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Lymphoproliferative disorders may occur in patients with rheumatoid arthritis (RA) who are treated with methotrexate. However, follicular thymic hyperplasia (FTH) associated with RA (FTH-RA) is generally not considered a lymphoproliferative disorder. To investigate the pathogenesis of FTH-RA, we examined 12 cases of FTH involving thymic enlargement, four of FTH involving RA and eight of FTH involving myasthenia gravis (MG). Increased numbers and larger germinal center (GC) size were observed in FTH-RA group. The percentage of distorted GCs was 13.3% in FTH-RA group and 3.25% in FTH associated with MG (FTH-MG) group. A greater meshwork of follicular dendritic cells was observed in the GCs of FTH-RA group. Positive indices of CD27

Background: Many cancers express heme oxygenase-1 ­(HO-1) at a higher frequency than healthy tissues, and this elevated expression is associated with cancer prognosis. Here, we aim to clarify the correlation between HO-1-expressing macrophage numbers and clinicopathological parameters of advanced colorectal cancer. Materials and Methods: Formalin-fixed and paraffin-embedded tissues of patients with advanced colorectal cancer were used. To detect HO-1 expression in macrophages, immunohistochemistry was performed. The number of positive cells was measured. Furthermore, HO-1 mRNA in colorectal cancer was examined by reverse transcription polymerase chain reaction. Results: Among the HO-1-negative and HO-1-positive groups, 58.02 and 85.00% of cases, respectively, were positive for lymph node metastasis. The disease-free survival (DFS) time was significantly shorter (p < 0.05) in the ­HO-1-positive group (2.44 years) than in the HO-1-negative group (4.09 years). However, according to the Cox proportional-hazards regression model, the HO-1-positive group could not be a risk factor of poor prognosis. HO-1 mRNA expression was confirmed in colorectal normal and cancer tissues. Conclusion: In this study, the correlation between HO-1-expressing macrophages and clinicopathological parameters in the tumor microenvironment of colorectal cancer was studied for the first time, and the expression was associated with lymph node metastasis and shortening of DFS.

Background It is yet a mystery whether dendritic cells (DCs) contact cancer stem cells (CSCs) and uptake CSC antigens in intrahepatic cholangiocarcinoma (ICC). The aim of this study was to examine the histological relationship between tumour cells expressing CSC markers and DCs infiltrating ICC. In addition, clinicopathological factors, including progression-free survival (PFS) and overall survival (OS), were compared between cases with many and few CSC marker-positive cells. Materials and methods Resected tissue sections of 22 cases with ICC were used for immunostaining to detect DC infiltration into ICC tumour nests positive for CD1a, DC-SIGN, DEC205, DC-LAMP, and CD123 and to detect ICC tumour cells positive for CSC markers such as CD44v9, EpCAM, and Sox9. The relationship between the number of CSC marker-positive cells and ICC clinicopathological factors was examined by Kaplan-Meier method and univariate and multivariate analyses using the Cox proportional hazards model. Results CD1a+ immature DCs infiltrated ICC tumour nests significantly more than the other types of DCs. Furthermore, they were frequently localized within CD44v9− and EpCAMhigh ICC tumour nests. According to Kaplan-Meier method, PFS and OS were longer in the Sox9high group than in the Sox9low group, and according to both univariate and multivariate analyses, Sox9 expression was an independent factor. Conclusion The present study first demonstrated that CD1a+ immature DCs frequently infiltrated CD44v9− and EpCAMhigh ICC tumour nests, suggesting the possibility of cell-to-cell contact between epithelial type immature DCs and CSCs in ICC. Furthermore, it was suggested that Sox9 expression in ICC may be a prognostic factor.

Blastic plasmacytoid dendritic cell (pDC) neoplasm (BPDCN) is a relatively rare hematological malignancy with significantly complex clinicopathological features that are still unclear. This study aimed to analyze the clinicopathological data of BPDCN and evaluate immunohistochemical detection of minimal bone marrow (BM) involvement. In this study, we examined skin and BM lesions from 6 patients with BPDCN. Neoplastic cells tested positive for CD303 (polyclonal, 100%; monoclonal, 40%) in the skin lesions and for CD303 (polyclonal, 100%; monoclonal, 67%) in the BM clots. Although immunostaining of CD4, CD56, CD123, CD303, and TCLl detected minimal BM involvement in 3 patients, morphological identification was challenging in the BM clots stained with hematoxylin–eosin. In conclusion, our results demonstrate the significance of observing BM smears to detect neoplastic cells and that immunohistochemical examination, including CD303 antibodies, is useful to detect minimal BM involvement. This study is the first to report the expression of thymic stromal lymphopoietin (TSLP) and its receptor in BPDCN cells. Therefore, the TSLP/TSLP receptor axis may be associated with the proliferation of BPDCN, and consequently, the survival of patients.

