We clarified regulatory signal transduction mechanisms of the acinar cells of the mammalian nasal gland using patch-clam techniques and fluorescence ratio imaging microscopy. Acetylcholine (ACh) indirectly activates both Cl⁻ and K⁺ channels by raising intracellular Ca²⁺. Subsequent membrane depolarization resulting from Cl⁻ efflux via the Cl⁻ channels in the luminal membrane leads to further activation of the basolateral K⁺ channels and a favorable electrochemical gradient for K⁺ efflux. Both K⁺ and CI⁻ enter the cell mediated by Na⁺-K⁺ATPase and Na-K-CI cotransport. The Na-K-CI cotransport is activated directly by increased Ca²⁺ presumably involving phosphorylation by Ca²⁺/Calmodulin-dependent myosin light chain kinase. The resultant luminal negativity draws Na’ into the lumen via the paracellular pathway. The activation of the Cl⁻ channel plays a critical role in producing isotonic glandular secretion rich in NaCl. Several medicines affect stimulus-response coupling mediated by the above-mentioned cellular signaling pathways.

Epstein-Barr virus (EBV) is associated with the carcinogenesis of nasopharyngeal carcinoma (NPC). In contrast, human papillomavirus (HPV) is associated with the carcinogenesis of oropharyngeal carcinoma. However, it is unknown why such two distinguished neoplasms occur in the closed region.

Nasopharyngeal carcinoma is a highly metastatic neoplasm initiated by EBV genes. Among EBV genes, latent membrane protein 1 (LMP1) is a key regulator of metastasis and oncogenesis. Moreover, LMP1 promotes metastasis with one of the factors, hypoxia-related genes, Siah1. In addition, Siah1 expression is a prognostic factor of NPC. Conversely, we also revealed that LMP1 induces cancer stemness that is important for the initiation of cancer.

Several studies showed that the incidence of HPV-related oropharyngeal carcinoma (HPV-OPC) has increased rapidly in developed countries. Recent studies showed that intrinsic immunity, APOBEC3 is a trigger of viral gene integration to the host genome that is closely associated with the initiation of HPV-OPC.

In terms of tissue tropism with EBV and HPV infection, one report showed that HPV positivity is very rare in EBV-related NPC. However, the copy numbers of EBV-DNA in pharyngeal tonsil (nasopharynx) are higher than those in palatine tonsil (oropharynx) in children. These phenomena suggest EBV tissue tropism to the nasopharynx. It is mandatory to investigate viral carcinogenesis and finally plan to develop new targeted therapies.

We summarized our basic and clinical studies regarding tonsillar focal disease. We think that the pathogenesis of tonsillar focal disease is hyper-activation of tonsillar lymphocytes against tonsillar commensal bacteria and bacterial DNA followed by over-expression of several homing receptors on tonsillar T-cells and over-production of IgA from tonsillar B-cells. We called the disease caused by this series of abnormal immunological response tonsil induced autoimmune/inflammatory syndrome (TIAS). Disease severity of pathologies such as palmoplantar pustulosis, IgA nephropathy, and sternocostoclavicular hyperostosis are known to be ameliorated by tonsillectomy. Tonsillectomy should be recommended for patients with TIAS introduced by dermatologists, nephrologists, orthopedists, and other doctors.

The most common endotype-based chronic rhinosinusitis (CRS) classification includes the eosinophilic CRS (ECRS) and non-eosinophilic CRS (non-ECRS) subtypes. ECRS is characterized by severe type 2 inflammation and is therapeutically challenging. Moreover, nasal polyp (NP) recurrences are frequent in patients with ECRS, despite medical treatment and surgical interventions. Comorbid asthma, including aspirin/non-steroidal anti-inflammatory drug intolerance is also common in ECRS. Therefore, the main therapeutic target in patients with ECRS is to completely eliminate or diminish the bulk of the NP tissue. An accurate understanding of the pathogenesis of NP is important to improve the effectiveness of therapy for ECRS.

