contain cystic dilated bile ducts surrounded by abundant fibrous stroma [1]. VMCs are considered to be congenital bile duct malformations. To date, there have been no reports of any cases of VMC complicated with systemic vasculitis syndrome. Here, we report an extremely rare case of VMC complicated with microscopic polyangiitis (MPA). A 59-year-old man was referred to our hospital with general fatigue, appetite loss, high fever, and numbness of the distal extremities in August 2010. He had been hospitalized in another hospital and had several examinations. Blood tests showed a high white blood cell count (WBC), elevated C-reactive protein (CRP) levels, and elevation of hepatobiliary enzymes. Abdominal CT showed multiple small hypodense lesions scattered in both lobes of the liver, which were suspected to be multiple liver metastases or microabscesses. Although two antibiotics (meropenem and clindamycin) were administered, all symptoms remained. After the detection of high myeloperoxidase-specific antineutrophil cytoplasmic antibody (MPO-ANCA) levels (185 EU) in his serum, he was transferred to our hospital for further treatment. His height was 168 cm and his body weight was 65 kg. On examination his body temperature was 37.7 C and his blood pressure was 134/89 mmHg. Physical examination revealed peripheral edema on both lower legs, and neurological examination revealed polyneuropathy on the distal extremities. A blood test showed elevated hepatobiliary enzymes and high levels of WBC and CRP. Laboratory values were as follows: WBC 33000/lL (normal 3800–9800/ lL); red blood cells (RBC) 375 9 10/lL (normal 440–540 9 10/lL); hemoglobin 11.2 g/dL (normal 14–17 g/dL); platelet count 42.6 9 10/lL (normal 15.5–36.5 9 10/lL); CRP 17.91 mg/dL (normal \0.2 mg/dL); asparate aminotransferase (AST) 119 IU/L (normal 10–35 IU/L); alanine aminotransferase (ALT) 73 IU/L (12–33 IU/L); alkaline phosphatase (ALP) 1215 IU/L (115–359 IU/L); c-glutamyl transpeptidase (c-GTP) 148 IU/L (normal 10–47 IU/L); total bilirubin 2.6 mg/dL (normal \1.1 mg/dL). Negative results were obtained for HBs antigen and HCV antibody. His blood urea nitrogen was slightly elevated (23 mg/dL, normal 9–21 mg/dL), and his serum creatinine level was within normal limits (0.57 mg/dL, normal 0.6–1.2 mg/dL). Urine test was positive for protein (?2) and blood (?3). The urine sedimentation test was positive for RBC casts (0–1/10), WBC casts (0–1/10), and granulocyte casts (0–1/10) per high-power field. Anti-nuclear antibody was negative (1:80, normal \1:160), but MPO-ANCA levels were elevated to 402 EU (normal \10 EU). Chest CT showed bilateral ground-glass opacities in both lower lungs. Abdominal enhanced CT showed multiple small hypodense lesions scattered in both lobes of the liver (Fig. 1). Abdominal ultrasonography (AUS) showed multiple small high-echoic lesions in the liver. MRCP demonstrated multiple small hyperintense nodules that were scattered throughout the liver but did not communicate with the biliary tree (Fig. 2). His clinical symptoms—lung shadows and high MPO-ANCA levels—led S. Sato (&) H. Watanabe T. Asano R. Saito H. Iwadate H. Kobayashi H. Ohira Department of Gastroenterology and Rheumatology, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan e-mail: shuzo@fmu.ac.jp

Psychiatric Symptoms in a Patient with Churg-Strauss Syndrome

We report a case of Churg-Strauss syndrome (CSS) in a patient with multiple cerebral infarctions and psychotic symptoms. A 67-year-old man presented a high-grade fever and delirium. He was clinically diagnosed with Churg-Strauss syndrome on the basis of the presence of asthma, neuropathy, blood eosinophilia, and increased myeloperoxidase-specific anti-neutrophil cytoplasmic antibody (MPO-ANCA) activities. Though multiple cerebral infarctions are irreversible, this patient's psychiatric symptoms improved with steroid treatment. Psychiatric symptoms associated with CSS are very rare.