Aldehyde reductase encoded by the Akr1a gene catalyzes the NADPH-dependent reduction of a variety of aldehyde compounds, and it plays a role in the biosynthesis of ascorbic acid (AsA) by converting D-glucuronate to L-gulonate. Although supplementing drinking water with AsA (1.5 mg/mL) ameliorates the fertility of Akr1a −/− (KO) female mice, litter sizes in the KO mice are typically smaller than those for Akr1a +/+ (WT) mice, and about one-third of the neonates have a reduced stature. Half of the neonates in the smallest, developmentally retarded group died before weaning, and the remaining half (less than 6 g in weight) also barely grew to adulthood. While no difference was found in the number of fetuses between the KO and WT mice at 14.5-embryonic days, the sizes of the KO fetuses had already diverged. Among the organs of these retarded KO neonates at 30 d, the spleen and thymus were characteristically small. While an examination of spleen cells showed the normal proportion of immune cells, apoptotic cell death was increased in the thymus, which would lead to thymic atrophy in the retarded KO neonates. Plasma AsA levels were lower in the small neonates despite the fact that their mothers had received sufficient AsA supplementation, and the corticosterone levels were inversely higher compared to wild-type mice. Thus, insufficient AsA contents together with a defect in corticosterone metabolism might be the cause of the retarded growth of the AKR1A-deficient mice embryos and neonates.

We aimed to clarify the characteristics of heme oxygenase (HO)-1 expressing cells in the synovium from rheumatoid arthritis (RA) and osteoarthritis (OA), and to investigate the co-expression of HO-1 and IgG-Fc/HLA-DR complex.The characteristics of HO-1 expressing cells in the synovium were investigated by using immunohistochemistry. The co-expression of HO-1 and IgG-Fc/HLA-DR complex was examined by anThe number of HO-1A portion of HO-1

Follicular lymphoma (FL) has a meshwork of follicular dendritic cells (FDCs). We previously demonstrated the presence of estrogen receptor alpha (ERα)+CD23+ FDCs in grades 1‐2 FL. The significance of FDCs as a prognostic factor in FL remains unknown. The current study aimed to compare clinicopathological features, including prognosis, between FL with and without ERα+ FDCs. This study evaluated the clinicopathological significance of ERα expression in 70 FL patients by immunostaining. The presence of ERα mRNA on FDCs from 5 FL patients was confirmed by CD21/ERα double staining (immunohistochemistry and in situ hybridization). We defined patients with frequent ERα expression as the ERαhigh group and those with infrequent ERα expression as the ERαlow group. Thirty‐two patients were assigned to the ERαhigh group (45.7%), and 38 patients were assigned to the ERαlow group (54.3%). Both overall survival (OS) and progression‐free survival (PFS) were significantly better in the ERαhigh group than in the ERαlow group (OS, log‐rank, P = .0465; PFS, log‐rank, P = .0336). Moreover, high ERα expression on FDCs was an independent prognostic factor for OS in both the univariate ([hazard ratio] HR, 0.163; P = .0260) and multivariate (HR, 0.050; P = .0188) analyses and for PFS in both the univariate (HR, 0.232; P = .0213) and multivariate (HR, 0.084; P = .0243) analyses. ERα mRNA expression was detected in CD21+ FDCs within the neoplastic follicles of FL patients. In conclusion, a neoplastic follicular microenvironment with ERα‐positive FDCs might affect the grade and presence of the follicular pattern of FL and improve patient prognosis.

