Publications by authors named "Utano Tomaru"

102 Publications

Elevated Myeloperoxidase-DNA Complex Levels in Sera of Patients with IgA Vasculitis.

Pathobiology 2021 Nov 23:1-6. Epub 2021 Nov 23.

Department of Dermatology, St. Marianna University School of Medicine, Kawasaki, Japan.

Introduction: IgA vasculitis is a systemic disease that results from the entrapment of circulating IgA-containing immune complexes in small-vessel walls in the skin, kidneys, and gastrointestinal tract. An excessive formation of neutrophil extracellular traps (NETs) is involved in the pathogenesis of vasculitis, especially in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. This study aimed to clarify whether NETs are implicated in IgA vasculitis.

Methods: Twenty-two patients with IgA vasculitis and 4 healthy volunteers were enrolled in this study. Serum levels of myeloperoxidase (MPO)-DNA complex, a fragment derived from NETs, were determined by enzyme-linked immunosorbent assay (ELISA), and the association between MPO-DNA complex levels and clinical parameters was examined. The presence of the ANCA was also assessed by ELISA specific for MPO and proteinase 3 (PR3) and indirect immunofluorescence (IIF), followed by assessing the differences in clinical parameters with and without the ANCA.

Results: Serum MPO-DNA complex levels were significantly higher in patients with IgA vasculitis than those in healthy controls. A significant positive correlation between the serum MPO-DNA complex and IgA levels was noted. Interestingly, 63.6% of IgA vasculitis patients were ANCA-positive in IIF with an atypical pattern, whereas neither MPO-ANCA nor PR3-ANCA was detected by ELISA. These findings indicated that some IgA vasculitis patients possessed the so called minor ANCA. Serum IgA and MPO-DNA complex levels and the frequency of hematuria in the minor ANCA-positive group were significantly higher than in the minor ANCA-negative group.

Conclusion: The collective findings suggested that NETs are certainly involved in the pathogenesis of IgA vasculitis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000519869DOI Listing
November 2021

Neutrophil fixation protocols suitable for substrates to detect anti-neutrophil cytoplasmic antibodies by indirect immunofluorescence.

Pathol Res Pract 2021 Oct 21;228:153661. Epub 2021 Oct 21.

Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Japan. Electronic address:

Anti-neutrophil cytoplasmic antibodies (ANCAs) are autoantibodies that recognize neutrophil cytoplasmic antigens. The major ANCA antigens are myeloperoxidase and proteinase 3. Necrotizing small vessel vasculitis accompanied by ANCA production is called ANCA-associated vasculitis (AAV). In addition to AAV, ANCA is sometimes produced in patients with connective tissue diseases, such as systemic lupus erythematosus, and inflammatory bowel diseases. Indirect immunofluorescence (IIF) and enzyme immunoassay (EIA) have been used to detect ANCAs. Recently, the accuracy of EIA has improved and it has become the gold standard for ANCA detection. However, IIF does not lose its role in ANCA detection because EIA cannot detect ANCAs that recognize antigens other than those coated on the plate. For IIF, neutrophil substrates prepared with two different fixations, namely, ethanol fixation and formalin fixation, are used. There is a recommended protocol for ethanol fixation but not for formalin fixation. This study prepared neutrophil substrates according to the recommended protocol for ethanol fixation and protocols in the literature and original protocols for formalin fixation and then examined ANCA specificity and how storage period would influence the number of cells, antigen distribution, and antigenicity of the substrates. As a result, the number of cells and antigen distribution did not change after storage for up to 2 months regardless of fixation protocols, whereas a time-dependent decline in ANCA antigenicity and a fixation protocol-dependent difference in ANCA specificity were observed. How neutrophils are fixed on the glass slide needs to be checked upon evaluation of ANCAs by IIF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.prp.2021.153661DOI Listing
October 2021

A case of radio-insensitive SMARCA4-deficient thoracic undifferentiated carcinoma with severe right heart failure.

Respir Med Case Rep 2021 18;32:101364. Epub 2021 Feb 18.

Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, 060-8638, Japan.

SMARCA4-deficient thoracic sarcomatoid tumors were characterized by inactivating mutations of SMARCA4 and often found in the chest of young and middle-aged males with a smoking history. Recently, SMARCA4-deficient thoracic sarcomatoid tumors were reported to represent primarily smoking-associated undifferentiated/de-differentiated carcinomas rather than primary thoracic sarcomas. The main complication of this tumor is compression of the respiratory tract and/or blood vessels. A 39-year-old man presented with a 2-month history of fever and dyspnea. Computed tomography revealed a mediastinal tumor invading the right and left pulmonary arteries. Because of severe right heart failure, we considered him ineligible for bronchoscopy. We scheduled palliative irradiation with 40 Gy/20 Fr to improve hemodynamics and perform endobronchial ultrasound transbronchial needle aspiration later. However, irradiation was ineffective, and his general condition deteriorated quickly and he died after a 7-week hospitalization. An autopsy revealed that the diagnosis was SMARCA4-deficient thoracic undifferentiated carcinoma. It has been reported that this tumor is insensitive to radiotherapy and there were some cases which responded to an immune checkpoint inhibitor. Therefore, when caring for patients with mediastinal tumors that invade and compress the trachea and large vessels, it is important to consider this tumor as a differential diagnosis and try to make a pathological diagnosis as soon as possible.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.rmcr.2021.101364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906892PMC
February 2021

RNase in the saliva can affect the detection of severe acute respiratory syndrome coronavirus 2 by real-time one-step polymerase chain reaction using saliva samples.

Pathol Res Pract 2021 Apr 16;220:153381. Epub 2021 Feb 16.

Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Sapporo, Japan. Electronic address:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a single-stranded RNA virus that causes coronavirus disease 2019, which spread worldwide immediately after the first patient infected with this virus was discovered in Wuhan, China, in December 2019. Currently, polymerase chain reaction (PCR) specimens for the detection of SARS-CoV-2 include saliva, nasopharyngeal swabs, and lower respiratory tract-derived materials such as sputum. Initially, nasopharyngeal swab specimens were applied mainly to the PCR detection of SARS-CoV-2. There was a risk of infection to healthcare workers due to coughing or sneezing by the subjects at the time of sample collection. In contrast, saliva specimens have a low risk of droplet infection and are easy to collect, and their application to PCR testing has been promoted. In this study, we have determined the detection limit of SARS-CoV-2 in saliva samples and examined the effects of storage temperature and storage time of saliva samples on the PCR detection results. As a result, 5 × 10 copies of SARS-CoV-2 could be detected in 1 mL phosphate-buffered saline, whereas 5 × 10 copies of SARS-CoV-2 were needed in 1 mL saliva to detect the virus by real-time one-step PCR. Interestingly, SARS-CoV-2 (5 × 10 copies/mL) could be detected in saliva supplemented with an RNase inhibitor. Concerning the saliva samples supplemented with an RNase inhibitor, the optimal temperature for sample storage was -20 °C, and PCR detection was maintained within 48 h without problems under these conditions. These finding suggest that RNase in the saliva can affect the detection of SARS-CoV-2 by PCR using saliva samples.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.prp.2021.153381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885625PMC
April 2021

Anti-phosphatidylserine/prothrombin complex antibodies in patients with cutaneous vasculitis: Possible involvement in the pathogenesis.

J Dermatol 2021 May 18;48(5):703-706. Epub 2021 Feb 18.

Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Sapporo, Japan.

We assessed the IgG and IgM prevalence of anti-phosphatidylserine/prothrombin complex (aPS/PT) antibodies (Abs) in patients with vasculitis using a novel commercial ELISA kit. To examine whether aPS/PT Abs were involved in the pathogenesis of cutaneous vasculitis, inbred wild-type rats were intravenously administered with a rat IgM class aPS/PT monoclonal Ab established previously or with rat immunoglobulins as controls. To express PS on the surface of vascular endothelium, these rats were given a subcutaneous injection of cell-free histones in advance. Serum IgM aPS/PT Ab levels were elevated in patients with systemic vasculitis with skin involvement and cutaneous arteritis compared to those in patients with systemic vasculitis without skin involvement and healthy controls. There was no significant difference in the serum levels of IgG aPS/PT Abs between the patients and healthy controls. Correspondingly, inbred wild-type rats intravenously administered with the aPS/PT monoclonal IgM Ab after appropriate priming-subcutaneous histone injection developed cutaneous vasculitis. Some rats given rat IgM instead of the aPS/PT monoclonal Ab also developed cutaneous vasculitis, whereas vasculitis did not occur in rats given IgG or only priming by histones. We suggested that IgM aPS/PT Abs could be involved in the pathogenesis of cutaneous vasculitis based on these findings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1346-8138.15810DOI Listing
May 2021

Decreased Proteasomal Function Induces Neuronal Loss and Memory Impairment.

Am J Pathol 2021 01;191(1):144-156

Department of Pathology, Hokkaido University, Sapporo, Japan.

Alzheimer disease (AD) is a progressive neurodegenerative disorder and the most common type of dementia worldwide. There is considerable evidence of age-related disruption of proteostasis being responsible for the development of AD. The proteasome is a multicatalytic enzyme complex that degrades both normal and damaged proteins, and an age-related decline in its activity has been implicated in age-related pathologies. Although proteasomal dysfunction is assumed to be a key AD hallmark, it remains unclear whether its role in disease onset is causative or secondary. In this study, we demonstrate that mice with proteasomal dysfunction exhibited memory impairment with associated neuronal loss, accumulation of phosphorylated tau, and activation of endoplasmic reticulum (ER) stress-related apoptosis pathways. Impaired proteasomal activity also activated ER stress-related apoptosis pathways in HT-22, a murine hippocampal neuronal cell line. HT-22 cell death, caused by proteasomal inhibition, was prevented by an inhibitor of c-Jun N-terminal kinase, an ER stress-related molecule. Collective evidence suggests that impaired proteasomal activity alters proteostasis, and subsequent ER stress-mediated pathways play pivotal roles in neuronal loss. Because aging decreases proteasomal function, age-related impairment of proteasomes may be involved in the development and progression of AD in elderly patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajpath.2020.10.004DOI Listing
January 2021

Expression of the immunoproteasome subunit β5i in non-small cell lung carcinomas.

J Clin Pathol 2021 May 17;74(5):300-306. Epub 2020 Sep 17.

Department of Pathology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

Aim: The immunoproteasome is a specific proteasome isoform whose proteolytic activity enhances the generation of antigenic peptides to be presented by major histocompatibility complex class I molecules to CD8 T cells. Physiologically, it is expressed abundantly in immune cells and is induced in somatic cells by cytokines, especially interferon-γ. Recently, variable expression of immunoproteasomes has been demonstrated in different types of cancers. However, the clinical significance of immunoproteasome expression in malignant tumours is poorly understood. In this study, we performed clinicopathological evaluation of immunoproteasome subunit β5i in non-small cell lung carcinomas (NSCLCs).

Methods: Tumour tissues were collected from 155 patients with NSCLCs, and immunohistochemical analysis for β5i was performed in relation to the prognosis of patients.

Results: High expression of β5i was found in about 20% of all NSCLCs and was found significantly more frequently (40%) in the adenocarcinoma subset. High expression of β5i was associated with a better 5-year relative survival rate in patients with pStage I to II adenocarcinoma and was also a significant and independent favourable prognostic factor in adenocarcinoma patients. In addition, when we performed in vitro analysis using NSCLC cell lines, combined treatment with the immunoproteasome-specific inhibitor ONX0914 and the proteasome inhibitor MG132 enhanced cell death in β5i-expressing NSCLC cell lines.