NPs are histopathologically characterized by intense edematous stroma filled with plasma proteins, mainly albumin, and minimal fibrosis, owing to decreased levels of collagen production. We previously reported that excessive fibrin deposition was observed in NP tissue. Excessive fibrin deposition contributes to the retention of plasma proteins exuded from capillaries and thereby perpetuates mucosal edema, which could be implicated in the etiopathogenesis of NPs. Fibrin, an end product of the coagulation cascade, plays a major role in blood clotting at the site of vascular injury. However, disturbances in fibrin turnover result in abnormal fibrin deposition and can produce detrimental effects owing to its pro-inflammatory properties. Tissue fibrin is generated by the coagulation cascade and broken down by the fibrinolysis cascade. Recent studies have reported disturbances in both coagulation and fibrinolysis cascades in ECRS.

Mucosal edema and excessive fibrin deposition are known to contribute to retention of exuded plasma proteins from capillaries and thereby perpetuate mucosal edema that may participate in the etiopathogenesis of NPs. Up-regulation of the coagulation cascade and down-regulation of fibrinolysis are strongly associated with abnormal fibrin deposition in the nasal mucosa, and type 2 inflammation plays a key role in the imbalance between coagulation and fibrinolysis.

Thirteen billion years have passed since the Big Bang. Additionally, it has been 3 billion years since the appearance of most primitive organism on earth. Organism is defined as those with the potential to undergo replication and metabolism. Considering these criteria, it has been a topic of discussion whether viruses are alive or unalive, despite having close interaction with specific organisms. They have generally been considered the antagonist. However, the acquisition of placenta would not have been accomplished without the interaction with viruses. Along with the history of viral research, we deeply reconsider the topics covered by JIAIO, such as alive and unalive viruses, self and non-self, and pathogenesis and symbiosis.

Extranodal NK/T cell lymphoma, nasal type (nasal NK/T cell lymphoma) is a rare malignant disease, which mainly involves the head and neck. In the late 20^th century, monoclonal expression of Epstein–Barr virus (EBV) was detected in a clinical specimen. Subsequently, accumulating evidence has suggested that EBV and its related protein play an etiological role in the aggressive proliferation of this lymphoma. The viral load of EBV in serum has been used as a prognostic marker in clinical practice. EBV-derived micro-RNA is also a reliable marker for the progression of lymphoma. This lymphoma produces several cytokines and chemokines to proliferate under the EBV-LMP1-mediated pathway. In addition to its pathological role, EBV is an ideal target for immunotherapy. We have previously described that EBV-LMP1 contains an epitope that could activate antitumor CD4 helper T cells. Here, I briefly summarize the current knowledge regarding the etiological role of EBV in nasal NK/T cell lymphoma, the immune microenvironment surrounding this lymphoma, and the novel treatment strategy of targeting EBV with antitumor immune cells.

Regarding the relationship between tonsil-induced autoimmune/inflammatory syndrome (TIAS) and the tonsillar bacterial flora, alpha-hemolytic streptococcus and Hemophilus parainfluenzae were reported to be frequently detected and induced an excess immunological response in the palatine tonsils of patients with palmoplantar pustulosis (PPP) and IgA nephropathy (IgAN), respectively. No bacteria were frequently observed in the focal tonsils by our 16S rRNA bacterial flora analysis; however, we confirmed that the excess immunological response against the bacteria was detected in the focal tonsillar lymphocytes. Presently, we focus on CpG-ODN (deoxycytidyl-deoxyguanosine oligodeoxynucleotides) inherent in those bacteria, which bind to toll-like receptor 9 (TLR9) and induce immune modulation such as the hyperproduction of gammaglobulin. We found an excess response against CpG-ODN in the tonsillar lymphocytes obtained from IgAN patients. In this review, we will demonstrate the relationship between TIAS and the tonsillar bacterial flora on the basis of the results derived from our basic research about TIAS.

In Japan, Japanese cedar pollen and house dust mite are the most common allergens causing nasal allergy. There are several studies of dual sublingual immunotherapy (SLIT) of these two antigens. In this study, we introduce the procedure of dual SLIT and frequency of adverse events (AEs).