CD205 can be used to detect myoepithelial cells (MECs) and dendritic cells (DCs) in breast tissue. However, the usefulness of CD205 immunostaining in the pathological diagnosis of breast tumors is not fully understood. The objective of this study was to re-evaluate CD205 co-expression with other MEC markers, such as p63 and CD10, in nonneoplastic and neoplastic breast tissue and to evaluate its pathological diagnostic utility in these types of breast cancer.Nonneoplastic breast tissue samples with a terminal duct lobular unit and duct were obtained from fibroadenoma and mastopathy patients. Neoplastic breast tissue samples included ductal carcinoma in situ (DCIS) (n=43) and invasive ductal carcinoma (IDC) (n=60), including the tubule-forming type (n=20). These specimens were investigated by CD205, p63, and CD10 immunostaining.In addition to p63 and CD10, CD205 was expressed on MECs in nonneoplastic breast and DCIS tissue samples; CD205 was simultaneously detected on DCs that had infiltrated DCIS and IDC tumor nests. CD205 was expressed on cancer cells themselves in only 7.3% of the breast cancer samples. The number of intratumoral CD205⁺ DCs in tubular IDC was significantly higher than that in DCIS (P0.01).Because CD205 was simultaneously detected on MECs and DCs in the same breast tissue sections, it may be useful for distinguishing tubular IDC from DCIS.

Activation of the osteogenic signaling cascade (OSC) is thought to be involved in aortic valve stenosis. The aim of this study was to clarify the distribution of macrophage (M) subtypes in the calcified aortic valve and to clarify the relationship between osteoblast-like cells (OLC) and OSC activation. Thirty-six cases of calcified aortic valve were set as the calcification group, and six autopsy cases of aortic valve without pathological calcification comprised the noncalcification group. Aortic valve tissues were used in histological studies including single and double immunostaining to identify M subtypes, bone morphogenetic protein 2 (BMP2) and osteopontin, reverse transcription polymerase chain reaction (RT-PCR) for CD206, heme oxygenase-1 (HO-1), and BMP2 mRNAs and in situ RT-PCR for BMP2 mRNA. Ms positive for CD68, CD163, CD206, and HO-1 were significantly higher in the calcification group than in the noncalcification group (P < 0.01). Comparison of the positive cells in each section of the calcification group showed that cells of all M subtypes were found around calcifications. Osteopontin(+) cells were also observed around calcifications. CD163(+)/CD206(+) M2 and CD163(+)/HO-1(+) Mox were significantly higher in the sponge layer in both groups. In double immunofluorescence, CD206(+) and a portion of HO-1(+) Ms expressed BMP2, and in RT-PCR, CD206 or HO-1 mRNA was expressed in cases in which BMP2 was expressed. In in situ RT-PCR, expression of BMP2 mRNA was observed around calcifications. This work clarifies the distribution of M subtypes in calcified aortic valves. In addition, the results suggest that CD206(+) M2 and HO-1(+) Mox, which express BMP2 in calcified aortic valves, are OLC candidates.

In the present study, we investigated a part of the mechanism responsible for the effects of hot and cold compresses for extravasation of doxorubicin. We injected 20 μl of doxorubicin (DOX) (1 μg/μl) subcutaneously into the dorsal area in mice and observed the resulting skin lesions macroscopically and histologically from day 1 to day 14 thereafter in groups treated with a cold pack (18-20°C) and a hot pack (38-40°C) or left untreated (control). Immunofluorescence and RT-PCR for C5a receptor (CD88), interleukin-8 receptor (IL-8RA), and transient receptor potential cation channel subfamily V member 1 (TRPV1) were also performed. Macroscopic observation showed that the area of the skin lesion was significantly smaller in the cold group than in the control group, but was significantly larger in the hot group. The neutrophil count in the lesion was significantly higher in the hot group than in the cold (3 hrs) and control groups. The numbers of inflammatory cells expressing CD88 and IL-8RA were significantly lower in the cold group than that in the other groups at almost time points and in the hot groups at later time points, respectively. The number of nerve fascicles expressing TRPV1 was higher in the hot group than in the cold group on days 1, 3 and 14. mRNA for CD88, IL-8RA and TRPV1 was detectable by reverse transcription-polymerase chain reaction in both the cold and hot pack groups. Consequently, these results suggested that the cold pack for the extravasation of DOX might reduce inflammation.

