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The thymus is an organ required for T cell development and is also an eosinophil-rich organ; however, the nature and function of thymic eosinophils remain unclear. Here, we characterized the gene expression and differentiation mechanism of thymic eosinophils in mice. Thymic eosinophils showed a distinct gene expression profile compared with other organ-resident eosinophils. The number of thymic eosinophils was controlled by medullary thymic epithelial cells (mTECs). In Rag-deficient mice, the unique gene expression signature of thymic eosinophils was lost but restored by pre-T cell receptor signalling, which induces CD4+ CD8+ thymocyte differentiation, indicating that T cell differentiation beyond the CD4- CD8- stage is necessary and sufficient for the induction of thymic eosinophils. These results demonstrate that thymic eosinophils are quantitatively and qualitatively regulated by mTECs and developing thymocytes, respectively, suggesting that thymic eosinophils are a distinct, thymus-specific cell subset, induced by interactions with thymic cells., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Society for Immunology.)

Background: In allergic models, administration of rice that expresses a hybrid peptide consisting of 7 major T cell epitopes of Cry j 1 and Cry j 2 (7Crp), suppressed allergic symptoms, IgE elevation and specific T cell response to Japanese cedar pollen., Objective: To evaluate the efficacy and safety of 7Crp-expressing rice in patients with Japanese cedar pollinosis., Methods: A 24-week randomized, double-blind, placebo-controlled study was performed to see the efficacy of 7Crp on allergic symptoms using scoring systems, in which 45 patients were assigned to take either 5 g, 20 g test rice, or placebo daily. A 96-week open study was also conducted to determine its inhibitory effect on serum IgE and T cell proliferative response for Japanese cedar pollen, in which 10 patients consumed 5 g test rice daily., Results: No adverse events associated with the test rice occurred, and the intake rate was more than 96%. The test rice did not show suppression of symptoms related to Japanese cedar pollinosis within 24 weeks. However, intake of 5 g test rice led to a significant decrease in T cell response to Japanese cedar pollen during and after the second disperse season in a 96-week open trial, whereas the specific IgE titer remained unchanged., Conclusions: Tolerability and safety of 7Crp-expressing rice was accepted. Daily intake of up to 20 g transgenic rice did not provide beneficial effects on Japanese cedar pollinosis within 24 weeks, however, continuous intake of 5 g rice might reduce allergen specific T cell response.

Medullary thymic epithelial cells (mTECs) help shape the thymic microenvironment for T-cell development by expressing a variety of peripheral tissue-restricted antigens (TRAs). The self-tolerance of T cells is established by negative selection of autoreactive T cells that bind to TRAs. To increase the diversity of TRAs, a fraction of mTECs terminally differentiates into distinct subsets resembling atypical types of epithelial cells in specific peripheral tissues. As such, thymic tuft cells that express peripheral tuft cell genes have recently emerged. Here, we show that the transcription factor SRY-box transcription factor 4 (Sox4) is highly expressed in mTECs and is essential for the development of thymic tuft cells. Mice lacking Sox4 specifically in TECs had a significantly reduced number of thymic tuft cells with no effect on the differentiation of other mTEC subsets, including autoimmune regulator (Aire)+ and Ccl21a+ mTECs. Furthermore, Sox4 expression was diminished in mice deficient in TEC-specific lymphotoxin β receptor (LTβR), indicating a role for the LTβR-Sox4 axis in the differentiation of thymic tuft cells. Given that Sox4 promotes differentiation of peripheral tuft cells, our findings suggest that mTECs employ the same transcriptional program as peripheral epithelial cells. This mechanism may explain how mTECs diversify peripheral antigen expression to project an immunological self within the thymic medulla., (© The Japanese Society for Immunology. 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A 59-year-old man presented with fever and lower extremity myalgia. Laboratory studies revealed elevated C-reactive protein. F-FDG PET/CT demonstrated FDG uptake not only in the brachial arteries, femoral arteries, and their main ramifications, which were equivalent to small- to medium-sized arteries but also in the kidneys. Angiography revealed a renal aneurysm, confirming the diagnosis of polyarteritis nodosa. The increased FDG uptake in the vessels and kidneys resolved after 6 months of glucocorticoid treatment.