Conclusion: The expression of immunoproteasome can be explored as both a prognostic factor and a potential therapeutic target in NSCLCs. Since immunoproteasomes have crucial role in the antigen presentation, further studies may help to provide essential knowledge for therapeutic strategies in anticancer immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jclinpath-2020-206618DOI Listing
May 2021

Association of Neutrophil Extracellular Traps with the Development of Idiopathic Osteonecrosis of the Femoral Head.

Am J Pathol 2020 11 21;190(11):2282-2289. Epub 2020 Jul 21.

Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Sapporo, Japan. Electronic address:

Idiopathic osteonecrosis of the femoral head (ONFH) is defined as necrosis of osteocytes due to a non-traumatic ischemia of the femoral head. Iatrogenic glucocorticoid administration and habitual alcohol intake are regarded as risk factors. It has been suggested that glucocorticoid-induced activation of platelets contributes to the local blood flow disturbance of the femoral head. Both activated platelets and alcohol can induce neutrophil extracellular traps (NETs). To determine the association of NETs with the development of idiopathic ONFH, surgically resected femoral heads of patients with idiopathic ONFH and osteoarthritis were assessed for existence of NET-forming neutrophils by immunofluorescence staining. NET-forming neutrophils were present in small vessels surrounding the femoral head of patients with idiopathic ONFH but not osteoarthritis. Moreover, Wistar-Kyoto rats were intravenously injected with NET-forming neutrophils or neutrophils without NET induction, and then the ischemic state of the tissue around the femoral head was evaluated by immunohistochemistry for hypoxia-inducible factor-1α. NET-forming neutrophils circulated into the tissue around the femoral head, and hypoxia-inducible factor-1α expression in the tissue was higher compared with that of rats intravenously administered with neutrophils without NET induction. Furthermore, ischemic change of osteocytes was observed in the femoral head of rats given an i.v. injection of NET-forming neutrophils. The collective findings suggest that NETs are possibly associated with the development of idiopathic ONFH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajpath.2020.07.008DOI Listing
November 2020

Expression of cathepsins B, D and K in thymic epithelial tumours.

J Clin Pathol 2021 Feb 28;74(2):84-90. Epub 2020 May 28.

Pathology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

Aim: Cathepsins are proteases that regulate a wide range of physiological processes, including protein turnover, cell signalling and antigen presentation. Recent studies have shown that cathepsins are highly upregulated in many types of tumours. Of the 15 cathepsins in humans, cathepsins V and S are abundantly expressed in the thymus, and we previously showed that the immunostaining of these cathepsins could serve as diagnostic markers for thymic epithelial tumours. However, little is known about the expression of other cathepsins in thymic epithelial tumours. To determine the diagnostic implications of cathepsins, we performed immunohistochemical analysis of cathepsin B (CTB), cathepsin D (CTD) and cathepsin K (CTK), all of which have been reported to correlate with the progression of squamous cell carcinoma.

Methods: The association between cathepsin expression and clinicopathological features was evaluated in 122 cases of thymoma and thymic carcinoma.

Results: CTB and CTD were frequently expressed in type A and type AB thymomas. In contrast, CTB and CTD were significantly less common in type B thymomas than in type A or AB thymomas. In type AB thymomas, the expression of CTB correlated with histological features, and was found predominantly in the type A component. Notably, CTK was expressed most commonly in thymic carcinomas, and patients who died of the disease showed increased expression of CTK.

Conclusions: The expression of CTB and CTD correlated with the histological subtype of thymoma. In addition, the expression of CTK appears to be useful for the diagnosis of thymic carcinomas and as a prognostic marker.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jclinpath-2020-206551DOI Listing
February 2021

Fluvastatin prevents the development of arthritis in env-pX rats via up-regulation of Rho GTPase-activating protein 12.

Exp Mol Pathol 2020 08 16;115:104454. Epub 2020 May 16.

Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Sapporo, Japan. Electronic address:

The pleiotropic effects of statins, including an antiarthritic potential, have been noted. This study aimed to determine the efficacy of statins on rheumatoid arthritis (RA) and clarify how statins affect its pathogenesis. Fluvastatin (500 μg/kg/day) or vehicle was given per os to env-pX rats, which carry the human T-cell leukemia virus type I env-pX gene and spontaneously develop destructive arthritis mimicking RA, for 30 days. Blood sampling and ultrasonography (US) of the ankle joints were conducted on days 0, 10, 20, and 30. On day 30, all rats were euthanized, and the ankle joints were subjected to histological analysis. To clarify how fluvastatin affects the pathogenesis of RA, comprehensive serum exosomal microRNA (miRNA) analysis was performed. Gene expression in the primary culture of synovial fibroblasts derived from arthritic rat and human and non-arthritic rat periarticular tissues was determined quantitatively by real-time reverse transcription-polymerase chain reaction (RT-PCR). As a result, the development of arthritis in env-pX rats was significantly suppressed by fluvastatin, which was evident from the viewpoints of serology, US imaging, and histology. Comprehensive serum exosomal miRNA analysis suggested that the expression of Rho GTPase-activating protein 12 (Arhgap12) was decreased in arthritic env-pX rats but increased with the administration of fluvastatin. Corresponding results were obtained by quantitative RT- PCR using primary culture of synovial fibroblasts. The collective findings suggest that fluvastatin prevents the development of arthritis in env-pX rats via the up-regulation of ARHGAP12. This study suggests that ARHGAP12 can be a possible therapeutic target of RA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yexmp.2020.104454DOI Listing
August 2020

Relationship between lysosomal-associated membrane protein-2 and anti-phosphatidylserine/prothrombin complex antibody in the pathogenesis of cutaneous vasculitis.

Clin Exp Rheumatol 2020 Mar-Apr;38 Suppl 124(2):161-165. Epub 2020 Jan 27.

Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Sapporo, Japan.

Objectives: We investigated the relationship between lysosomal-associated membrane protein-2 (LAMP-2) and anti-phosphatidylserine/prothrombin (PS/PT) antibody in the pathogenesis of cutaneous vasculitis.