A case of slowly progressive type 1 diabetes mellitus developing myeloperoxidase-specific anti-neutrophil cytoplasmic antibody-associated vasculitis with hypertrophic pachymeningitis manifesting as multiple cranial nerve palsy

We report a 63-year-old man with a 35-year history of slowly progressive type 1 diabetes mellitus (SPIDDM), complicated with myeloperoxidase-specific anti-neutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitis presenting alveolar hemorrhage and pachymeningitis. The patient was first diagnosed as having DM at age of 28 years old and deteriorated secretion of insulin and the typical clinical course led us to the diagnosis of SPIDDM. When he was 58 years old, he suffered from fever, headache, and alveolar hemorrhage. He was diagnosed as having MPO-ANCA associated vasculitis based on a high titer of MPO-ANCA and histological findings of lung biopsy. Treatment with steroid pulse therapy, followed by oral prednisolone and oral cyclophosohamide, resulted in clinical improvement. Five years later, he complained of double vision. A gadolinium-enhanced magnetic resonance imaging (MRI) study of the brain showed normal. Two months later, he developed right cranial nerve V~XII palsy. A second MRI study revealed thickening of the right temporal region and cerebellar dura mater, leading us to the diagnosis of hypertrophic pachymeningitis. He responded well to oral prednisolone (50 mg/day) and intravenous cyclophosohamide (500 mg). This is the first case report of SPIDDM complicated with MPO-ANCA-associated vasculitis, manifesting as alveolar hemorrhage and hypertrophic pachymeningitis.

A Case of Microscopic Polyangiitis and Giant Cell Arteritis after Influenza Vaccination

We report a case of microscopic polyangiitis (mPA) and giant cell arteritis (GCA) (polyangiitis overlap syndrome) after influenza vaccination. A 67-year-old female with chronic kidney disease, who had been observed by a physician, presented fever and headache after immunization of influenza vaccine. She was diagnosed as having with mPA and GCA based on symptoms, worsening of renal function, biopsy of temporal artery (giant cell arteritis) and skin (microscopic polyangiitis), pulmonary involvement and the presence of myeloperoxidase-specific anti-neutrophil cytoplasmic antibodies (MPO-ANCA). She was treated with prednisolone (PSL) and the symptoms were improved. However, two months later she was presented with general physical weariness. She was diagnosed as having with pneumocystis pneumonia, cytomegalovirus infection and cryptococcosis. Despite intensive treatment, she was died and autopsy was performed. The present case suggests that the influenza vaccination may cause different types of vasculitis, mPA and GCA, through the common mechanism in pathophysiology. This patient is also the first case of mPA and GCA proven by histological examination.

A patient with intravascular lymphoma presenting with cerebral infarction and a high serum MPO-ANCA level

A 74-year-old woman presented with multiple brain infarctions, an inflammatory reaction, and a high serum titer (414 U/ml) of myeloperoxidase-specific antineutrophil cytoplasmic antibody (MPO-ANCA) with no hematological abnormalities. After the inflammation and ANCA titers were resolved with steroid therapy for suspected microscopic polyangiitis, hemophagocytic syndrome developed. Biopsies revealed non-Hodgkin's intravascular lymphoma (IVL). The flare of IVL with negative serum ANCA suggested that the initial high serum MPO-ANCA had not originated from tumor cells.

MPO-ANCA crescentic glomerulonephritis complicated by membranous nephropathy: MPO demonstrated in epimembranous deposits

An elderly woman presented with haematuria and proteinuria accompanied by elevated serum myeloperoxidase (MPO)-specific anti-neutrophil cytoplasmic antibodies (MPO-ANCA). A renal biopsy revealed mild mesangial proliferation with fibrocellular crescent formation and a membranous glomerular lesion. Immunofluorescence microscopy using FITC-labelled rabbit anti-human MPO antibodies revealed granular MPO deposition along the glomerular capillary walls (GCW) with a staining profile similar to that of glomerular IgG deposition. The one-year follow-up renal biopsy revealed minimal IgG and undetectable MPO deposition. Both MPO and MPO-ANCA might have been responsible for the IgG immune depositions along the GCW in this patient.