Patients who assented to participate in this study were enrolled from October 2017 to November 2018. We used CEDARTOLEN® or CEDARCURE® as SLIT medicine for Japanese cedar pollinosis (JCP) and ACTAIR® for perennial allergic rhinitis (PAR) caused by house dust mite. In the beginning, patients received the first SLIT medicine for JCP or PAR for at least 4 weeks. When there was no severe AE, they received dual SLIT medicines. These medicines were dividedly administered in the morning and evening for at least 4 weeks. After confirming that there was no severe AEs, they received dual SLIT medicines sequentially in 5 min intervals. The selection of the first SLIT medicine was not random, but it was decided by the attending physicians and patients during consultations.

Thirty patients were enrolled this study (18 males and 12 females) aged between 17–62 years (mean 38.5 year), and the duration of observation were 3 months to 18 months (median, 7 months). Twenty-nine patients were able to continue taking dual SLIT, however, one patient discontinued because of taste dislike of the liquid medicine of JCP. Moreover, 27 patients could receive sequential dual SLIT; however, two patients dividedly received SLIT medicines due to AEs in sequential dual SLIT. AEs were detected in 60% of patients. The ratio of AEs was significantly higher in SLIT for medicines for PAR than for JCP. All of the AEs were mild.

In conclusion, dual SLIT for JCP and PAR is a safe and acceptable therapy in routine medical care.

In this study, we analyzed aging-related changes in the mucosal immune responses of the upper airway to outer membrane protein (OMP) from nontypeable Haemophilus influenzae, focusing on the differentiation of T cells. Mice of different ages (5 weeks, 6 months, and 1 year old) were vaccinated with 10 μg of OMP and 1 μg of cholera toxin for a total of three times seven days apart. On day 7 after immunization, mononuclear cells were collected from the middle ear, nasal mucosa, nasal-associated lymphoid tissue, cervical lymph node, and spleen to analyze T cell differentiation using flow cytometry. Non-immunized mice at each age group served as the controls. An analysis of the lymphocyte region of mononuclear cells using flow cytometry showed that CD3-positive T cells tended to decrease in lymphoid tissues due to aging. In contrast, among CD4-positive T cells, the memory T cell ratio was increased in the upper airway mucosa of young mice after immunization. Similarly, the effector T cell ratio was increased markedly in the lymphoid tissues of young mice after immunization. Therefore, it was suggested that the T cell immune responses against OMPs in the upper airway mucosa and lymphoid tissues may decrease due to aging.

Advances in both surgical technique and flap design have decreased the incidence of wound-related complications in cochlear implant (CI) surgery. However, cases of post-implantation wound sepsis requiring ex-plantation and re-implantation, or temporoparietal flap reconstruction have been reported, resulting to delayed CI use and consequent detrimental effects on childhood language development. Therefore, conservative treatment of post-CI wound infection is desirable. Herein, we report a case of a successful conservative treatment of post-CI wound infection in a 23-month-old boy, who was diagnosed with bilateral severe-to-profound sensorineural hearing loss secondary to recurrent otitis media. At 13 months of age, the patient received a right CI operation due to the limited effects of hearing aids. A left CI implant was also carried out 10 months later at the age of 23 months. After discharge from the hospital, a foul-smelling odor was noticed from the wound. On day 13 after surgery, wound dehiscence and purulent discharge were both observed at an auditory training center. As a result, he was immediately brought to our department and was diagnosed with post-CI wound infection. The patient was admitted, and the wound was swabbed for culture. The wound was treated with normal saline irrigation twice daily, and meropenem was administered to cover for possible methicillin-resistant Staphylococcus aureus (MRSA) infection. Culture finally revealed a methicillin-sensitive Staphylococcus aureus (MSSA), and the antibiotic was changed to cefazolin on day 16 after surgery. The wound was closed under general anesthesia on day 20, and wound healing was observed to progress favorably. By day 58, the CI was operational with no recurrence of wound sepsis.