Abstract IgG4-related disease (IgG4-RD) is a chronic inflammatory disorder, characterized by elevated serum IgG4 levels as well as abundant infiltration of IgG4-positive plasmacytes and fibrosis in ...various organs, including the head and neck region. In particular, the salivary glands, orbit, and thyroid are common sites of disease involvement. IgG4-RD is diagnosed based on various clinical, serological, and histopathological findings, none of which are pathognomonic. Hence, various differential diagnoses, which exhibit elevated serum IgG4 levels and infiltration of IgG4-postive cells into tissues, need to be excluded, especially malignant diseases and mimicking disorders. Systemic corticosteroids are generally effective in inducing IgG4-RD remission; however, recurrent or refractory cases are common. In addition, although the pathogenic mechanisms of IgG4-RD remain unclear, an antigen-driven inflammatory condition is believed to be involved. Recent studies have indicated the important pathogenic role of B cell/T cell collaboration and innate immunity in this disease. Nevertheless, additional research and discussions are needed to resolve many remaining questions. In this review, we provide an overview of the recent insights on the history, clinical features, diagnosis, and treatment of IgG4-RD in the head and neck region. Furthermore, we have also addressed the pathogenesis of this disease.
In the elevation of the muco-perichondrium flap during septoplasty and septorhinoplasty, it is important to elevate the subperichondrial layer. When performing subperichondrial elevation of the flap, ...the surgeon uses differences in color tone to distinguish the perichondrium from cartilage; however, it is relatively difficult to understand these differences and to share them with assistants. Furthermore, the perichondrium at the caudal end adheres tightly to the cartilage, making it difficult to detach accurately the subperichondrial layer. Narrow band imaging (NBI) is an optical technology that facilitates detailed observation of microvessels in the mucosal surface layer. In this study, we investigated whether NBI is better than white light (WL) in accentuating differences in contrast between cartilage and perichondrium in the elevation of the muco-perichondrium flap during septoplasty and septorhinoplasty.
Twenty-six sides of 15 patients (the modified Killian approach was used in two patients, the hemitransfixion approach was used in seven patients, and open septorhinoplasty was used in six patients) with elevated muco-perichondrium flaps were studied under WL endoscopy and NBI. The brightness of the perichondrium and cartilage and the differences between the two tissues were compared between WL and NBI using ImageJ 1.53a. Next, the WL and NBI endoscopic images used for cartilage identification were divided into the three separate primary color channels of red, green, and blue, and the brightness of the perichondrium and cartilage were measured separately for each channel.
Under WL, the perichondrium appeared reddish-white and the cartilage appeared white, whereas under NBI the perichondrium appeared greenish-gray, differentiating it from the white cartilage. The difference in brightness between the cartilage and perichondrium was significantly higher on NBI (grayscale difference 80.8 (SD 42.4)) than on WL imaging (grayscale difference 35.6 (SD 31.1)) (p<0.001). In the red channel, the difference in image intensity between cartilage and perichondrium was significantly higher on NBI than on WL imaging (Red WL grayscale difference -1.5 (SD 33.7), Red NBI grayscale difference 90.0 (SD 56.7); p<0.001).
NBI is better than WL at accentuating the difference in contrast between cartilage and the perichondrium during the elevation of the muco-perichondrium flap during septoplasty and septorhinoplasty. The difference in the processing of red light between WL and NBI provides the largest contribution to the differentiation of cartilage from the perichondrium under WL and NBI. We believe that NBI can be usefully applied during septoplasty and septorhinoplasty to distinguish cartilage from the perichondrium with precision.
The mechanism underlying the anti-inflammatory effect of macrolide antibiotics, such as clarithromycin (CAM), remains to be clarified. The CAM-binding proteins 4-nitrophenylphosphatase domain and ...non-neuronal synaptosomal associated protein 25 (SNAP25)-like protein homolog (NIPSNAP) 1 and 2 are involved in the immune response and mitochondrial homeostasis. However, the axis between CAM-NIPSNAP-mitochondria and Toll-like receptor (TLR) and their molecular mechanisms remain unknown. In this study, we sought to elucidate the relationship between mitochondrial homeostasis mediated by NIPSNAP1 and 2 and the immunomodulatory effect of CAM. NIPSNAP1 or 2 knockdown (KD) by RNA interference impaired TLR4-mediated interleukin-8 (IL-8) production. Similar impairment was observed upon treatment with mitochondrial function inhibitors. However, IL-8 secretion was not impaired in NIPSNAP1 and 2 individual knockout (KO) and double KO (DKO) cells. Moreover, the oxygen consumption rate (OCR) in mitochondria measured using a flex analyzer was significantly reduced in NIPSNAP1 or 2 KD cells, but not in DKO cells. CAM also dose-dependently reduced the OCR. These results indicate that CAM suppresses the IL-8 production via the mitochondrial quality control regulated by temporary functional inhibition of NIPSNAP1 and 2. Our findings provide new insight into the mechanisms underlying cytokine production, including the TLR-mitochondria axis, and the immunomodulatory effects of macrolides.
