Katsushi Miyazaki

Development of Autoimmune Exocrinopathy Resembling Sjögren’s Syndrome in Estrogen-Deficient Mice of Healthy Background

Although a number of autoimmune diseases are known to develop in postmenopausal women, the mechanisms by which estrogen deficiency influences autoimmune lesions remain unclear. We speculate that antiestrogenic actions might be a potent factor in the formation of pathogenic autoantigens. Previously, we have identified 120-kd alpha-fodrin as an important autoantigen in Sjögrens syndrome (SS). When healthy C57BL/6 (B6) mice were treated with an ovariectomy (Ovx), we found a significant increase in TUNEL(+)-apoptotic epithelial cells in the salivary gland cells associated with alpha-fodrin cleavage during 2 and 3 weeks after Ovx. By contrast, no apoptotic cells were found in estrogen receptor-alpha knockout mice. In in vitro studies using primary cultured mouse salivary gland cells and human salivary gland cells, we found a cleavage product of 120-kd alpha-fodrin in cells that had undergone tamoxifen (Tam)-induced apoptosis through caspase activation, especially caspase-1. Adoptive transfer of alpha-fodrin-reactive T cells into Ovx-B6 and -SCID mice resulted in the development of autoimmune exocrinopathy quite similar to SS. These results suggest that estrogen deficiency exerts a crucial influence on autoantigen cleavage, and may cause, in part, autoimmune exocrinopathy in postmenopausal women.

Analysis of in vivo role of α-fodrin autoantigen in primary Sjögren's syndrome

The α-fodrin N-terminal portion (AFN) autoantigen mediates in vivo immunoregulation of autoimmune responses in primary Sjogrens syndrome (SS). We further examined this process and found that cleavage products of AFN were frequently detected in the salivary gland duct cells of SS patients. In in vitro studies using human salivary gland HSY cells, anti-Fas-induced apoptosis resulted in specific cleavage of α-fodrin into the 120-kd fragment, in association of α-fodrin with μ-calpain, and activation of caspase 3. Significant proliferative responses against AFN autoantigen were observed in the peripheral blood mononuclear cells (PBMCs) from SS patients with higher pathological score (grade 4) and with short duration from onset (within 5 years). In vivo roles of AFN peptides were investigated using PBMCs from patients with SS, systemic lupus erythematosus, and rheumatoid arthritis. Significant proliferative T-cell responses of PBMCs to AFN peptide were detected in SS but not in systemic lupus erythematosus or rheumatoid arthritis. AFN peptide induced Th1-immune responses and accelerated down-regulation of Fas-mediated T-cell apoptosis in SS. Our data further elucidate the in vivo role of AFN autoantigen on the development of SS and suggest that the AFN autoantigen is a novel participant in peripheral tolerance.

Hybrid peripheral nerve sheath tumor of the nasal cavity showing schwannomatous, neurofibromatous, and perineuriomatous areas.

Soft tissue hybrid peripheral nerve sheath tumors (PNST), including schwannoma-perineurioma or neurofibroma-perineurioma, have recently been described. However, there are no reports on hybrid PNST arising in the nasopharyngeal area. In this article, we report such a case. A 58-year-old Japanese man presented with nasal obstruction and was found to have bilateral polypoid lesions in the middle meatus of the nose. Subsequently, nasal polypectomy was performed. Histologically, the tumor consisted of three components including schwannoma, neurofibroma, and perineurioma. Immunohistochemically, schwannoma, neurofibroma, and perineurioma components were positive for S-100 protein, CD34, and epithelial membrane antigen, respectively. In conclusion, this is the first case of hybrid PNST reported to occur in the nasopharyngeal area. Pathologists should be aware of the possibility that hybrid PNST may present outside soft tissue.

Efficacy of proton pump inhibitor in combination with rikkunshito in patients complaining of globus pharyngeus

OBJECTIVE Globus pharyngeus (GP) is a common symptom of laryngopharyngeal reflux disease (LPRD), and proton pump inhibitor (PPI) and rikkunshito, a traditional Japanese medicine having prokinetic effect improve LPRD symptoms. In the present study, we examined the efficacy of high-dose PPI in combination with rikkunshito in patients complaining of GP. METHODS 106 patients complaining of GP without any organic endoscopic findings were enrolled. RESULTS Patients were first administrated with high-dose PPI alone for 4 to 8 weeks and the symptom was improved in 65 patients. Among 41 patients with PPI-refractory GP, 22 patients were administrated with high-dose PPI in combination with rikkunshito, and the symptom was improved in 14 of 22 patients 4 weeks later. The average value of a modified reflux symptom index of the responders was similar to that of non-responders. Only a few patients had positive values in reflux finding scores in both groups. CONCLUSION The present findings suggest the existence of a high prevalence of LPRD in patients complaining of GP. The data also suggest that gastroesophageal dysmotility is involved in GP, in addition to excessive acid reflux. The pre-therapeutic laryngopharyngeal symptoms and endoscopic findings could not predict the efficacy of the treatment for GP. J. Med. Invest. 63: 227-229, August, 2016.