NKT cells promote antibody-induced joint inflammation by suppressing transforming growth factor β1 production

Although NKT cells has been known to exert protective roles in the development of autoimmune diseases, the functional roles of NKT cells in the downstream events of antibody-induced joint inflammation remain unknown. Thus, we explored the functional roles of NKT cells in antibody-induced arthritis using the K/BxN serum transfer model. NKT cell–deficient mice were resistant to the development of arthritis, and wild-type mice administrated with α-galactosyl ceramide, a potent NKT cell activator, aggravated arthritis. In CD1d−/− mice, transforming growth factor (TGF)-β1 was found to be elevated in joint tissues, and the blockade of TGF-β1 using neutralizing monoclonal antibodies restored arthritis. The administration of recombinant TGF-β1 into C57BL/6 mice reduced joint inflammation. Moreover, the adoptive transfer of NKT cells into CD1d−/− mice restored arthritis and reduced TGF-β1 production. In vitro assay demonstrated that interleukin (IL)-4 and interferon (IFN)-γ were involved in suppressing TGF-β1 production in joint cells. The adoptive transfer of NKT cells from IL-4−/− or IFN-γ−/− mice did not reverse arthritis and TGF-β1 production in CD1d−/− mice. In conclusion, NKT cells producing IL-4 and IFN-γ play a role in immune complex–induced joint inflammation by regulating TGF-β1

Diagnostic Value of Galectin-3, HBME-1, Cytokeratin 19, High Molecular Weight Cytokeratin, Cyclin D1 and p27kip1 in the Differential Diagnosis of Thyroid Nodules

The distinction between benign and malignant thyroid tumors is critical for the management of patients with thyroid nodules. We applied immunohistochemical staining for galectin-3, HBME-1, cytokeratin 19 (CK19), high molecular weight cytokeratin (HMWCK), cyclin D1 and p27kip1 in 295 thyroid lesions to determine their diagnostic accuracy. The expression of all markers was significantly associated with differentiated thyroid carcinoma (DTC).The sensitivity for the diagnosis of DTC was 94.7% with galectin-3, 91.3% with HBME-1, and 90.3% with CK19. The specificities of these markers were 95.5%, 69.7%, and 83.1%, respectively. Combining these markers, co-expression of galectin-3 and CK19 or galectin-3 and HBME-1 was seen in 93.2% of carcinomas but in none of the benign nodules. Comparing follicular variant of papillary carcinoma (FVPC) with follicular carcinoma (FC), the expression of galectin-3, CK19, and HMWCK was significantly higher in FVPC. When comparing FC with FA, the expression of galectin-3 and HBME-1 was significantly higher in FC. These results suggest that 1) galectin-3 is a useful marker in the distinction between benign and malignant thyroid tumors, 2) the combined use of HBME-1 and CK19 can increase the diagnostic accuracy, and 3) the use of CK19 and HMWCK can aid in the differential diagnosis between PC and FC

Immunohistochemical and Molecular Characteristics of Follicular Patterned Thyroid Nodules with Incomplete Nuclear Features of Papillary Thyroid Carcinoma