Tumor angiogenesis is an important therapeutic target in colorectal cancer (CRC). We aimed to identify novel genes associated with angiogenesis in CRC. Using RNA sequencing analysis in normal and ...tumor endothelial cells (TECs) isolated from primary CRC tissues, we detected frequent upregulation of adipocyte enhancer‐binding protein 1 (AEBP1) in TECs. Immunohistochemical analysis revealed that AEBP1 is upregulated in TECs and stromal cells in CRC tissues. Quantitative RT‐PCR analysis showed that there is little or no AEBP1 expression in CRC cell lines, but that AEBP1 is well expressed in vascular endothelial cells. Levels of AEBP1 expression in Human umbilical vein endothelial cells (HUVECs) were upregulated by tumor conditioned medium derived from CRC cells or by direct coculture with CRC cells. Knockdown of AEBP1 suppressed proliferation, migration, and in vitro tube formation by HUVECs. In xenograft experiments, AEBP1 knockdown suppressed tumorigenesis and microvessel formation. Depletion of AEBP1 in HUVECs downregulated a series of genes associated with angiogenesis or endothelial function, including aquaporin 1 (AQP1) and periostin (POSTN), suggesting that AEBP1 might promote angiogenesis through regulation of those genes. These results suggest that upregulation of AEBP1 contributes to tumor angiogenesis in CRC, which makes AEBP1 a potentially useful therapeutic target.
We identified that adipocyte enhancer‐binding protein 1 (AEBP1) is upregulated in tumor endothelial cells in primary colorectal cancers. Upregulation of AEBP1 in vascular endothelial cells promotes cell proliferation, migration, and angiogenesis. We also found that AEBP1 might mediate tumor angiogenesis through regulating expression of angiogenesis‐related genes, including aquaporin 1 (AQP1) and periostin (POSTN).
Of the schwannomas that arise from the parapharyngeal space, those in the high cervical region are particularly invasive, requiring mandibular dissection. Because these tumors are benign, however, ...excessive surgical invasion and postoperative neurological complications should be avoided. Postoperative dropout symptoms may be avoided by intracapsular extraction, including nerve integrity monitoring (NIM) and narrow-band imaging (NBI). Video laryngoscopy surgery is reported to be useful for transoral resection of pharyngeal and laryngeal tumors. This report describes the transoral removal of a giant schwannoma located in the high cervical region from a 74-years-old man using a surgical support device without mandibular dissection.
The tumor was located on the right lateral pharyngeal wall and extended from the upper oropharynx to the hypopharynx while compressing the epiglottis to the skull base. No separation was observed between the internal jugular vein and the internal carotid artery. The tumor was diagnosed as a schwannoma with no malignancy on the basis of the histology of a core needle biopsy (CNB), and was completely and safely removed endoscopically using NIM and NBI, with no need for an external incision or mandibular dissection. This case illustrates that even a huge sympathetic schwannoma located in the parapharyngeal space at a high cervical position can be excised transorally using video-laryngoscopic surgery (TOVS) without mandibular dissection.
IgG4-related disease (IgG4-RD) is a newly recognized systemic chronic fibroinflammatory disease. However, the pathogenesis of IgG4-RD remains unknown. To determine the pathophysiologic features of ...IgG4-RD, we examined T follicular helper (Tfh) cells in lesions and blood from patients with IgG4-RD. Patients with IgG4-related dacryoadenitis and sialadenitis (IgG4-DS) showed increased infiltration of Tfh cells highly expressing programmed death 1 and ICOS in submandibular glands. Tfh cells from IgG4-DS submandibular glands had higher expression of B cell lymphoma 6 and a greater capacity to help B cells produce IgG4 than did tonsillar Tfh cells. We also found that the percentage of programmed death 1
circulating Tfh cells in IgG4-DS patients was higher than that in healthy volunteers and was well correlated with clinical parameters. Our findings indicate that anomalous Tfh cells in tissue lesions of IgG4-RD have features distinct from those in lymphoid counterparts or blood and potentially regulate local IgG4 production in IgG4-RD.
