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Regulatory T (Treg) cells play key roles in various immune responses. For example, Treg cells contribute to the complex pathogenesis of inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis during onset or development of that disease. Many animal models of IBD have been used to investigate factors such as pathogenic cytokines, pathogenic bacteria, and T-cell functions, including those of Treg cells. In addition, analyses of patients with IBD facilitate our understanding of the precise mechanism of IBD. This review article focuses on the role of Treg cells and outlines the pathogenesis and therapeutic strategies of IBD based on previous reports.

Allergic contact hypersensitivity to metals is a delayed-type allergy. Although various metals are known to produce an allergic reaction, nickel is the most frequent cause of metal allergy. Researchers have attempted to elucidate the mechanisms of metal allergy using animal models and human patients. Here, the immunological and molecular mechanisms of metal allergy are described based on the findings of previous studies, including those that were recently published. In addition, the adsorption and excretion of various metals, in particular nickel, is discussed to further understand the pathogenesis of metal allergy.

Aurora-A is a well-known mitotic kinase that regulates mitotic entry, spindle formation, and chromosome maturation as a canonical role. During mitosis, Aurora-A protein is stabilized by its phosphorylation at Ser51 via blocking anaphase-promoting complex/cyclosome-mediated proteolysis. Importantly, overexpression and/or hyperactivation of Aurora-A is involved in tumorigenesis via aneuploidy and genomic instability. Recently, the novel function of Aurora-A for DNA replication has been revealed. In mammalian cells, DNA replication is strictly regulated for preventing over-replication. Pre-replication complex (pre-RC) formation is required for DNA replication as an initiation step occurring at the origin of replication. The timing of pre-RC formation depends on the protein level of geminin, which is controlled by the ubiquitin–proteasome pathway. Aurora-A phosphorylates geminin to prevent its ubiquitin-mediated proteolysis at the mitotic phase to ensure proper pre-RC formation and ensuing DNA replication. In this review, we introduce the novel non-canonical role of Aurora-A in DNA replication.

Several autoimmune diseases are known to develop in postmenopausal women. However, the mechanism by which estrogen deficiency influences autoimmunity is unknown. Aromatase is a converting enzyme from androgens to estrogens. In the present study, we used female aromatase gene knockout (ArKO) mice as a model of estrogen deficiency to investigate the molecular mechanism that underlies the onset and development of autoimmunity. Histological analyses showed that inflammatory lesions in the lacrimal and salivary glands of ArKO mice increased with age. Adoptive transfer of spleen cells or bone marrow cells from ArKO mice into recombination activating gene 2 knockout mice failed to induce the autoimmune lesions. Expression of mRNA encoding proinflammatory cytokines and monocyte chemotactic protein-1 (MCP-1) increased in white adipose tissue (WAT) of ArKO mice and was significantly higher than that in wild-type mice. Moreover, an increased number of inflammatory M-1 macrophage was observed in WAT of ArKO mice. A significantly increased MCP-1 mRNA expression of the salivary gland tissue in ArKO was found together with adiposity. Furthermore, the autoimmune lesions in a murine model of Sjögren’s syndrome (SS) were exacerbated by administration of an aromatase inhibitor. These results suggest that aromatase may play in a key role in the pathogenesis of SS-like lesions by controlling the target organ and adipose tissue-associated macrophage.

Background: To improve the effectiveness of chemo- and radiotherapy only in cancer tissue is important for avoiding side effects. Results: Emi1 depletion enhanced the sensitivity of anticancer reagents and X-ray irradiation in cancer cells. Conclusion: Emi1 siRNA would be a useful new modality for enhancing the effect of chemo- and radiotherapy in various tumors. Significance: This work provides new insights regarding synergistic effect of Emi1 knockdown in combination therapies.