We report on a rare manifestation of myeloid sarcoma with chronic myelogenous leukemia. The neoplasm arising from a rib showed osteolytic changes and infiltrated the surrounding muscles. We resected the lesion to relieve chest pain caused by pathologic rib fractures. The patient has continued receiving systemic therapy and is doing well as of 1 year postoperatively. Experience with a surgical approach for myeloid sarcoma is limited in thoracic surgery. The clinical course in our case suggests that surgical resection can be a valid choice of treatment., (Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

A 53-year-old man was referred to our hospital for treatment of two anterior mediastinal tumors. The anterior mediastinal tumors were resected by thymectomy under the probable diagnosis of double thymomas. The final pathological diagnosis was multiple thymic carcinoids. Although 20%-25% of patients with thymic carcinoid have a family history of multiple endocrine neoplasia type 1 (MEN-1), radiographic screening just after the operation did not detect any endocrine tumors. However, the patient had a urinary calculus 4 months 7 months after the operation. Endocrinological examination then revealed mild hypercalcemia, hypophosphatemia, hyperinsulinemia, and hyperprolactinemia. Radiologically, a parathyroid tumor and a pancreatic tumor were found. The patient was referred to a university hospital and a mutation of MEN-1 gene was detected. The diagnosis of MEN-1 was confirmed about 1 year after the operation.

The patient was a 76-year-old man who had a prior history of recurrent pneumonia and severe, chronic sinusitis. Computed tomography showed a thymoma, and laboratory results revealed hypogammaglobulinemia. Therefore, Good's Syndrome (GS, rare adult-onset immunodeficiency with thymoma) was diagnosed. To treat his sinusitis, we started the patient on long-term clarithromycin therapy, preoperatively. A thymothymectomy was performed, but the immunological disorder was not resolved. Although standard gamma globulin replacement was not given, his sinusitis symptoms were ameliorated, and he has not had pneumonia since the operation. Long-term macrolide therapy probably plays some role in managing sino-pulmonary infections associated with GS.

Solitary osteochondroma of the rib is a rare primary chest wall tumor. Herein, we report a case of a successfully resected osteochondroma of the rib. The patient was a 73-year-old asymptomatic woman who came to our hospital regularly for treatment of hypertension and hyperlipidemia. A checkup chest roentgenogram showed a shadow at the right anterior chest wall consistent with a mass, and computed tomography showed a tumor arising from the right fourth rib. Because it was impossible to exclude completely the diagnosis of a well-differentiated chondrosarcoma, we performed resection of the right anterior chest wall and a re construction with a rigid prosthesis. The post operative course of the patient was unremarkable. The final pathological diagnosis of the rib tumor was osteochondroma.

Background: Mutations in Kelch-like ECH-associated protein 1 (Keap1) have been reported to protect tumor cells from chemotherapeutic agents. However, their prognostic significance in nonsmall cell lung cancer (NSCLC) is still unclear. In this study, we examined the effect of Keap1 gene mutations on survival and disease-free interval using resected primary NSCLC tissue., Methods: We retrospectively analyzed the tumors from 79 patients with completely resected pathological Stage I-II NSCLC for the presence of Keap1 gene mutations and examined the prognosis of the patients., Results: Keap1 gene mutations were detected in four patients (5.1%). The postoperative 5-year survival rate for patients with Keap1 mutations was significantly lower than those without a mutation (25% vs. 76%, P = 0.038). The postoperative 5-year disease-free survival rate for patients with a mutant Keap1 tumor was slightly lower than for patients with Keap1 wild-type tumors (25% vs. 66%, P = 0.057)., Conclusions: Keap1 gene mutations are likely to be associated with a worse prognosis and lower postoperative disease-free survival rates in pathological Stage I-II NSCLC., ((c) 2010 Wiley-Liss, Inc.)

