Bob1 maintains T follicular helper cells for long-term humoral immunity.

Humoral immunity is vital for host protection, yet aberrant antibody responses can trigger harmful inflammation and immune-related disorders. T follicular helper (Tfh) cells, central to humoral immunity, have garnered significant attention for unraveling immune mechanisms. This study shows the role of B-cell Oct-binding protein 1 (Bob1), a transcriptional coactivator, in Tfh cell regulation. Our investigation, utilizing conditional Bob1-deficient mice, suggests that Bob1 plays a critical role in modulating inducible T-cell costimulator expression and cellular respiration in Tfh cells. This regulation maintains the long-term functionality of Tfh cells, enabling their reactivation from central memory T cells to produce antibodies during recall responses. In a bronchial asthma model induced by house dust mite (HDM) inhalation, Bob1 is observed to enhance HDM-specific antibodies, including IgE, highlighting its pivotal function in Tfh cell regulation. Further exploration of Bob1-dependent mechanisms in Tfh cells holds promise for governing protective immunity and addressing immune-related disorders.

CD4+CD8+ T follicular helper cells regulate humoral immunity in chronic inflammatory lesions.

T follicular helper (Tfh) cells drive humoral immunity by facilitating B cell responses at the initial and recall phases. Recent studies have indicated the possible involvement of Tfh cells in the process of chronic inflammation. However, the functional role of Tfh cells in persistent immune settings remains unclear. Here, we report that CD4+CD8+ (double-positive, DP; CD3+CD4+CD8+CXCR5hiPD-1hi) Tfh cells, a subset of germinal-center-type Tfh cells, were abundantly present in the fibroinflammatory lesions of patients with immunoglobulin G4-related disease (IgG4-RD). Transcriptome analyses showed that these DP-Tfh cells in the lesions of IgG4-RD preferentially expressed signature genes characteristic of cytotoxic CD8+ T cells, such as Eomes, CRTAM, GPR56, and granzymes, in addition to CD70. Scatter diagram analyses to examine the relationships between tissue-resident lymphocytes and various clinical parameters revealed that the levels of DP-Tfh cells were inversely correlated to the levels of serum IgG4 and local IgG4-expressing (IgG4+) memory B cells (CD19+CD27+IgD-) in patients with IgG4-RD. Cell culture experiments using autologous tonsillar lymphocytes further suggested that DP-Tfh cells possess a poor B-cell helper function and instead regulate memory B cells. Since CD4+ (single positive, SP; CD3+CD4+CD8-CXCR5hiPD-1hi) Tfh cells differentiated into DP-Tfh cells under stimulation with IL-2 and IL-7 as assessed by in vitro experiments, these data imply that SP-Tfh cells are a possible origin of DP-Tfh cells under persistent inflammation. These findings highlight the potential feedback loop mechanism of Tfh cells in immune tolerance under chronic inflammatory conditions. Further studies on DP-Tfh cells may facilitate control of unresolved humoral responses in IgG4-RD pathological inflammation.

Real-world treatment patterns and outcomes in Japanese patients with cervical esophageal cancer.

BACKGROUND: Cervical esophageal cancer (CEC) carries a poor prognosis; however, due to its low incidence, optimal treatment for CEC remains to be established. The purpose of this study was to clarify the current status of treatment of CEC in Japan and obtain evidence for establishing the appropriate treatment method. PATIENTS AND METHODS: We asked specialist training facilities accredited by the Japanese Broncho-Esophageal Society to register data on CEC cases that received curative treatment from January 2009 to December 2014, and conducted a retrospective review of the clinical data of 302 cases registered from 27 facilities. RESULTS: In regard to the initial therapy, of the 302 patients, 33 had undergone endoscopic resection, 41 had undergone surgery, 67 had received induction chemotherapy (IC), and 143 had received chemoradiotherapy (CRT). There were no significant differences in the 5-year overall survival rates among the patient groups that had received surgery, IC or CRT as the initial treatment; advanced stage and recurrent nerve invasion were identified as independent poor prognostic factors. Among the patients who had received IC or CRT as laryngeal-preserving surgery was not indicated at the time of the initial diagnosis, the functional laryngeal preservation rate at the end of the observation period was 34.8%. CONCLUSION: Even in patients with advanced CEC, there is the possibility of preserving the larynx by adopting IC or CRT. However, if the laryngeal function cannot be preserved, there is a risk of complications from aspiration pneumonia, so that the choice of treatment should be made carefully.