Background : Follicular patterned thyroid nodules with incomplete nuclear features of papillary thyroid carcinoma (FTN-INPTCs) are difficult to diagnose, and their biological behavior and association with follicular variants of PTC (FVPTCs) have not yet been established. The aim of this study is to determine immunohistochemical and molecular characteristics of FTN-INPTCs. Methods : We investigated immunohistochemical features (galectin-3, HBME-1, CK19, fibronectin-1, CITED1), BRAF V600E mutation and RASSF1A promoter methylation status in 30 FTN-INPTC cases, along with 26 FVPTCs, 21 follicular adenomas (FAs) and 14 nodular hyperplasias (NHs). Results : Expression of galectin-3, HBME-1, CK19 and CITED1 was significantly higher in FTN-INPTCs than in FAs or NHs, but expression of galectin-3, CK19 and fibronectin-1 was lower in FTN-INPTCs than in FVPTCs. The BRAF V600E mutation was not detected in the benign nodules or FTN-INPTCs, whereas 57% of FVPTCs had the mutation. RASSF1A promoter methylation was higher in FTN-INPTCs than in benign nodules but there was no difference between FTN-INPTCs and FVPTCs. Conclusions : Our results represent the borderline immunohistochemical and molecular characteristics of FTN-INPTC. We conclude that FTN-INPTC is an intermediate lesion between a benign nodule and a FVPTC, and that it is pathogenetically related to FVPTC.This work was supported by the Korea Research Foundation Grant funded by the Korean Government (MOEHRD) (KRF-2006- 331-E00050).Arora N, 2008, WORLD J SURG, V32, P1237, DOI 10.1007/s00268-008-9484-1Park YJ, 2007, J KOREAN MED SCI, V22, P621CHAN JKC, 2007, DIAGNOSTIC HISTOPATH, P997Rhoden KJ, 2006, J CLIN ENDOCR METAB, V91, P2414, DOI 10.1210/jc.2006-0240de Matos PS, 2005, HISTOPATHOLOGY, V47, P391, DOI 10.1111/j.1365-2559.2005.02221.xNakamura N, 2005, LAB INVEST, V85, P1065, DOI 10.1038/labinvest.3700306Xing M, 2005, ENDOCR-RELAT CANCER, V12, P245, DOI 10.1677/erc.1.0978Papotti M, 2005, MODERN PATHOL, V18, P541, DOI 10.1038/modpathol.3800321Prasad ML, 2005, MODERN PATHOL, V18, P48, DOI 10.1038/modpathol.3800235Weisenberger DJ, 2005, NUCLEIC ACIDS RES, V33, P6823, DOI 10.1093/nar/gki987Vasko VV, 2004, EUR J ENDOCRINOL, V151, P779Kim KH, 2004, YONSEI MED J, V45, P818Gasbarri A, 2004, BRIT J CANCER, V91, P1096, DOI 10.1038/sj.bjc.6602097Xing MZ, 2004, CANCER RES, V64, P1664Kimura ET, 2003, CANCER RES, V63, P1454Hirokawa M, 2002, AM J SURG PATHOL, V26, P1508Schagdarsurengin U, 2002, CANCER RES, V62, P3698Fusco A, 2002, AM J PATHOL, V160, P2157Shivakumar L, 2002, MOL CELL BIOL, V22, P4309, DOI 10.1128/MCB.22.12.4309-4318.2002Coli A, 2002, HISTOPATHOLOGY, V40, P80Bartolazzi A, 2001, LANCET, V357, P1644Eads CA, 2001, CANCER RES, V61, P3410Williams ED, 2000, INT J SURG PATHOL, V8, P181Orlandi F, 1998, CANCER RES, V58, P3015Sack MT, 1997, MODERN PATHOL, V10, P668Herman JG, 1996, P NATL ACAD SCI USA, V93, P9821OKAYASU I, 1995, CANCER, V76, P2312BERHO M, 1995, ANN CLIN LAB SCI, V25, P513RAPHAEL SJ, 1994, MODERN PATHOL, V7, P295ROSAI J, 1992, ATLAS TUMOR PATHOL, P65

CD4+ T cells from MHC II-dependent thymocyte–thymocyte interaction provide efficient help for B cells

Recently, a novel CD4+ T-cell developmental pathway was reported that generates thymocyte–thymocyte (T–T) CD4+ T cells. We established a mouse system (CIITAtgCIITApIV−/−) where thymic positive selection occurred only by major histocompatibility complex (MHC) class II+ thymocytes. T–T CD4+ T cells selected via MHC class II-dependent T–T interaction are comprised of PLZF-negative and innate PLZF-positive populations. Until recently, the functional role of the PLZF-negative population was unclear. In this study, we demonstrate that naïve T–T CD4+ T cells provide B-cell help to a level comparable with that of naïve conventional CD4+ T cells. Considering the absence of PLZF expression in naïve T–T CD4+ T cells, these results suggest that PLZF-negative naïve T–T CD4+ T cells are functionally equivalent to conventional naïve CD4+ T cells in terms of B-cell help

MHC class II engagement inhibits CD99-induced apoptosis and up-regulation of T cell receptor and MHC molecules in human thymocytes and T cell line

AbstractMajor histocompatibility complex (MHC) class II surface levels on thymocytes increase after CD99 ligation. The functional implication of the up-regulated MHC class II was assessed by engaging MHC class II on CD99-ligated cells. MHC class II engagement down-modulated surface levels of T cell receptor and MHC molecules, and inhibited apoptosis of CD99-ligated thymocytes and CEM tumor cells, antagonistic effects on the previously reported CD99 functions. The results were reproducible regardless of the order of ligation of MHC class II and CD99. We suggest that signaling via MHC class II on CD99-engaged cells might be involved in the thymic maturation process by damping CD99 ligation effects

Generation of PLZF+ CD4+ T cells via MHC class II–dependent thymocyte–thymocyte interaction is a physiological process in humans

