Cyclophilins are a family of proteins that bind the immunosuppressant cyclosporin A, possess peptidyl-prolyl cis-trans isomerase activity, and assist in the folding of proteins. Human cyclophilins A and B are host cell proteins that bind specifically to the HIV-1 Gag polyprotein p55gag in vitro. Here we report that viral particles formed by p55gag, in contrast to particles formed by the Gag polyproteins of other retroviruses, contain significant amounts of cyclophilin A. Sequences in the capsid domain of p55gag are both required and sufficient for the virion-association of cyclophilin A. The association of cyclophilin A with HIV-1 virions was inhibited in a dose-dependent manner by cyclosporin A as well as by SDZ NIM811 ([Melle-4]cyclosporin), a non-immunosuppressive analogue of cyclosporin A. Drug-induced reductions in virion-associated cyclophilin A levels were accompanied by reductions in virion infectivity, indicating that the association is functionally relevant. Moreover, SDZ NIM811 inhibited the replication of HIV-1 but was inactive against SIVMAC, a primate immunodeficiency virus closely related to HIV-1, which does not incorporate cyclophilin A.

IgG4-related disease is a recently proposed clinical entity with several unique clinicopathological features. Ocular adnexal IgG4-related disease, however, has not well been clarified. The purpose of the present study was to examine 21 patients (10 men, 11 women; age range, 39-86 years) with ocular adnexal IgG4-related disease. In 17 out of 21 patients (81%), the lacrimal glands were involved and bilateral lacrimal gland swelling was frequently observed (n = 12; 70.6%). In contrast, the conjunctiva was not involved in any of the patient. Histology was uniform with marked lymphoplasmacytic infiltration admixed with dense fibrosis, similar to previous reports of IgG4-related disease. Immunostaining detected numerous aggregates of IgG4-positive plasma cells. Serum IgG4 was higher than normal in 10 of the 13 patients tested, although it was measured after treatment in almost all cases. Interestingly, immunoglobulin heavy chain gene rearrangement was detected in two of 17 patients (12%) examined. The present results show that ocular adnexal IgG4-related disease has uniform clinicopathology: that is, disease involving the bilateral lacrimal glands with lymphoid hyperplasia and fibrosis, but not the conjunctiva. And presence of immunoglobulin heavy chain gene rearrangement suggests the possibility of B-cell lymphoma arising in a background of IgG4-related chronic inflammation. 2 Additionally, AIP has been described in association with other autoimmune disorders, such as chronic sclerosing sialadenitis (Küttner's tumor), sclerosing cholangitis and retroperitoneal fibrosis. 3-15IgG4-related disease is a recently proposed clinical entity and it has several unique clinical findings, but its pathogenesis and pathophysiology remain unclear.3-9 And ocular adnexal IgG4-related disease is either not mentioned or only briefly alluded to in previous reports. 6,[10][11][12] In the present study we examined ocular adnexal IgG4-related disease in detail, with specific reference to clinicopathological features. MATERIALS AND METHODS Patients and materialsWe reviewed the cases of 112 patients (orbital lesions, n = 78; conjunctival lesions, n = 34) with ocular adnexal lymphoproliferative disorders diagnosed between 1990 and 2006. All cases were retrieved from the files of the Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. Histology and immunohistochemistrySurgically resected or biopsied specimens of ocular adnexal lymphoid disorders were fixed in 10% formaldehyde and embedded in paraffin. Serial sections (4 mm) were cut from

It is not known how the protein Bcl-2 inhibits cell death induced by calcium signalling and growth-factor withdrawal. Here we report that Bcl-2 forms a tight complex with calcineurin, resulting in the targeting of calcineurin to Bcl-2 sites on cytoplasmic membranes, and show that this interaction is dependent on the BH4 domain of Bcl-2. Calcineurin bound to Bcl-2 is an active phosphatase but is unable to promote the nuclear translocation of NF-AT, a transcription-factor required for induction of interleukin-2 expression, suggesting a mechanism by which Bcl-2 suppresses NF-AT activity. We also show that Bax, a pro-apoptotic member of the Bcl-2 family, interferes with interactions between calcineurin and Bcl-2. We propose that the ability of Bcl-2 to block NF-AT signalling is due to the sequestering of active calcineurin to the same domain of Bcl-2 which associates with Rad-1 (ref. 5), and that calcineurin may act in Bcl-2-regulated functions.

