Cognitive impairment is common in multiple sclerosis (MS). Unfortunately, the synaptic and molecular mechanisms underlying MS-associated cognitive dysfunction are largely unknown. We explored the presence and the underlying mechanism of cognitive and synaptic hippocampal dysfunction during the remission phase of experimental MS. Experiments were performed in a chronic-relapsing experimental autoimmune encephalomyelitis (EAE) model of MS, after the resolution of motor deficits. Immunohistochemistry and patch-clamp recordings were performed in the CA1 hippocampal area. The hole-board was utilized as cognitive/behavioural test. In the remission phase of experimental MS, hippocampal microglial cells showed signs of activation, CA1 hippocampal synapses presented an impaired long-term potentiation (LTP) and an alteration of spatial tests became evident. The activation of hippocampal microglia mediated synaptic and cognitive/behavioural alterations during EAE. Specifically, LTP blockade was found to be caused by the reactive oxygen species (ROS)-producing enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. We suggest that in the remission phase of experimental MS microglia remains activated, causing synaptic dysfunctions mediated by NADPH oxidase. Inhibition of microglial activation and NADPH oxidase may represent a promising strategy to prevent neuroplasticity impairment associated with active neuro-inflammation, with the aim to improve cognition and counteract MS disease progression.
Although the mechanisms underlying FAS overexpression in cancer are largely unknown, recent evidence (7-10) strongly suggests that, as in liver, FAS gene transcription in tumor cells is modulated by the sterol regulatory element binding protein-1 (SREBP-1).SREBP-1 is synthesized as an integral protein of the endoplasmic reticulum membranes. As its C-terminal regulatory domain interacts with SREBP cleavage-activating protein (SCAP), the SREBP/SCAP complex migrates to the Golgi membranes, where a two-step cleavage catalyzed by a serine protease [site-1 protease (S1P)] and a metalloprotease [site-2 protease (S2P)] is responsible for the release of the N-terminal sequence of SREBP-1 in the cytoplasm. At the nuclear level, mature SREBP-1, a transcription factor of the basic helix-loop-helix leucine zipper family, activates genes encoding FAS and other lipogenic enzymes by interacting with sterol response elements present in their promoter region (11). Insulin and dietary carbohydrates activate FAS gene transcription by this mechanism, whereas dietary polyunsaturated fatty acids (PUFAs) of both -6 and -3 series negatively modulate FAS expression by depressing SREBP-1 mRNA level and reducing the cleavage of the native protein (12, 13).Recently, it was found that pharmacological inhibitors of FAS are selectively cytotoxic to tumor cells in culture and in vivo (14-17). In particular, the FAS inhibitors cerulenin (2 S ,3 R -epoxy-4-oxo-7 E ,10 E -dodecadienamide) and C75 (3-carboxy-4-octyl-2-methylenebutyrolactone) induce Abbreviations: ACC, acetyl-CoA carboxylase; C/EBP, CCAAT enhancer binding protein; COX-2, cyclooxygenase-2; CPT-1, carnitine palmitoyltransferase-1; FAS, fatty acid synthetase; PPAR ␣ , peroxisome proliferator-activated receptor-␣ ; SCAP, sterol regulatory element binding protein-1 cleavage activating protein; S1P, site-1 protease; S2P, site-2 protease; SREBP-1, sterol regulatory element binding protein-1.
We found an overexpression of IgG free kappa light chain protein in both CIS and RR-MS patients, compared with control subjects and an increased expression of an apolipoprotein E isoform in RR-MS patients, compared with CIS and control groups. Our results confirm the presence of CSF proteome changes in MS patients. Future research should be aimed to investigate the role of these candidate CSF markers in larger cohorts of CIS and MS patients.