Cytotoxic Tph-like cells are involved in persistent tissue damage in IgG4-related disease.

OBJECTIVES: The aim of this study was to determine pathological features of T peripheral helper (Tph)-like (PD-1+CXCR5-CD4+ T) cells in IgG4-related disease (IgG4-RD). METHODS: Tph-like cells in the blood and submandibular glands (SMGs) from IgG4-RD patients were analyzed by flow cytometry. Correlations between level of a Tph-like cell subset and clinical parameters of IgG4-RD were investigated. The cytotoxic capacity of Tph-like cells was also examined. Expression profiles of a molecule related to a Tph-like cell subset in IgG4-RD SMGs were assessed by immunohistochemistry. RESULTS: Tph-like cells from IgG4-RD patients highly expressed a fractalkine receptor, CX3CR1. Percentages of circulating CX3CR1+ Tph-like cells were significantly correlated with clinical parameters including IgG4-RD Responder Index, number of involved organs, and serum level of soluble IL-2 receptor. CX3CR1+ Tph-like cells abundantly possessed cytotoxic T lymphocyte-related molecules such as granzyme A, perforin, and G protein-coupled receptor 56. Functional assays revealed their cytotoxic potential against vascular endothelial cells and ductal epithelial cells. Immunohistochemistry showed that fractalkine was markedly expressed in vascular endothelial cells and ductal epithelial cells in IgG4-RD SMGs. CONCLUSION: CX3CR1+ Tph-like cells are thought to contribute to persistent tissue injury in IgG4-RD and are a potential clinical marker and/or therapeutic target for inhibiting progression of IgG4-RD.

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.

A Case Study of Anisakiasis in the Palatine Tonsils.

Anisakidosis is a nematode infection caused by the ingestion of larvae-infected raw or undercooked fish. Although gastric anisakiasis is a common disease in Japan due to the popularity of eating raw and undercooked fish, reports of anisakiasis in the tonsils are extremely rare. A 68-year-old man presenting with clinical features of peritonsillitis was admitted for examination. The right peritonsillar region exhibited slight edematous swelling and rash, and a white foreign body was observed. This foreign body was removed, and pathological examination revealed Anisakis.

A Clinical Study of Maxillary Sinus Squamous Cell Carcinoma.

We report a retrospective study of 26 patients with maxillary sinus squamous cell carcinoma who were treated at the Sapporo Medical University between January 2002 and December 2008. The 5-year local control rate was 85.7% in patients with stage T2-3 disease and 61.0% in patients with stage T4a disease. The overall 5-year survival rate was 71.3% and the 5-year disease-specific survival rate was 79.9%. The 5-year disease-specific survival rate was 100% in patients with T2-3 disease and 44.4% in patients with T4 disease. The 5-year disease-specific survival rate was 76.3% in patients with N0 disease and 87.5% in patients with N+ disease. Five patients died of stage T4a disease. Two died of uncontrolled tumors at the primary site and 3 patients died of lung metastasis. We should consider another approach for the treatment of patients with advanced maxillary sinus carcinoma in the future.

A Clinical Review of Thyroid Cancer at Sapporo Medical University Hospital.

Thyroid cancer is a disease that affects 8,000 new individuals a year, a number that has increased approximately 3-fold in the past 30 years. The increase in the incidence of thyroid cancer can be related to various factors. The evolution of diagnostic technology has distinctly occurred in the fields of diagnostic imaging, cytology and immunochemistry. For example, liquid-based cytology, developed to assess gynecological lesions, has improved diagnostic accuracy over conventional smear cytology. This technique can also be positively applied to cytological analyses of thyroid cancer. In the field of tumor biomarkers, thyroglobulin and trefoil factor-1 are well known and useful. On the other hand, a new specific biomarker of thyroid cancer has been developed. Furthermore, definitive diagnosis of follicular thyroid tumors is extremely difficult or impossible with current tumor biomarkers and cytological methods. Although the standard treatment for thyroid cancer is a basic surgical resection, iodine adjuvant therapy after surgery is a well-known treatment. Here we present a treatment strategy for thyroid cancer according to the statistics obtained at our facility.

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)-1ß, 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-1ß, 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.