Human thymocytes, unlike mouse thymocytes, express major histocompatibility complex (MHC) class II molecules on their surface, especially during the fetal and perinatal stages. Based on this observation, we previously identified a novel developmental pathway for the generation of CD4+ T cells via interactions between MHC class II–expressing thymocytes (thymocyte–thymocyte [T–T] interactions) with a transgenic mouse system. However, the developmental dissection of this T–T interaction in humans has not been possible because of the lack of known cellular molecules specific for T–T CD4+ T cells. We show that promyelocytic leukemia zinc finger protein (PLZF) is a useful marker for the identification of T–T CD4+ T cells. With this analysis, we determined that a substantial number of fetal thymocytes and splenocytes express PLZF and acquire innate characteristics during their development in humans. Although these characteristics are quite similar to invariant NKT (iNKT) cells, they clearly differ from iNKT cells in that they have a diverse T cell receptor repertoire and are restricted by MHC class II molecules. These findings define a novel human CD4+ T cell subset that develops via an MHC class II–dependent T–T interaction

Regorafenib Regulates AD Pathology, Neuroinflammation, and Dendritic Spinogenesis in Cells and a Mouse Model of AD

The oral multi-target kinase inhibitor regorafenib, which targets the oncogenic receptor tyrosine kinase (RTK), is an effective therapeutic for patients with advanced gastrointestinal stromal tumors or metastatic colorectal cancer. However, whether regorafenib treatment has beneficial effects on neuroinflammation and Alzheimer's disease (AD) pathology has not been carefully addressed. Here, we report the regulatory function of regorafenib in neuroinflammatory responses and AD-related pathology in vitro and in vivo. Regorafenib affected AKT signaling to attenuate lipopolysaccharide (LPS)-mediated expression of proinflammatory cytokines in BV2 microglial cells and primary cultured microglia and astrocytes. In addition, regorafenib suppressed LPS-induced neuroinflammatory responses in LPS-injected wild-type mice. In 5x FAD mice (a mouse model of AD), regorafenib ameliorated AD pathology, as evidenced by increased dendritic spine density and decreased Aβ plaque levels, by modulating APP processing and APP processing-associated proteins. Furthermore, regorafenib-injected 5x FAD mice displayed significantly reduced tau phosphorylation at T212 and S214 (AT100) due to the downregulation of glycogen synthase kinase-3 beta (GSK3β) activity. Taken together, our results indicate that regorafenib has beneficial effects on neuroinflammation, AD pathology, and dendritic spine formation in vitro and in vivo.1

Molecular Cytogenetic Analysis of Gene Rearrangements in Childhood Acute Lymphoblastic Leukemia

The aims of this study were to estimate the incidences of BCR/ABL, MLL, TEL/AML1 rearrangements, and p16 deletions in childhood acute lymphoblastic leukemia (ALL), to identify new abnormalities, and to demonstrate the usefulness of interphase fluorescence in situ hybridization (FISH). We performed G-banding analysis and FISH using probes for BCR/ABL, MLL, TEL/AML1 rearrangements, and p16 deletions on 65 childhood ALL patients diagnosed and uniformly treated at a single hospital. Gene rearrangements were identified in 73.8% of the patients using the combination of G-banding and FISH, while the chromosomal abnormalities were identified in 49.2% using G-banding alone. Gene rearrangements were disclosed by FISH in 24 (72.7%) of 33 patients with normal karyotype or no mitotic cell in G-banding. Among the gene rearrangements detected by FISH, the most common gene rearrangement was p16 deletion (20.3%) and the incidences of others were 14.1% for TEL/AML1, 11.3% for MLL, and 1.8% for BCR/ABL translocations. Infrequent or new aberrations such as AML1 amplification, MLL deletion, ABL deletion, and TEL/AML1 fusion with AML1 deletion were also observed. We established the rough incidences of gene rearrangements in childhood ALL, found new abnormalities and demonstrated the diagnostic capability of interphase FISH to identify cryptic chromosome aberrations

The MAO Inhibitor Tranylcypromine Alters LPS- and A beta-Mediated Neuroinflammatory Responses in Wild-type Mice and a Mouse Model of AD

Monoamine oxidase (MAO) has been implicated in neuroinflammation, and therapies targeting MAO are of interest for neurodegenerative diseases. The small-molecule drug tranylcypromine, an inhibitor of MAO, is currently used as an antidepressant and in the treatment of cancer. However, whether tranylcypromine can regulate LPS- and/or Aβ-induced neuroinflammation in the brain has not been well-studied. In the present study, we found that tranylcypromine selectively altered LPS-induced proinflammatory cytokine levels in BV2 microglial cells but not primary astrocytes. In addition, tranylcypromine modulated LPS-mediated TLR4/ERK/STAT3 signaling to alter neuroinflammatory responses in BV2 microglial cells. Importantly, tranylcypromine significantly reduced microglial activation as well as proinflammatory cytokine levels in LPS-injected wild-type mice. Moreover, injection of tranylcypromine in 5xFAD mice (a mouse model of AD) significantly decreased microglial activation but had smaller effects on astrocyte activation. Taken together, our results suggest that tranylcypromine can suppress LPS- and Aβ-induced neuroinflammatory responses in vitro and in vivo.1