Hormone therapy has been used for patients with estrogen receptor alpha (ERα)–positive breast cancers. Recently, some studies reported the expression of ERα on neoplastic cells from B‐cell lymphomas. However, there has been only one report of ERα expression on the follicular dendritic cells (FDCs) that structurally and functionally support the microenvironment of follicular lymphomas (FLs). The objective of this study was to investigate the frequency of ERα expression on FDCs in nonneoplastic reactive lymphoid tissues and to compare the frequency of ERα expression on FDCs in the axillary lymph nodes between patients with and without antiestrogen therapy and among patients with grades 1‐3 of FL. Reverse transcription–polymerase chain reaction was performed to detect ERα mRNA in FL. In nonneoplastic germinal centers (GCs) from patients with tonsillitis or reactive lymphadenitis, ERα was expressed in the light zone. ERα‐positive cells strongly correlated with the width of GCs (r s = 0.81, P

Transient receptor potential melastatin 8 (TRPM8) is a member of the transient receptor potential superfamily of Ca2+ channels. The aim of the present study was to clarify TRPM8 expression in reactive lymphoid tissues and mature B-cell neoplasms. Reactive and neoplastic lymphoid tissues were used to evaluate TRPM8 expression by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). TRPM8+ cells were frequently detected in the follicular light zone and marginal zone of reactive lymphoid tissues. Double immunostaining revealed that TRPM8+ cells co-expressed cluster of differentiation (CD) 38, CD79a, CD138, interferon regulatory factor 4/melanoma associated antigen (mutated) 1, B cell CLL/lymphoma 6 and transmembrane activator and CAML interactor. TRPM8+ neoplastic cells were frequently detected in plasma cell myeloma. The positive band of TRPM8 mRNA was confirmed by RT-PCR in cases of myeloma. The present study is, to the best of our knowledge, the first to demonstrate the expression of TRPM8 in reactive lymphoid tissues and mature B-cell neoplasms, revealing that TRPM8 is frequently expressed in pre-plasmablasts, plasmablasts, plasma cells and mature B-cell lymphomas that are likely to differentiate into plasma cells.

The aim of this study was to evaluate the localization of collagen modifying enzymes (CMEs) on fibroblastic reticular cells (FRCs) and follicular dendritic cells (FDCs) in non-neoplastic lymphoid tissues and various malignant lymphomas. The expression of prolyl 4-hydroxylase 1 (P4H1), lysyl hydroxylase 3 (LH3), and protein disulfide isomerase (PDI) was frequently observed on FRCs and FDCs in the germinal center (GC), except for the mantle zone. The expression of CMEs was lower in most lymphomas than in their respective postulated normal counterparts. The ratio of transglutaminase II+ FRCs/CD35+ FDCs was also lower in follicular lymphomas (FL) than in other lymphomas. The mRNAs of some CMEs (P4H1, prolyl 4-hydroxylase 3, LH3, and heat shock protein 47) were confirmed in almost all lymphomas. These results indicate that lymphoma cell proliferation suppresses/decreases the number of CMEs expressing FRCs and FDCs in most lymphomas.

A 70-year-old man complained of fever and sore throat accompanied by hoarseness of voice. On physical examination, there was no systemic abnormality but a mild lymphadenopathy of cervical lymph nodes. With laryngoscopy, there was a marked outgrowth of the bilateral palatine tonsils proximal to the vocal cord. The histology of the resected tumor was compatible with angioimmunoblastic T cell lymphoma (AITL), revealing the effacement of normal tonsillar architecture and small to medium-sized neoplastic cell proliferation around marked vascular proliferation and atrophic lymphoid follicles. Tumor cells were positive for conventional T-cell antigens as well as for the follicular helper T-cell marker, PD-1, and CXCL13. Large hodgkinoid cells, but no tumor cells, were positive for latent membrane protein-1 and Epstein-Barr virus-encoded small RNA (EBER)-1 (in situ hybridization). Non-neoplastic, double positive cells for EBER-1 and CD20 were also scattered. Southern blot analysis revealed dual TCR-Cβ1 and IGH-JH gene rearrangements. Although the swelling of bilateral inguinal and perigastric lymph nodes developed later, the radical resection of tumor and chemotherapy appeared to be effective for the treatment of AITL with clinical stage IIIa. We here report a rare case of AITL involving palatine tonsil as primary site and give a review of the literature.

学位論文(Thesis), 学位論文要約