Methods: Cell surface LAMP-2 expression of human neutrophils was measured using flow cytometry. Twenty inbred wild-type Wistar-King-Aptekman-Hokudai (WKAH) rats were divided into four groups: Group 1, rabbit IgG injection only as negative control (n=5); Group 2, both histone and rabbit IgG injection (n=5); Group 3, anti-LAMP-2 antibody injection only (n=5); and Group 4, both histone and anti-LAMP-2 antibody injection (n=5). Ten WKAH rats were divided into two groups: Group A, histone, anti-PS/PT antibody, and anti-LAMP-2 antibody injection (n=5), and Group B, histone, anti-PS/PT antibody, and rabbit IgG injection as control (n=5).

Results: LAMP-2 expression on human neutrophils was induced by cell-free histone exposure in a dose- and time-dependent manner. Histopathological examination revealed the recruitment of neutrophils in cutaneous small vessels in all Group 4 rats. These observations were not evident in systemic organs other than the skin. LAMP-2 expression on the surface of vascular endothelial cells was evident in Group 2, exclusively in the skin, but not in Group 1. Thrombi were detected in various organs in all Groups A and B rats. However, no apparent thrombi were observed in the skin.

Conclusions: Anti-PS/PT and anti-LAMP-2 antibodies are responsible for independent effector mechanisms in the rats given intravenous injection of cell-free histones. We considered that undetermined factors other than cell-free histones could be required for the induction of cutaneous vasculitis by anti-PS/PT and anti-LAMP-2 antibodies.
View Article and Find Full Text PDF

Download full-text PDF

Source
September 2020

A histopathological report of a 16-year-old male with peripheral pulmonary artery stenosis and Moyamoya disease with a homozygous mutation.

Respir Med Case Rep 2020 14;29:100977. Epub 2019 Dec 14.

First Department of Medicine, Hokkaido University School of Medicine, North 15, West 7, Kita-ku, Sapporo, 060-8638, Japan.

Peripheral pulmonary artery stenosis (PPAS) is a rare pulmonary vasculopathy characterized by multiple stenoses and obstructions in the peripheral pulmonary arteries. PPAS often develops in children with congenital diseases such as Williams syndrome and Alagille syndrome; however, recent studies have reported PPAS cases in adults with Moyamoya disease (MMD). Recent genetic studies have demonstrated that ring finger protein 213 (RNF213) is a susceptibility gene for MMD. However, the pathophysiology of combined PPAS and MMD and the relationship between the two diseases remain largely unknown. Here we report a case of PPAS in a 16-year-old male, with a history of MMD, who died suddenly at 24. An autopsy was performed, and remarkable pathological changes were identified in the pulmonary arteries and in other arteries. Furthermore, genetic analysis revealed that the patient had a homozygous c.14576G > A (p.R4859K) mutation in RNF213. This is the first report to demonstrate the histopathology of systemic arteriopathy in a case with MMD and PPAS with a confirmed homozygous RNF213 mutation. We also review immunohistochemical data from the case and discuss how RNF213 mutation could have resulted in the observed vascular abnormalities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.rmcr.2019.100977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938952PMC
December 2019

Recombinant thrombomodulin ameliorates autoimmune vasculitis via immune response regulation and tissue injury protection.

J Autoimmun 2020 03 26;108:102390. Epub 2019 Dec 26.

Faculty of Health Sciences, Hokkaido University, Sapporo, Japan.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is characterized by necrotizing vasculitis with the presence of pathogenic ANCA. ANCA can potentially cause neutrophil activation and induce neutrophil extracellular traps (NETs), resulting in endothelial damage as well as activation of autoreactive B cells and alternative complement pathway. Recombinant thrombomodulin (rTM) protects the endothelium from vascular injury during disseminated intravascular coagulation, thus we hypothesized that rTM ameliorates necrotizing vasculitis in AAV. In this study, rTM was administered in an experimental AAV rat model. Treatment of experimental AAV rats with rTM improved pulmonary hemorrhage and glomerulonephritis, with a suppression of ANCA production and NETs formation. In addition, in vitro experiments showed that rTM bound to neutrophils via Mac-1 (macrophage-1 antigen) and inhibited ANCA-induced NETs formation accompanied by a suppression of histone citrullination, leading to a protection of the endothelium from NETs toxicity. Additionally, rTM affected lymphocytes leading to the inhibition of pro-inflammatory cytokine/chemokin in PBMC during the antibody production process, which might indirectly be involved in the reduction of pathogenic ANCA. Our data revealed that the rTM could ameliorate autoimmune vasculitis through a combination of different biological mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaut.2019.102390DOI Listing
March 2020

Native myeloperoxidase is required to make the experimental vasculitis model.

Arthritis Res Ther 2019 12 21;21(1):296. Epub 2019 Dec 21.

Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Kita-12, Nishi-5, Kita-ku, Sapporo, 0600812, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13075-019-2084-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925855PMC
December 2019

Detection of Increased Vascular Signal in Arthritis-Prone Rats Without Joint Swelling Using Superb Microvascular Imaging Ultrasonography.

Ultrasound Med Biol 2019 08 11;45(8):2086-2093. Epub 2019 May 11.

Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Kita-ku, Sapporo, Japan. Electronic address:

This study aimed to determine whether ultrasonography (US) can detect increased vascular signal in the synovial tissue before overt synovitis in rheumatoid arthritis (RA). Env-pX rats that spontaneously develop RA-like synovitis were used. Ankle joints of 15 pre-morbid env-pX rats were observed with power Doppler and superb microvascular imaging (SMI) using an ultrahigh-frequency (8-24 MHz) probe. Signal values were counted as the number of pixels. The total number of vessels and vessel area in the synovial tissue were histologically evaluated. Dilated vessels were determined from the mean value of synovial vessels in three wild-type rats. In all env-pX rats, apparent synovial proliferation was not observed. However, vasodilation was evident. Only SMI values were significantly correlated with the number of dilated vessels (r = 0.585, p = 0.022) but not with the total number of vessels. US with SMI using ultrahigh-frequency probe can detect increased vascular signal in the synovial tissue of arthritis-prone rats.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ultrasmedbio.2019.04.002DOI Listing
August 2019

Pharmaceutical immunoglobulins reduce neutrophil extracellular trap formation and ameliorate the development of MPO-ANCA-associated vasculitis.