The transcription factor FOXO3 is necessary to preserve cochlear hair cells. Growth factors, including TGF-β, closely contribute to cochlear hair cell regeneration. In the present study, to ...investigate the roles of FOXO3 in the ciliogenesis and cell functions of cochlear hair cells, UB/OC-2 temperature-sensitive mouse cochlear precursor hair cells were treated with TGF-β receptor type 1 inhibitor EW-7197 or EGF receptor inhibitor AG-1478 after transfection with or without siRNA-FOXO3a. GeneChip analysis revealed that treatment with EW-7197 increased
Foxo3
genes and decreased genes of Smads. During cell differentiation, treatment with EW-7197 or AG-1478 induced an increase in length of cilia-like structures that were positive for acetylated tubulin and inhibited cell migration. Treatment with EW-7197 also increased cell metabolism measured as mitochondrial basal respiration (oxygen consumption rate). The effects of EW-7197 were stronger than those of AG-1478. Knockdown of FOXO3 prevented the growth of cilia-like structures induced by EW-7197 or AG-1478 and induced cell migration under treatment with EW-7197. No change of the epithelial cell polarity molecule PAR3 was observed with any treatment. Treatment with the antimicrobial agent amikacin prevented the growth of cilia-like structures induced by EW-7197 and induced apoptosis. Pretreatment with the glucocorticoid dexamethasone inhibited the apoptosis induced by amikacin. This in vitro model of mouse cochlear hair cells suggests that FOXO3/TGF-β signaling plays a crucial role in ciliogenesis and cell functions during differentiation of cochlear hair cells. This model is useful for analysis of the mechanisms of hearing loss and to find therapeutic agents to prevent it.
Abstract Human norovirus (HuNoV) is an enteric infectious pathogen belonging to the Caliciviridae family that causes occasional epidemics. Circulating alcohol-tolerant viral particles that are ...readily transmitted via food-borne routes significantly contribute to the global burden of HuNoV-induced gastroenteritis. Moreover, contact with enzymes secreted by other microorganisms in the environment can impact the infectivity of viruses. Hence, understanding the circulation dynamics of Caliciviridae is critical to mitigating epidemics. Accordingly, in this study, we screened whether environmentally abundant secretase components, particularly proteases, affect Caliciviridae infectivity. Results showed that combining Bacillaceae serine proteases with epsilon-poly- l -lysine (EPL) produced by Streptomyces— a natural antimicrobial—elicited anti- Caliciviridae properties, including against the epidemic HuNoV GII.4_Sydney_2012 strain . In vitro and in vivo biochemical and virological analyses revealed that EPL has two unique synergistic viral inactivation functions. First, it maintains an optimal pH to promote viral surface conformational changes to the protease-sensitive structure. Subsequently, it inhibits viral RNA genome release via partial protease digestion at the P2 and S domains in the VP1 capsid. This study provides new insights regarding the high-dimensional environmental interactions between bacteria and Caliciviridae , while promoting the development of protease-based anti-viral disinfectants.
Abstract Since Morgan's report in 1953, Mikulicz's disease (MD) has been considered part of primary Sjögren's syndrome (SS). However, MD has a unique presentation, including persistent swelling of ...the lacrimal and salivary glands, and is characterized by good responsiveness to glucocorticoids, leading to recovery of gland function. Recently, it has been revealed that MD patients show elevated serum immunoglobulin G4 (IgG4) levels and prominent infiltration of IgG4-positive plasmacytes. The complications of MD include autoimmune pancreatitis, retroperitoneal fibrosis, tubulointerstitial nephritis, autoimmune hypophysitis, and Riedel's thyroiditis, all of which show IgG4 involvement in their pathogenesis. Thus, MD is a systemic “IgG4-related disease.” In addition, recent analyses have revealed that Küttner's tumor (KT), a chronic sclerosing sialadenitis that presents with asymmetrical firm swelling of the submandibular glands, is also associated with prominent infiltration of IgG4-positive plasmacytes. MD and KT differ from SS and are thought to be singular systemic IgG4-related plasmacytic diseases. Here we discuss the results of recent studies and provide an overview of MD as an IgG4-related disease.
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