Fumie Ito

Cutting Edge: A Critical Role of Lesional T Follicular Helper Cells in the Pathogenesis of IgG4-Related Disease

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 1hi 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.

Pseudoaneurysm of an aberrant internal carotid artery in the middle ear caused by myringotomy.

An aberrant internal carotid artery (ICA) is a rare abnormality associated with life-threatening otorrhagia if inadvertently injured during middle-ear surgery including myringotomy. We present a case where a 3-year-old girl experienced massive otorrhagia following myringotomy, and computed tomographic scan showed the aberrant ICA. Bleeding was controlled by ear canal packing, but rebleeding occurred. Investigations by carotid angiography demonstrated a pseudoaneurysm of the aberrant ICA in the middle ear. We attempted surgical repair using a high-flow bypass technique; however, the bypass graft was occluded by embolic complications, and eventually, ligation of the ICA was performed, which led to the paralysis of the patients left limbs. In this report, management of iatrogenic aberrant ICA injuries and pseudoaneurysms in the middle ear are discussed based on the case that we experienced.

Expression and Localization of Human Defensins in Palatine Tonsils

Defensins are small antimicrobial peptides and effector components of innate immune responses. Recent studies have shed light on their beneficial functions for the prevention of infection and potential for development of new drugs. Here, we showed the expression profiles of human defensins in palatine tonsils with 3 different diseases: tonsillar hypertrophy, recurrent tonsillitis and focal infection of the tonsil. RT-PCR analysis and immunofluorescence revealed that the expression of human α-defensin 4 and β-defensin 3 (β3) in palatine tonsils with tonsillar hypertrophy was lower than that in recurrent tonsillitis and focal infection of the tonsil, suggesting that chronic inflammation induces defensin expression. Interestingly, β2 and β3 mRNAs were specifically expressed by palatine tonsil tissues but not in human peripheral blood mononuclear cells and mucosa of the small intestine. Additionally, we observed that exposure to a Toll-like receptor 4 ligand, lipopolysaccharide, which is used as a bacterial infection model, increases the production of β2 in culture supernatants from tonsillar epithelial cells in a dose-dependent manner. Taken together, these results indicate that β2 produced by tonsillar epithelial cells plays an important role in the innate immune response for bacterial infections.

Diagnosis and Treatment of Obstructive Sleep Apnea Syndrome in Children.

Sleep is important for children pertaining to their physical and mental growth. Obstructive sleep apnea syndrome (OSAS) in children has been shown to have different effects as compared to OSAS in adults, including deficits in cognition and neuropsychological functions, hyperactivity, ADHD, behavior problems, aggressive behavior, learning problems and nocturnal enuresis. Hypertrophy of the adenoids and tonsils is a major cause of OSAS in children; therefore, adenotonsillectomy may decrease the effects of OSAS pertaining to physical and mental growth. It is important to accurately diagnose and appropriately treat OSAS in children to prevent OSAS in their adulthood.

Expression of Inflammasome-Associated Proteins in Human Oropharyngeal Squamous Cell Carcinoma.

Inflammasomes, large protein complexes typically consisting of a Nod-like receptor (NLR), adapter protein apoptosis-associated speck-like protein containing CARD (ASC) and caspase-1, are postulated to be activated in response to danger signals arising from tumors. Inflammasomes are thought to have critical but contrasting roles through facilitating antitumor immunity and inducing oncogenic factors. However, the role and function of inflammasomes in oropharyngeal carcinoma remain unclear. We analyzed nine specimens of oropharyngeal squamous cell carcinoma (SCC) and determined the expression of NLRP3, ASC, interleukin (IL)-1β, IL-18 and caspase-1 in the specimens with and without human papilloma virus (HPV) infection using immunohistochemistry, and analyzed the correlations between the altered expression of these proteins and clinicopathological factors of oropharyngeal SCC. We found strong expression of NLRP3, ASC, IL-1β, IL-18 and caspase-1 in human oropharyngeal SCC and weak or no expression of these proteins in normal tonsils. Furthermore, the distribution of mindbomb E3 ubiquitin protein ligase 1 and inflammasome-associated proteins in oropharyngeal SCC was not significantly different; there was no correlation between the expression of inflammasome-associated proteins and HPV infection. These findings suggest that inflammasomes in oropharyngeal SCC play a key role through facilitating antitumor immunity and the possibility of new roles for inflammasomes in the oropharynx.

Circulating PD-1+CXCR5-CD4+ T cells underlying the immunological mechanisms of IgG4-related disease

Abstract Objective The aim was to study the pathological role of lymphocytes with a peripheral T helper-cell-like phenotype (PD-1+CXCR5−CD4+) in IgG4-related disease (IgG4-RD). Methods PD-1+CXCR5−CD4+ T cells in the blood of patients with IgG4-RD (n = 53), patients with SS (n = 16) and healthy volunteers (n = 34) as controls were analysed by flow cytometry. Correlations between results obtained by flow cytometry and clinical parameters relevant to IgG4-RD were also analysed. Results The percentage and absolute number of PD-1+CXCR5− cells within total CD4+ T cells in IgG4-RD patients were significantly increased compared with those in healthy volunteers. Further analysis showed that there were marked positive correlations of the percentage of PD-1+CXCR5−CD4+ T cells with the serum level of IgG4 and the number of organs involved. Interestingly, granzyme A (GZMA)+ cells were enriched in PD-1+CXCR5−CD4+ T cells, and the percentage and absolute number of GZMA+PD-1+CXCR5−CD4+ T cells were significantly elevated in IgG4-RD patients. Although no obvious change was observed in the percentage of total CD4+ T cells, the percentage and absolute number of PD-1+CXCR5−CD4+ T cells decreased in accordance with a reduction of serum IgG4 level after treatment with glucocorticoids. Conclusion In IgG4-RD, circulating CD4+ T-cell populations were composed of PD-1+CXCR5− cells, and the ratios of these cells were correlated with clinical manifestations of IgG4-RD. Further analysis of GZMA+PD-1+CXCR5−CD4+ T cells might lead to a deeper understanding of the pathogenesis of ectopic lymphoid follicles and the persistent inflammation in IgG4-RD.