Mod Rheumatol 2020 May 12;30(3):544-550. Epub 2019 Apr 12.

Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Sapporo, Japan.

Intravenous immunoglobulin (IVIG) therapy is effective against some autoimmune diseases. We examined the effects of pharmaceutical immunoglobulins on the development of MPO-ANCA-associated vasculitis (MPO-AAV). Peripheral blood neutrophils were pretreated with 5 mg/ml sulfo-immunoglobulins (IVIG-S) and then exposed to 100 nM phorbol myristate acetate (PMA). Thereafter, neutrophil extracellular traps (NETs) were detected by flow cytometry. Next, Wistar-Kyoto rats were given oral administration of 10 mg/kg/day propylthiouracil for 28 days and intraperitoneal (i.p.) injection of 1 μg PMA on days 0 and 7. These rats were divided into two groups: Group 1 with i.p. injection of 400 mg/kg IVIG-S on days 8-12 and Group 2 with vehicle similarly. ANCA titers were chronologically determined by indirect immunofluorescence. On day 28, all rats were killed to examine NET formation in the peritoneum and the development of AAV. IVIG-S significantly inhibited NET formation induced by PMA . NET amounts in the peritoneum in Group 1 were significantly smaller than in Group 2, and ANCA titers in Group 1 were significantly lower than in Group 2. The degree of pulmonary hemorrhage in Group 1 was also smaller than in Group 2. IVIG-S reduce NET formation and ameliorate the development of MPO-AAV.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14397595.2019.1602292DOI Listing
May 2020

The presence of anti-neutrophil extracellular trap antibody in patients with microscopic polyangiitis.

Rheumatology (Oxford) 2019 07;58(7):1293-1298

Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Sapporo, Japan.

Objective: Although ANCA is the major autoantibody in patients with ANCA-associated vasculitis, previous studies have suggested the presence of anti-neutrophil extracellular trap (NET) antibody in patients with microscopic polyangiitis (MPA), one type of ANCA-associated vasculitis. In this study, we aimed to determine the prevalence and pathogenic role of anti-NET antibody (ANETA) in MPA.

Methods: We examined the presence or absence of ANETA in sera obtained from 19 MPA patients by indirect immunofluorescence. We compared the clinical parameters, including age, sex, MPO-ANCA, creatinine, CRP, MPO-DNA complexes and vasculitis activity, in ANETA-positive and ANETA-negative MPA patients. We investigated the serum NET induction and degradation abilities of ANETA-positive and ANETA-negative MPA patients with reference to healthy controls (n = 8). Furthermore, we assessed the relationship between ANETA and the effect of IgG depletion on the serum NET degradation ability.

Results: ANETA was present in 10 of the 19 MPA patients. There was no significant difference in the clinical parameters in ANCA-positive and ANCA-negative MPA patients. Although the NET induction ability was higher and the NET degradation ability was lower in MPA sera than those in healthy controls, these abilities were not different between ANETA-positive and ANETA-negative MPA sera. Interestingly, the NET degradation ability in some sera with ANETA was markedly increased by IgG depletion.

Conclusion: Some MPA patients produce ANETA and some ANETA possess an inhibitory function against the serum NET degradation ability. Although further studies are needed, ANETA is worthy of attention in order to understand the pathophysiology of MPA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/rheumatology/kez089DOI Listing
July 2019

Epitope recognized by anti-glomerular basement membrane (GBM) antibody in a patient with repeated relapse of anti-GBM disease.

Exp Mol Pathol 2019 04 25;107:165-170. Epub 2019 Feb 25.

Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Sapporo, Japan. Electronic address:

The major epitopes recognized by autoantibodies in anti-glomerular basement membrane (GBM) disease are found in the α3-subunit non-collagenous domain of type IV collagen [α3(IV)NC1], which is present in the glomerular and alveolar basement membranes. These epitopes are structurally cryptic, owing to the hexamer formation of the non-collagenous domain of α3, α4, and α5 subunits and are expressed by the dissociation of the hexamer. Anti-GBM disease usually manifests as a single attack (SA), and we rarely see patients who repeatedly relapse. We recently treated a patient with anti-GBM disease who exhibited repeated relapse (RR). Here, we conducted immunohistochemistry of formalin-fixed paraffin-embedded normal kidney sections and immunoblotting using recombinant human α3(IV)NC1 to compare the epitopes recognized by anti-GBM antibodies in the RR patient and SA patients. Although a clear staining of GBM especially in the connecting basement membrane of Bowman's capsule was observed when IgGs of SA patients were used as primary antibodies, such staining was not obtained when IgG of the RR patient was employed. In immunoblotting of α3(IV)NC1 using the IgG of the RR patient as a primary antibody, an 18-kDa band was detected besides the 56.8-kDa band corresponding to the whole-size α3(IV)NC1. Whereas the 56.8-kDa band disappeared after digestion of the recombinant α3(IV)NC1 by protease, the 18-kDa band remained. Furthermore, the 18-kDa band was not detected by a commercially available anti-α3(IV)NC1 monoclonal antibody. These findings suggest that the IgG of the RR patient recognizes the epitope distinct from that recognized by the anti-α3(IV)NC1 monoclonal antibody.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yexmp.2019.02.005DOI Listing
April 2019

Formation and Disordered Degradation of Neutrophil Extracellular Traps in Necrotizing Lesions of Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis.

Am J Pathol 2019 04 21;189(4):839-846. Epub 2019 Jan 21.

Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Sapporo, Japan. Electronic address:

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is characterized by the production of ANCAs and systemic necrotizing vasculitis in small vessels. Disordered regulation of neutrophil extracellular traps (NETs) is critically involved in the pathogenesis of AAV. NETs are web-like DNA decorated with antimicrobial proteins; they are extruded from activated neutrophils. The principal degradation factor of NETs in vivo is DNase I; however, NETs resistant to DNase I can persist in tissues and can lead to the production of ANCAs. Deposition of NETs has been demonstrated in glomerular crescents and necrotizing vasculitis in AAV. Here, the amount of NETs in formalin-fixed, paraffin-embedded tissue sections was examined, and the results for AAV were compared with the results for diseases that should be distinguished from AAV. NETs were more abundant in necrotizing vasculitis of AAV than in non-ANCA-associated vasculitis, or in granulomatous angiitis. Pulmonary granulomas in AAV and non-ANCA-associated diseases were further studied. The amount of NETs was significantly greater in necrotizing granulomas of AAV than in granulomas of sarcoidosis without necrosis. Although NETs were formed in necrotizing granulomas of tuberculosis equivalently to those formed in AAV, they were more susceptible to degradation by DNase I than were NETs in AAV. The formation and disordered degradation of NETs in necrotizing lesions are characteristics of AAV and are possibly related to its pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajpath.2019.01.007DOI Listing
April 2019

Author Correction: Pathogenesis and therapeutic interventions for ANCA-associated vasculitis.

Nat Rev Rheumatol 2019 Feb;15(2):123

Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Sapporo, Japan.

In the originally published online version of this article there were errors in the Supplementary Information. All three Supplementary Tables had incorrectly numbered references. These errors have now been corrected in the HTML and PDF versions of the manuscript.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41584-019-0168-zDOI Listing
February 2019

Restricted Expression of the Thymoproteasome Is Required for Thymic Selection and Peripheral Homeostasis of CD8 T Cells.

Cell Rep 2019 01;26(3):639-651.e2

Department of Pathology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.

The thymoproteasome subunit β5t is specifically expressed in cortical thymic epithelial cells (TECs) and generates unique peptides to support positive selection. In this study, using a mouse model ubiquitously expressing β5t, we showed that aberrant expression of self-peptides generated by β5t affects CD8 T cell homeostasis, including thymic selection and maintenance of the peripheral naive pool of CD8 T cells. In mice in which β5t was expressed both in cortical and medullary TECs, the abundance of CD8 lineage thymocytes was reduced, and extra-thymic expression of β5t caused accumulation of CD8 T cells with the memory or exhausted phenotype and induced autoreactive T cell responses. We found that thymoproteasomes are essential for positive selection but that the subsequent change in peptide repertoire in the medulla is also crucial for thymic selection and that β5t-derived peptide must be confined to the thymus to avoid autoimmunity in peripheral tissues.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2018.12.078DOI Listing
January 2019

The Diagnostic and Clinical Utility of the Myeloperoxidase-DNA Complex as a Biomarker in Otitis Media With Antineutrophil Cytoplasmic Antibody-associated Vasculitis.

Otol Neurotol 2019 02;40(2):e99-e106

Department of Otolaryngology - Head and Neck Surgery.

Objective: This prospective study aimed to evaluate the diagnostic and clinical utility of the myeloperoxidase (MPO)-DNA complex as a NETosis-derived product in the middle ear fluid of patients with otitis media with antineutrophil cytoplasmic antibody-associated vasculitis (OMAAV).

Study Design: Prospective study.

Setting: Tertiary referral center.

Patients: Twenty-two patients diagnosed with OMAAV.

Intervention: Collection of the fluid samples from middle ear.

Main Outcome Measure: The levels of the MPO-DNA complex in the fluid samples were quantified using an enzyme-linked immunosorbent assay.

Results: Patients with both systemic and localized forms of OMAAV showed significantly higher levels of the MPO-DNA complex compared to the controls (p < 0.001 and p = 0.002, respectively). In particular, they showed significantly higher levels of MPO-DNA complex compared to the controls, regardless of serum antineutrophil cytoplasmic antibody status (p < 0.001 and p < 0.001, respectively) or immunosuppressive therapy (p < 0.001 and p < 0.001, respectively) at the time of sampling. An optical density cutoff value of 0.16 at 405 nm according to the receiver operating characteristic curve showed a sensitivity of 86.4%, specificity of 95.5%, positive predictive value of 95.0% and negative predictive value of 87.5% for the diagnosis of OMAAV. Significant positive correlations were observed between the levels of MPO-DNA complex and the values for air conduction - (r = 0.49, p = 0.022) and bone conduction - pure tone average thresholds (r = 0.45, p = 0.035).

Conclusions: The detection and quantification of the MPO-DNA complex in the otitis media fluid may aid in providing a definite diagnosis as well as predicting the activity and severity of OMAAV.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MAO.0000000000002081DOI Listing
February 2019

Pathogenesis and therapeutic interventions for ANCA-associated vasculitis.

Nat Rev Rheumatol 2019 02;15(2):91-101

Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Sapporo, Japan.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) affects systemic small vessels and is accompanied by the presence of ANCAs in the serum. This disease entity includes microscopic polyangiitis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis and drug-induced AAV. Similar to other autoimmune diseases, AAV develops in patients with a predisposing genetic background who have been exposed to causative environmental factors. The mechanism by which ANCAs cause vasculitis involves ANCA-mediated excessive activation of neutrophils that subsequently release inflammatory cytokines, reactive oxygen species and lytic enzymes. In addition, this excessive activation of neutrophils by ANCAs induces formation of neutrophil extracellular traps (NETs). Although NETs are essential elements in innate immunity, excessive NET formation is harmful to small vessels. Moreover, NETs are involved not only in ANCA-mediated vascular injury but also in the production of ANCAs themselves. Therefore, a vicious cycle of NET formation and ANCA production is considered to be involved in the pathogenesis of AAV. In addition to this role of NETs in AAV, some other important discoveries have been made in the past few years. Incorporating these new insights into our understanding of the pathogenesis of AAV is needed to fully understand and ultimately overcome this disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41584-018-0145-yDOI Listing
February 2019

Detection of Autoreactive Type II NKT Cells: A Pilot Study of Comparison Between Healthy Individuals and Patients with Vasculitis.