MPO-ANCA induces IL-17 production by activated neutrophils in vitro via its Fc region- and complement-dependent manner

The elevation of serum anti-neutrophil cytoplasmic autoantibodies (ANCA) is significantly associated with the progression of some patients with systemic vasculitis. Especially, myeloperoxidase-specific ANCA (MPO-ANCA) play a pivotal role in the progression of systemic vasculitis including crescentic glomerulonephritis. Here we demonstrated that MPO-ANCA-activated neutrophils allow the local environment to differentiate Th 17 cells through IL-6, IL-17A, and IL-23 production. We found a variety of elevated serum cytokines, especially IL-17A, in ANCA-mediated systemic vasculitis mice. Furthermore, activated peritoneal neutrophils in vitro also produced IL-17A and IL-23 in response to MPO-ANCA. Co-stimulation of fungal mannoprotein and complements significantly enhanced the MPO-ANCA-mediated IL-17A expression, but F( ab)′ 2 fragments of MPO-ANCA diminished the cytokine response. These results suggest that the activated neutrophils produce IL-17A and IL-23 in response to MPO-ANCA via their Fc-region and classical complement pathway, which initiate the first steps of chronic autoimmune inflammation by allowing the local environment to develop Th 17-mediated autoimmunity.

Trafficking of QD‐Conjugated MPO‐ANCA in Murine Systemic Vasculitis and Glomerulonephritis Model Mice

In systemic vasculitis, the serum level of myeloperoxidase (MPO)-specific anti-neutrophil cytoplasmic autoantibodies (MPO-ANCA) is significantly elevated with the progression of disease. We have established a model of murine systemic vasculitis by administration of MPO-ANCA and fungal mannoprotein to C57BL/6 mice. We examined the role of MPO and MPO-ANCA in the pathogenesis of glomerulonephritis and systemic vasculitis in this model using quantum dots (QDs). We demonstrated that QD-conjugated MPO-ANCA (ANCA-QD) visualized the translocation of MPO on the neutrophil membrane surface after stimulation with proinflammatory cytokines. We also observed that MPO translocation on neutrophils in both patients with rapid progressive glomerulonephritis and these model mice without any stimulation, suggesting that MPO translocation is certain to contribute to the development of glomerular lesion. In addition, blood flow on the kidney surface vessel was significantly decelerated in both SCG/Kj mice and this model, suggesting that ANCA induces the damage of blood vessel. These results indicate that MPO-ANCA and surface-translocated MPO on the activated neutrophils coordinately plays essential roles in the initial steps of the glomerulonephritis.

Mechanisms of Disease: pathogenesis and treatment of ANCA-associated vasculitides

Wegener's granulomatosis and microscopic polyangiitis are idiopathic systemic vasculitides strongly associated with antineutrophil cytoplasmic autoantibodies (ANCA). In Wegener's granulomatosis, ANCA are mostly directed against proteinase 3 (PR3), whereas in microscopic polyangiitis ANCA are directed against myeloperoxidase; increases in levels of these autoantibodies precede or coincide with clinical relapses in many cases. In vitro, ANCA can further activate primed neutrophils to release reactive oxygen species and lytic enzymes, and, in conjunction with neutrophils, can damage and lyse endothelial cells. Patients with Wegener's granulomatosis or microscopic polyangiitis have an increased percentage of neutrophils that constitutively express PR3 on their membrane. These neutrophils can be stimulated by ANCA, without priming. In vivo, transfer of splenocytes from myeloperoxidase-deficient mice immunized with mouse myeloperoxidase into wild-type mice resulted in pauci-immune systemic vasculitis. A similar experiment in PR3-deficient mice did not cause significant vasculitic lesions. Together, clinical, in vitro and in vivo experimental data support a pathogenic role for ANCA in Wegener's granulomatosis and microscopic polyangiitis, although this role is more evident for myeloperoxidase-specific ANCA than for PR3-specific ANCA. Several controlled trials have led to an evidence-based approach for the treatment of ANCA-associated vasculitis, and further studies, based on new insights into pathogenesis, are in progress.