A typical feature in systemic lupus erythemathosus patients is the presence of autoantibodies to the carboxylterminal homologous P proteins (P0, P1, P2) domain (C-22 P0 epitope). In this report we provide evidence for the in vivo immunogenicity of the P0 protein in head and neck cancer patients as well as overexpression by immunohistochemistry of the C-22 P0 epitope in invasive carcinomas (55/57). Overexpression of this epitope was also significantly associated with a number of pathological lesions arising in the head and neck stratified epithelium including acanthosis (8/8), benign tumors (11/11), dysplasia (23/25) and in situ carcinomas (9/9). Intermediate cell layer restricted epitope overexpression was observed in well differentiated carcinomas, while undifferentiated tumors showed overexpression throughout the cell layers. Employing recombinant P proteins, sera from 40 of the 57 carcinoma patients and 39 normal donors, were subjected to immunoblot analysis. Immunity to P0 protein (7/40) was associated with malignancy and with advanced disease stage, but it was not dependent on the C-22 P0 epitope overexpression, although it was the preferential autoantibody target in 4 patients. Increased expression of the C-22 P0 epitope on the surface of pharynx cancer cells following cellular stress in vitro, may imply P0 protein presentation as an in vivo autoantibody target in cancer patients. Evidence for immunity to the P0 protein, as well as overexpression in patients with head and neck carcinoma may be relevant for monitoring cancer progression, in planning immunotherapeutic strategies, and contribute to the understanding of immuno-biological behaviour of head and neck carcinomas.
We generated a murine monoclonal antibody (B28p) detecting an antigenic determinant shared by the immunoglobulin superfamily receptor translocationassociated 1 (IRTA1) receptor (the immunogen used to raise B28p) and an unrelated 28-kDa protein that was subsequently subjected to extensive characterization. The expression of the 28-kDa protein in normal lymphohematopoietic tissues was restricted to B cells and plasma cells and clearly differed from that expected for IRTA1 (selectively expressed by mucosa-associated lymphoid tissue [ IntroductionDifferentiation of B cells to plasma cells, in which a crucial role is played by the plasma cell transcription factors B-lymphocyteinduced maturation protein 1 (Blimp1), X-box-binding protein 1 (XBP-1), and multiple myeloma oncogene-1 protein/interferon regulatory factor 4 (MUM1/IRF4), 1,2 results in down-regulation of B-cell-associated proteins and dramatic but still poorly understood changes in the phenotypic profile. 1,2 Better understanding of these changes is relevant to the study of normal B-cell ontogenesis as well as of multiple myeloma and lymphoma subtypes characteristically associated with plasma cell differentiation. 3,4 Proteins commonly used as immunohistochemical markers of plasma cell differentiation include, in addition to intracytoplasmic immunoglobulins, CD138/syndecan-1 (a collagen-1-binding proteoglycan possibly involved in plasma cell homing properties), 5 the p63 rough endoplasmic reticulum protein (antibody VS38c), 6,7 and MUM1/IRF4 (a transcription factor expressed by a late germinal center B-cell subset and plasma cells). 8 In the course of immunizations aimed at producing a monoclonal antibody (mAb) against the intracytoplasmic portion of the human immunoglobulin superfamily receptor translocationassociated 1 (IRTA1) protein, 9 a cell surface receptor we previously showed to be selectively expressed by mucosa-associated lymphoid tissue (MALT) marginal zone B cells and monocytoid B cells, 10 we generated a murine mAb (named B28p) that detects an antigenic determinant shared by IRTA1 and an unrelated 28-kDa protein. In this paper, we describe the characteristics of this 28-kDa molecule that by 2-dimensional polyacrylamide gel electrophoresis (2D-PAGE)/mass spectrometry was identified as the tumor protein D52 (TPD52) 11 and by immunohistochemistry showed a previously unrecognized 12,13 strong expression in all mature B cells, reaching its maximum level at the plasma cell stage. Moreover, in the Thiel myeloma cell line, TPD52 coimmunoprecipitated with annexin VI in a Ca 2ϩ -dependent manner, suggesting that these molecules may act in concert to regulate secretory processes of plasma cells, similarly to what was previously reported in pancreatic acinar cells. 14 These findings are of biologic relevance and also indicate that TPD52 can serve as a new tool for the diagnosis of B-cell malignancies. Materials and methods Generation of recombinant GST-IRTA1 proteinA cDNA fragment encoding the intracellular portion of the human IRTA1 protein was subcloned ...
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