Cytometry A 2018 11 25;93(11):1157-1164. Epub 2018 Sep 25.

Faculty of Health Sciences, Hokkaido University, Sapporo, Japan.

NKT cells are defined as T cells that recognize hydrophobic antigens presented by class I MHC-like molecules, including CD1d. Among CD1d-restricted NKT cells, type I and type II subsets have been noted. CD1d-restricted type I NKT cells are regarded as pro-inflammatory cells in general. On the contrary, accumulated evidence has demonstrated an anti-inflammatory property of CD1d-restricted type II NKT cells. In our earlier study using a rat model with vasculitis, we demonstrated the pro-inflammatory function of CD1d-restricted type II NKT cells and identified that one such cell recognized P of rat sterol carrier protein 2 (rSCP2 ), which appeared on vascular endothelial cells presented by CD1d. Based on this evidence, we attempted to detect human CD1d-restricted type II NKT cells in peripheral blood using hSCP2 , the human counterpart of rSCP2 together with a CD1d tetramer in flow cytometry. First, we determined the binding of hSCP2 to CD1d. Next, we detected CD3-positive hSCP2 -loaded CD1d (hSCP2 /CD1d) tetramer-binding cells in peripheral blood of healthy donors. The abundance of TGF-β-producing cells rather than TNF-α-producing cells in CD3-positive hSCP2 /CD1d tetramer-binding cells suggests the anti-inflammatory property of SCP2-loaded CD1d (SCP2/CD1d) tetramer-binding type II NKT cells in healthy individuals. Furthermore, we compared cytokine profile between healthy individuals and patients with vasculitis in a pilot study. Interestingly, the percentage of TGF-β-producing cells in SCP2/CD1d tetramer-binding type II NKT cells in vasculitic patients was significantly lower than that in healthy controls despite the greater number of these cells. Although further studies to clarify the mechanism and significance of this phenomenon are needed, SCP2/CD1d tetramer-binding type II NKT cells in peripheral blood should be examined in more detail to understand the pathophysiology of vasculitides in humans. © 2018 International Society for Advancement of Cytometry.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cyto.a.23618DOI Listing
November 2018

Clinicopathological significance of PSF3 expression in uterine endometrial carcinomas.

Hum Pathol 2018 10 21;80:104-112. Epub 2018 Jun 21.

Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.

PSF3 (Partner of SLD Five 3) is a member of the heterotetrameric complex termed GINS. Previous studies have shown that PSF3 is up-regulated in several cancers and is associated with tumor malignancy. However, the clinicopathological significance of PSF3 expression in endometrial lesions is still poorly understood. To investigate whether PSF3 could serve as a useful biomarker for endometrial carcinomas, we performed immunohistochemical analysis of PSF3 expression. In 155 cases of endometrial carcinomas (ECs), the mean tumor proportion score of PSF3 expression was 30.7% in G1 endometrioid carcinoma, 55.0% in G2 endometrioid carcinoma, 59.0% in G3 endometrioid carcinoma, and 58.9% in nonendometrioid carcinomas. In 25 cases of atypical hyperplasia, the mean tumor proportion score of PSF3 expression was significantly lower (10.4%). High expression of PSF3 was associated with more advanced pathologic T stage (P = .000), lymphatic invasion (P = .001), and poor clinical outcomes such as shorter relapse-free survival (P = .000) and overall survival (P = .001). When we compared the immunostaining of PSF3 and Ki-67, the proportions of PSF3-positive cells in tumor epithelial cells were comparable to those of Ki-67-positive cells. However, PSF3-positive cells were selectively found in tumor cells, whereas Ki-67-positive cells were also found in tumor stromal cells. These results demonstrated that PSF3 immunostaining was valuable as a histopathologic marker for differential diagnosis between atypical hyperplasia and ECs, for tumor histologic grading, and for determining a patient's prognosis. PSF3 may play a crucial role in tumor progression in EC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.humpath.2018.06.010DOI Listing
October 2018

Anti-neutrophil extracellular trap antibody in a patient with relapse of anti-neutrophil cytoplasmic antibody-associated vasculitis: a case report.

BMC Nephrol 2018 06 22;19(1):145. Epub 2018 Jun 22.

Faculty of Health Sciences, Hokkaido University, Kita-12, Nishi-5, Kita-ku, Sapporo, 0600812, Japan.

Background: Neutrophil extracellular traps (NETs) are web-like DNA decorated with antimicrobial proteins, such as myeloperoxidase (MPO), which are extruded from activated neutrophils. Although NETs are essential in innate immunity, an excessive formation of NETs has adverse effects, e.g., induction of anti-neutrophil cytoplasmic antibody (ANCA), to the hosts. Since ANCA can induce NET formation in the primed neutrophils, a positive feedback loop can be formed between NETs and ANCA, which is called "ANCA-NETs vicious cycle."

Case Presentation: A 79-year-old Japanese woman developed hydralazine-induced pauci-immune necrotizing crescentic glomerulonephritis with MPO-ANCA. Although the illness improved after cessation of hydralazine, MPO-ANCA-associated vasculitis relapsed 16 months later. Remission was achieved 5 months after beginning of administration of prednisone. In order to determine the involvement of ANCA-NETs vicious cycle in this patient, we examined NET degradation and induction activities in sera obtained at the disease onset (Serum A; MPO-ANCA, 107 IU/ml), at relapse (Serum B; MPO-ANCA, 195 IU/ml), at 3 months after treatment (Serum C; MPO-ANCA, 4.5 IU/ml), and at remission (Serum D; MPO-ANCA, 2.4 IU/ml). NET degradation activity was low in the all sera. NET induction activity was high in Sera A, B, and C but not in D. Additionally, we demonstrated the presence of anti-NET antibody (ANETA) in Sera B and C but not in A or D.