Background: A fusion gene between echinoderm microtubule-associated protein-like 4 (EML4) and the anaplastic lymphoma kinase (ALK) has recently been identified in nonsmall-cell lung cancers (NSCLCs). We screened for EML4-ALK fusion genes and examined the clinicopathological and genetic characteristics of fusion-harboring NSCLC tumors., Methods: We examined 313 NSCLC samples from patients who underwent resection at our hospital between May 2001 and July 2005. We screened for the fusion genes using reverse-transcription polymerase chain reaction (RT-PCR) assay and confirmed the results with direct sequencing. We also examined mutations in the epidermal growth factor receptor (EGFR), KRAS, and ERBB2 genes., Results: Five EML4-ALK fusion genes were detected (four from 111 female samples and one from 202 male samples; 1.6% overall). All five genes were found in adenocarcinomas and accounted for 2.4% of the 211 adenocarcinoma samples. One EML4-ALK fusion was variant 1, and two were variant 3. In addition, we also found two new fusion variants. Patients with fusion-positive tumors were nonsmokers or light smokers. Among the 211 adenocarcinomas, mutations in EGFR, KRAS, and ERBB2 were detected in 105, 29, and 7 tumors, respectively. Interestingly, all of the fusion-positive NSCLCs had no mutations within these genes., Conclusions: EML4-ALK fusion genes were observed predominantly in adenocarcinomas, in female or nonsmoking populations. Additionally, the EML4-ALK fusions were mutually exclusive with mutations in the EGFR, KRAS, and ERBB2 genes.

Background and Objectives: A disintegrin and metalloprotease 12 (ADAM12) has multiple domains and functions, and it plays important roles in the development of cancer. We conducted a retrospective study to determine whether the expression of the membrane type of ADAM12 (ADAM12-L) could be a prognostic factor in resected pathological (p-) stage I lung adenocarcinoma., Methods: ADAM12-L mRNA expression was quantified by a reverse-transcription polymerase chain reaction in tissue samples from 84 completely resected p-stage I lung adenocarcinoma patients. The patients were divided into ADAM12-L-Low and ADAM12-L-High groups, and correlations with clinicopathologic features were obtained., Results: Five-year survival rates of the ADAM12-L-Low and ADAM12-L-High groups were 95.1% and 71.9%, respectively. The postoperative prognosis for the ADAM12-L-High group was significantly poorer than for the ADAM12-L-Low group (P = 0.006). Multivariate analysis confirmed that high expression of ADAM12-L was an independent factor for poor prognosis (P = 0.007, hazard ratio 8.288). The ADAM12-L-High group was less differentiated and had a significantly higher rate of cancer recurrence., Conclusions: ADAM12-L mRNA expression is an independent prognostic factor in resected p-stage I lung adenocarcinoma, and is significantly correlated with tumor differentiation stage and postoperative cancer recurrence.

Background: The authors elucidated particular chemokine receptors that are expressed on lung cancer cells, as well as the clinical significance of the expression of these chemokine receptors in completely resected nonsmall cell lung cancer (NSCLC)., Methods: The authors examined gene expression of chemokine receptors (CCR1-11, CXCR1-7, XCR1, and CX3CR1) in 11 cell lines of lung cancer, and gene expression of CXCR3, CXCR4, and CXCR7 (CXCR3/4/7) in surgical specimens of 127 patients who underwent complete resection for their NSCLC between May 2001 and December 2002, using quantitative real-time reverse transcriptase-polymerase chain reaction (PCR). Mutation detection analysis of the EGFR genes using the PCR single-strand conformational polymorphism method was evaluated in patients with pathological (p-) stage I adenocarcinoma., Results: Substantial expression of CXCR3/4/7 mRNA was observed in all NSCLC cell lines examined. In p-stage I NSCLC, CXCR4 and CXCR7 expression values in patients with postoperative metastatic recurrence (Rec-Distant) were significantly higher than in those without recurrences (P = .003 and P = .007, respectively). In addition, the 5-year disease-free survival (DFS) rate of high CXCR7-expressing patients (63.2%) was significantly lower than that of low CXCR7-expressing patients (84.8%) (P = .033). The EGFR mutation was significantly more frequent in patients with higher CXCR7 expression (14 of 21 patients) than in those with lower CXCR7 expression (12 of 32 patients) (P = .038). A multivariate analysis confirmed that high CXCR7 expression was an independent and significant factor predicting a poor DFS in p-stage I NSCLC patients (P = .041)., Conclusions: Higher expression of CXCR7 is associated with Rec-Distant and poor DFS in patients with p-stage I NSCLC., ((c) 2009 American Cancer Society.)