Anti-neutrophil Cytoplasmic Antibody MPO-ANCA related with Disease Activity of Vasculitis

Myeloperoxidase (MPO)-specific anti-neutrophil cytoplasmic antibodies (MPO-ANCA) are involved in the development of vasculitis microscopic polyangiitis, a systemic vasculitis etc. We have showed a correlation of MPO-ANCA epitopes in vasculitis concerning contribution of N and C terminus of MPO to severity of the diseases. On the other hand, a role of activated neutrophils in inflammatory nephritis renal lesions using SCG/Kj mice. In the phase of nephritis with a low grade of proteinuria, the spontaneous release of MPO from peripheral neutrophils increased, indicating that neutrophils are activated and contribute to the development of active crescentic lesions in SCG/Kj mice. In addition, we have investigated that mice having CADS/CAWS-induced vasculitis also are good model animals for the analysis of the production of MPO-ANCA. Furthermore, we have clarified that MPO is a major antigen for MPO-ANCA production using MPO knock mice.

Development of Microscopic Polyangiitis in Patients with Chronic Airway Disease

Microscopic polyangiitis (MPA) is a rare systemic vasculitis syndrome, which is often accompanied by positive myeloperoxidase-specific antineutrophil cytoplasmic antibody (MPO-ANCA). While pulmonary involvement of MPA consists mainly of diffuse alveolar hemorrhage and interstitial pneumonia, bronchiectasis has been reported as a pulmonary lesion in association with MPA. To investigate the clinical features of patients with MPA, focusing on the presence or the absence of preceding chronic airway diseases (CAD), we conducted a retrospective observational study of 26 patients in the last 13 years at Saga University Hospital. The clinical records and radiologic chest examinations were reviewed retrospectively. Pulmonary manifestations were alveolar hemorrhage in 3 patients (12%) and interstitial pneumonia in 5 (19%). Bronchiectasis, defined by the findings of chest radiograph and computed tomography, was found in 9 patients (35%). Four patients (15%) with bronchiectasis and one patient (4%) with chronic bronchitis had experienced chronic bronchial suppuration prior to the onset of MPA. Ten patients were classified as having chronic airway disease (CAD) before the onset of MPA. MPO-ANCA tended to be lower in the CAD group than in the non-CAD group. None of the patients in the CAD group had pulmonary hemorrhage or interstitial pneumonia. Only one patient (10%) in the CAD group died within 90 days of the onset of MPA, while 7 (43.8%) of the non-CAD group died. Our study suggests that MPA may result in part from CAD and that the clinical course of MPA with CAD may be different from MPA without CAD.

Epitope analysis of myeloperoxidase-specific antineutrophil cytoplasmic autoantibodies (MPO-ANCA) in childhood onset Graves’ disease treated with propylthiouracil

This study aimed to elucidate the relationship between epitope profiles and clinical manifestations of patients with myeloperoxidase antineutrophil cytoplasmic autoantibodies-(MPO-ANCA) positive childhood onset Graves' disease treated with propylthiouracil (PTU). Sixteen patients were studied. The patients were grouped into ten without clinical vasculitis and nephritis (non-vasculitis group) and six with biopsy-proven pauci-immune necrotizing crescentic glomerulonephritis (vasculitis group). Epitope analysis was performed on serum samples by an enzyme-linked immunosorbent assay (ELISA) using a panel of recombinant deletion mutants of MPO. The high frequency sites were region upstream of Met341 (Ha region) near the N-terminus of the heavy chain, and regions downstream of Gly598 (Hf and Hg regions) near the C-terminus. Most patients in the non-vasculitis group had polyclonal MPO-ANCA recognizing both the above linear sites and other epitope sites of the heavy chain of MPO. Only one of ten patients in the non-vasculitis group, and four of six patients in the vasculitis group had MPO-ANCA recognizing only the linear sites of the heavy chain of the MPO molecule (Ha, Hf and/or Hg). Of the four patients in the vasculitis group, two had nephritis, like rapidly progressive glomerulonephritis and one had alveolar hemorrhage. These findings suggest that most patients with childhood onset Graves' disease treated with PTU who manifest no vasculitis have polyclonal MPO-ANCA recognizing both the linear and other epitope sites of the heavy chain of MPO. However, some patients who develop nephritis have MPO-ANCA recognizing only the linear sites of the heavy chain of MPO. This clonality of MPO-ANCA may be a risk factor that induces clinical vasculitis and nephritis in patients treated with PTU. Therefore, patients exposed to PTU should be monitored for MPO-ANCA level and epitopes.