Hippo and TGF-β converge on CTGF to promote malignant mesothelioma.

No abstract

Mouse B cells lacking NFATc1 exhibit defective proliferation, survival, isotype class switching, cytokine production, and T cell help.

Malignant lymphomas and reactive lymphoid hyperplasia (RLH) in the ocular adnexa are sometimes difficult to differentiate morphologically and have often been categorized together as a lymphoproliferative disorder. Immunogenotypic characters of these diseases have not yet been well clarified. This study included 76 cases of ocular adnexal lymphoproliferative disorders. These consisted of 52 cases of malignant lymphoma (43 primary and 9 secondary), 22 of RLH, and 2 borderline cases. There were slightly more male than female subjects. Diagnoses were based on morphology and immunophenotypic characteristics. Clonalities were detected by means of polymerase chain reaction (PCR), and immunoglobulin heavy-chain variable region (VH) genes were sequenced in 10 cases of mucosa-associated lymphoid tissue (MALT) lymphoma. MALT lymphoma constituted 86% (37 cases) of the primary lymphomas. MALT lymphomas were more indolent, more rarely disseminated, and had a lower death rate than the other primary lymphomas. Two patients exhibited coexistence of MALT and diffuse large B-cell lymphoma. The average age of patients with RLH was 5.5 years younger than that of those with MALT lymphoma. One of the cases of RLH later progressed to malignant lymphoma. B-cell clonality was detected by PCR in 57%, 55%, and 0% of primary lymphomas, MALT lymphomas and RLHs, respectively. Sequencing of VH genes revealed that the VH3 family was the most commonly expressed germline VH family (70%) and that DP-63, DP-54 and DP-47 genes were frequently found in the MALT lymphomas examined. PCR analysis was useful for differentiation between MALT lymphoma and RLH. Sequence analysis of VH genes showed that an autoimmune mechanism may be involved in the lymphomagenesis of ocular adnexal MALT lymphoma.

To investigate the lymphomagenesis of NK/T lymphoma, we comprehensively and systematically analyzed the expression pattern of the human NK/T cell line (NK-YS) genome by cDNA expression array and tissue microarray. We detected significant changes in the gene expression of NK-YS cell line: an increase in 18 and a decrease in 20 genes compared to normal NK cells or peripheral blood mononuclear cells. Among these genes, we found a strong decrease in hematopoietic cell specific protein-tyrosine-phosphatase SH-PTP1 (SHP1) mRNA by cDNA expression array and reverse transcriptase-polymerase chain reaction. Further analysis with standard immunohistochemistry and tissue microarray, which used 207 paraffin-embedded specimens of various kinds of malignant lymphomas, showed that 100% of NK/T lymphoma specimens and more than 95% of various types of malignant lymphoma were negative for SHP1 protein expression. On the other hand, SHP1 protein was strongly expressed in the mantle zone and interfollicular zone lymphocytes in reactive lymphoid hyperplasia specimens. In addition, various kinds of hematopoietic cell lines, particularly the highly aggressive lymphoma/leukemia lines, lacked SHP1 expression in vitro, suggesting that loss of SHP1 expression may be related to not only malignant transformation, but also tumor cell aggressiveness. SHP1 expression could not be induced in either of two NK/T cell lines by phorbol ester, suggesting that genetic impairment or modification with methylation of SHP1 DNA could be one of the critical events in the pathogenesis of NK/T lymphoma. This evidence strongly suggests that loss of SHP1 gene expression plays an important role in multistep tumorigenesis, possibly as an anti-oncogene in the wide range of lymphomas/leukemias as well as NK/T lymphomas.