Background and Objectives: Tissue inhibitor of metalloproteinase-3 (TIMP-3) inhibits the activity of metalloproteinases that play important roles in development and progression of malignant tumors. We conducted a retrospective study of TIMP-3 expression in resected non-small cell lung cancer (NSCLC)., Methods: TIMP-3 expression was examined immunohistochemically in primary tumor specimens from 143 patients who underwent complete resection for NSCLC. Correlations between TIMP-3 expression grade and tumor histology, TNM classification, MMP-2 and MMP-9 expression grade, VEGF expression grade, intra-tumoral microvessel density, proliferative index, apoptosis index, and prognosis were analyzed., Results: TIMP-3 expression was low in 40, moderate in 71, and high in 32 patients. Higher TIMP-3 expression was seen in squamous cell carcinoma than in adenocarcinoma (P = 0.001), and reduced TIMP-3 expression was significantly associated with nodal involvement (P = 0.016) and advanced pathologic stage (P = 0.036). MMP-2 expression was reduced along with enhanced TIMP-3 expression (P = 0.010). The 5-year overall survival rates of low, moderate, and high TIMP-3 patients were 53, 64, and 84%, respectively (P = 0.037). Multivariate analysis confirmed that enhanced TIMP-3 expression was an independent factor for a favorable prognosis (P = 0.037)., Conclusions: TIMP-3 expression status was significantly correlated with pathologic stage and nodal involvement, and was an independent prognostic factor in resected NSCLC.

Perforin is known as a pore-forming cytotoxic granule released from cytotoxic T cells. Previous experiments in vitro revealed the presence of precursor cells that are capable of producing perforin in the immune system cells. The present study was undertaken to examine whether perforin-positive cells could be induced in the digestive tract and to characterize their precursor cells. Expression of perforin-positive cells in the intestine of Balb/c mice induced by OK-432 was analyzed by immunohistochemical staining and RT-PCR. Oral treatment of Balb/c mice with OK-432 resulted in the occurrence of perforin-positive cells in the inferior segment of small intestine, the superior segment of large intestine, mesenteric lymph nodes and spleen. In the small intestine, perforin-positive cells were found in the lamina propria mucosa. The presence of perforin-positive cells was also noted following long-term OK-432 treatment. Similar results were obtained following treatment with biological response modifiers such as lipopolysaccharide. In mice with GVHD (graft-versus-host disease), the presence of perforin-positive cells was noted in the small intestine and spleen. When the serial sections of the small intestinal mucosa from OK-432-treated mice were immunostained with anti-perforin, anti-CD8 and anti-asialo-GM1 antibodies, the perforin-positive cells were found to be CD8-positive. The results suggest that CD8(+) cells in lamina propria mucosa play a significant role as effectors in the mucosal immune system which is activated by various stimuli.

1. Tsukuba hypertensive mice (THM) carry both human renin and angiotensinogen genes, and develop hypertension. The animal has high levels of renin activity and angiotensin II concentration in the plasma. 2. Urinary excretion in THM was greater than in the control animal, non-transgenic C57BL/6j. THM showed a greater amount of daily water intake. The osmolality of 24 h urine was lower than that of the control animal. 3. When water was deprived for 12 h and then loaded with 0.25 mL/10 g bodyweight, the osmolality of urine at the first 0-3 h period was the same in THM and control, but significantly lower in THM at the following 3-6 h period, indicating that the urine concentrating activity is insufficient in THM compared with the control animal. 4. Urinary excretion of vasopressin was significantly higher in THM. Plasma aldosterone concentration and urinary excretion of aldosterone were also higher in THM. Plasma potassium level was significantly low. 5. The mechanism underlying the pathophysiology of polyuria is not totally explained; however, hypokalaemia, which was probably the result of hyperaldosteronism, may be at least partially involved, since hypokalaemia is considered to be a factor hampering the action of vasopressin for concentration of urine at the site of the collecting duct of the kidney.