Conclusions: The collective findings suggest NET induction potential of ANETA in the present patient and that the ANETA could contribute to the enhancement of NETs resulting in amplification of the ANCA-NETs vicious cycle.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12882-018-0953-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013953PMC
June 2018

CD1d-Restricted Type II NKT Cells Reactive With Endogenous Hydrophobic Peptides.

Front Immunol 2018 15;9:548. Epub 2018 Mar 15.

Faculty of Health Sciences, Hokkaido University, Sapporo, Japan.

NKT cells belong to a distinct subset of T cells that recognize hydrophobic antigens presented by major histocompatibility complex class I-like molecules, such as CD1d. Because NKT cells stimulated by antigens can activate or suppress other immunocompetent cells through an immediate production of a large amount of cytokines, they are regarded as immunological modulators. CD1d-restricted NKT cells are classified into two subsets, namely, type I and type II. CD1d-restricted type I NKT cells express invariant T cell receptors (TCRs) and react with lipid antigens, including the marine sponge-derived glycolipid α-galactosylceramide. On the contrary, CD1d-restricted type II NKT cells recognize a wide variety of antigens, including glycolipids, phospholipids, and hydrophobic peptides, by their diverse TCRs. In this review, we focus particularly on CD1d-restricted type II NKT cells that recognize endogenous hydrophobic peptides presented by CD1d. Previous studies have demonstrated that CD1d-restricted type I NKT cells usually act as pro-inflammatory cells but sometimes behave as anti-inflammatory cells. It has been also demonstrated that CD1d-restricted type II NKT cells play opposite roles to CD1d-restricted type I NKT cells; thus, they function as anti-inflammatory or pro-inflammatory cells depending on the situation. In line with this, CD1d-restricted type II NKT cells that recognize type II collagen peptide have been demonstrated to act as anti-inflammatory cells in diverse inflammation-induction models in mice, whereas pro-inflammatory CD1d-restricted type II NKT cells reactive with sterol carrier protein 2 peptide have been demonstrated to be involved in the development of small vessel vasculitis in rats.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2018.00548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862807PMC
May 2019

Brain-derived neurotrophic factor induces angiogenin secretion and nuclear translocation in human umbilical vein endothelial cells.

Pathol Res Pract 2018 Apr 21;214(4):521-526. Epub 2018 Feb 21.

Faculty of Health Sciences, Hokkaido University, Sapporo, Japan. Electronic address:

Brain-derived neurotrophic factor (BDNF) is a well-known humoral protein that induces growth of neurons. Recent studies have suggested that BDNF could act as an angiogenesis inducer similar to vascular endothelial growth factor (VEGF). Angiogenin is a strong mediator of angiogenesis. It has particular characteristics both as a secreted protein and a transcription factor. After being incorporated into the cytoplasm, angiogenin is immediately transferred to the nucleus and then mediates the angiogenic effects of angiogenesis inducers, including VEGF. The aim of this study is to determine the association between BDNF and angiogenin. At first, we determined the secretion of angiogenin from human umbilical vein endothelial cells (HUVEC) induced by BDNF with enzyme-linked immunosorbent assay. Next, we determined BDNF-induced nuclear translocation of angiogenin by immunofluorescent staining. In addition, we examined the mRNA expression of angiogenin in HUVEC before and after BDNF stimulation by quantitative reverse transcriptase-polymerase chain reaction. As a result, we noted that BDNF induced angiogenin secretion and nuclear translocation without an increase in the mRNA expression in HUVEC. Furthermore, we demonstrated that BDNF-induced HUVEC proliferation was significantly suppressed when neomycin, a specific inhibitor of nuclear translocation of angiogenin, was administered. These findings indicate that nuclear translocation of angiogenin is critically involved in BDNF-induced proliferation of HUVEC. In conclusion, angiogenin contributes to angiogenesis induced by BDNF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.prp.2018.02.013DOI Listing
April 2018

Elevated Level of Myeloperoxidase-Deoxyribonucleic Acid Complex in the Middle Ear Fluid Obtained From Patients With Otitis Media Associated With Antineutrophil Cytoplasmic Antibody-associated Vasculitis.

Otol Neurotol 2018 04;39(4):e257-e262

Faculty of Health Sciences.

Objective: The purpose was to explore the presence of myeloperoxidase (MPO)-deoxyribonucleic acid (DNA) complex as a surrogate marker of neutrophil extracellular traps (NETs) in the middle ear fluid, and to clarify the correlation between its quantifiable level and hearing outcome in patients with otitis media associated with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).

Study Design: Prospective study.

Setting: Tertiary referral center.

Patients: Nine AAV patients presenting with otitis media.

Intervention: Collection of the fluid samples from middle ear.

Main Outcome Measure: The quantifiable levels of MPO-DNA complex using an enzyme-linked immunosorbent assay.

Results: The quantifiable levels of MPO-DNA complex in patients with AAV were significantly higher than those in controls (p < 0.001). In particular, both ANCA-positive and -negative cases indicated higher levels of MPO-DNA complex compared with the controls (p = 0.004 and p = 0.006, respectively). The significant negative correlations were observed between the level of MPO-DNA complex and the functional hearing values for air (r = -0.82, p = 0.009) and bone conduction (r = -0.73, p = 0.028), respectively.

Conclusion: This analysis is the first to reveal the presence of elevated levels of MPO-DNA complex in the middle ear fluid, suggesting the pathogenic role of NETs in otitis media associated with AAV. NETs may be a valuable biomarker for use in clinical decision-making and predicting hearing outcome, regardless of ANCA status.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MAO.0000000000001708DOI Listing
April 2018
-->