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Background: Although autoimmunity in MRL/lpr mice occurs due to a defect in Fas-mediated cell death of T cells, the role of Fas-independent apoptosis in pathogenesis has rarely been investigated. We have recently reported that receptor activator of nuclear factor (NF)-kB ligand (RANKL)-activated dendritic cells (DCs) play a key role in the pathogenesis of rheumatoid arthritis (RA) in MRL/lpr mice. We here attempted to establish a new therapeutic strategy with RANKL-activated DCs in RA by controlling apoptosis of peripheral T cells. Repeated transfer of RANKL-activated DCs into MRL/lpr mice was tested to determine whether this had a therapeutic effect on autoimmunity. Methods and Finding: Cellular and molecular mechanisms of Fas-independent apoptosis of T cells induced by the DCs were investigated by in vitro and in vivo analyses. We demonstrated that repeated transfers of RANKL-activated DCs into MRL/lpr mice resulted in therapeutic effects on RA lesions and lymphoproliferation due to declines of CD4+ T, B, and CD4‾CD8‾ double negative (DN) T cells. We also found that the Fas-independent T-cell apoptosis was induced by a direct interaction between tumor necrosis factor (TNF)-related apoptosis-inducing ligand-receptor 2 (TRAIL-R2) on T cells and TRAIL on Fas-deficient DCs in MRL/lpr mice. Conclusion: These results strongly suggest that a novel Fas-independent apoptosis pathway in T cells maintains peripheral tolerance and thus controls autoimmunity in MRL/lpr mice.

Takeo Fukuchi, Hidenobu Matsuda, Jun Ueda, Akiko Yamada, Kieko Suda, Haruki AbeDivision of Ophthalmology and Visual Science, Graduated School of Medical and Dental Sciences, Niigata University, Niigata, JapanPurpose: To report corneal lamellar grafting to repair the late-onset complications after MMC trabeculectomy.Methods: Multiple case reports.Results: A 76-year-old male with primary open-angle glaucoma (POAG) and a 55-year-old male with late developmental glaucoma complicated by bleb leaks from a microhole 10 and eight years after surgery, respectively. Severe ciliochoroidal detachment and a shallow anterior chamber were persistent in one case and bleb-related infection recurred in another. Additionally, a 46-year-old male with POAG had hypotony maculopathy with a giant ischemic bleb 18 months after surgery. Although these patients were quite resistant to medical and surgical treatments, they were successfully treated by corneal lamellar grafting without complications. Conclusions: Tectonic corneal lamellar grafting is a reliable and final surgical method to improve severe cases of hypotony maculopathy or bleb leak after mitomycin C trabeculectomy.Keywords: mitomycin C, trabeculectomy, postoperative complications, hypotony maculopathy, bleb leak, corneal lamellar grafting

Takeo Fukuchi, Kimiko Wakai, Kieko Suda, Tomoko Nakatsue, Hideko Sawada, Hiroaki Hara, Jun Ueda, Takayuki Tanaka, Akiko Yamada, Haruki AbeDivision of Ophthalmology and Visual Science, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, JapanPurpose: To evaluate the incidence, severity, and factors related to drug-induced keratoepitheliopathy in eyes using antiglaucoma eye drops.Patients and methods: In a cross-sectional study, 749 eyes from 427 patients who had used one or more antiglaucoma eye drops were examined at Niigata University Medical and Dental Hospital or related facilities. The incidence and severity of superficial punctate keratitis (SPK), patient gender and age, type of glaucoma, and type of eye drops were recorded. SPK was graded according to the AD (A, area; D, density) classification. The severity score (SS) was calculated from A × D.Results: SPK was observed in 382 (51.0%) of 749 eyes that had received any type of antiglaucoma eye drops. While 254 eyes (33.9%) were classified as A1D1 (SS 1), 34 eyes (4.6%) had severe SPK with SS 4 or more. The number of eye drops and the total dosing frequency per day were significantly greater in SPK-positive eyes than in eyes without SPK. The number of eye drops was proportional to the frequency and severity of SPK. Among eyes that were treated with three or more eye drops, SPK was more severe and more frequent in older patients (≥71 years). In addition, a considerable difference was detected for each type of glaucoma.Conclusion: Drug-induced keratoepitheliopathy is often observed in eyes that have received recent antiglaucoma eye drops. The number of eye drops, the total dose frequency per day, patient age, and type of glaucoma may affect this condition. We have to consider not only the effects on intraocular pressure but also the incidence and severity of drug-induced keratoepitheliopathy as a frequent side effect of glaucoma medications.Keywords: glaucoma, medications