Loss of sorting nexin 5 stabilizes internalized growth factor receptors to promote thyroid cancer progression

Thyroid carcinoma is the most common endocrine malignancy and its prevalence has recently been increasing worldwide. We previously reported that the level of sorting nexin 5 (Snx5), an endosomal translocator, is preferentially decreased during the progression of well‐differentiated thyroid carcinoma into poorly differentiated carcinoma. To address the functional role of Snx5 in the development and progression of thyroid carcinoma, we established Snx5‐deficient (Snx5−/−) mice. In comparison to wild‐type (Snx5+/+) mice, Snx5−/− mice showed enlarged thyroid glands that consisted of thyrocytes with large irregular‐shaped vacuoles. Snx5−/− thyrocytes exhibited a higher growth potential and higher sensitivity to thyroid‐stimulating hormone (TSH). A high content of early endosomes enriched with TSH receptors was found in Snx5−/− thyrocytes, suggesting that loss of Snx5 caused retention of the TSH receptor (TSHR) in response to TSH. Similar data were found for internalized EGF in primary thyrocytes. The increased TSH sensitivities in Snx5−/− thyrocytes were also confirmed by results showing that Snx5−/− mice steadily developed thyroid tumors with high metastatic potential under high TSH. Furthermore, a thyroid cancer model using carcinogen and an anti‐thyroidal agent revealed that Snx5−/− mice developed metastasizing thyroid tumors with activation of MAP kinase and AKT pathways, which are postulated to be major pathways of malignant progression of human thyroid carcinoma. Our results suggest that thyrocytes require Snx5 to lessen tumorigenic signaling driven by TSH, which is a major risk factor for thyroid carcinoma. Copyright

High frequency of Bob1lo T follicular helper cells in florid reactive follicular hyperplasia

Florid reactive follicular hyperplasia (FRFH), which is characterized by large germinal centers (GCs) within normal lymphoid follicles, is often observed in benign lesions of lymph nodes and other tissues. Because of the histologic similarity of FRFH to tumorous lesions such as follicular lymphoma, careful pathological examination is required to evaluate such lesions; however, little is known about the mechanism underlying the development of FRFH. In this study, we investigated T follicular helper (Tfh) cells in hyperplastic tonsils of patients with obstructive sleep apnea syndrome (OSA), which frequently exhibits typical FRFH. When we analyzed tonsils of OSA and recurrent tonsillitis (RT) as a control, tonsils of OSA were found to harbor Tfh cells with a nearly 3-fold higher ratio in total CD4+ T cells than that in tonsils of RT. Further analysis showed that, in comparison to Tfh cells of RT tonsils, Tfh cells of OSA tonsils were relatively tolerant to CD3-mediated activation-induced cell death (AICD) and also expressed lower levels of a Bob1 transcription coactivator and IL-4, which fosters the development of GC-B cells. Given that Bob1 controls the proliferative activity in response to CD3 stimulation and has been suggested to have a role in the production of IL-4 in Tfh cells, the unique structure of FRFH is possibly associated with the function of Bob1lo Tfh cells.

Clinical Review of Cochlear Implantation Performed at Sapporo Medical University Hospital

More than 20 years have passed since cochlear implantation (CI) was first introduced in Japan. We began CI at the Sapporo Medical University Hospital in 1988; since then, up to the first half of 2015, we have performed CI on 280 ears. In patients aged less than and those aged over 18 years, 121 and 159 ears, respectively, have undergone surgery. This report presents typical cases of CI, such as an adult case, a bilateral case, a case where both hearing and vision were impaired, a pediatric case, a case with multiple handicaps, a case with a genetic mutation leading to severe hearing loss, and a complicated case. In addition, complications with CI cases experienced during extended follow-up periods are also summarized.

Radiological Assessment of the Anatomy of Frontal Recess Cells and the Anterior Ethmoidal Artery

It is necessary for the surgeon to be familiar with frontal recess anatomy during an endoscopic approach to the frontal sinuses. The aim of this study was to evaluate the prevalence of frontal recess cells in Japanese adults as well as the association between the frontal recess and the location of the anterior ethmoidal artery (AEA). The frontal recess cells and the AEAs were retrospectively evaluated in CT scans of the nasal and paranasal sinuses for 89 patients. The prevalence of agger nasi cells was 90.7%. The frequency of frontal cell types 1, 2, 3 and 4 was 28.8, 0.6, 2.6 and 0%, respectively. Suprabullar cells (SBCs) and frontal bullar cells (FBCs) were identified in 78/96 sides (81.3%) and 24/96 sides (24%), respectively. The prevalence of the medial group of frontal recess cells (interfrontal sinus septal cells) was 12.4%. In 42/61 sides (68.9%), the AEAs were located within the posterior margin of the SBCs or the FBCs. Therefore, SBCs, FBCs and the vertical portion of the middle turbinate are reliable landmarks for the identification of AEAs.