Transgenic Expression of Soluble Human CD5 Enhances Experimentally-Induced Autoimmune and Anti-Tumoral Immune Responses

CD5 is a lymphoid-specific transmembrane glycoprotein constitutively expressed on thymocytes and mature T and B1a lymphocytes. Current data support the view that CD5 is a negative regulator of antigen-specific receptor-mediated signaling in these cells, and that this would likely be achieved through interaction with CD5 ligand/s (CD5L) of still undefined nature expressed on immune or accessory cells. To determine the functional consequence of loss of CD5/CD5L interaction in vivo, a new transgenic mouse line was generated (shCD5EμTg), expressing a circulating soluble form of human CD5 (shCD5) as a decoy to impair membrane-bound CD5 function. These shCD5EμTg mice showed an enhanced response to autologous antigens, as deduced from the presentation of more severe forms of experimentally inducible autoimmune disease (collagen-induced arthritis, CIA; and experimental autoimmune encephalitis, EAE), as well as an increased anti-tumoral response in non-orthotopic cancer models (B16 melanoma). This enhancement of the immune response was in agreement with the finding of significantly reduced proportions of spleen and lymph node Treg cells (CD4+CD25+FoxP3+), and of peritoneal IL-10-producing and CD5+ B cells, as well as an increased proportion of spleen NKT cells in shCD5EμTg mice. Similar changes in lymphocyte subpopulations were observed in wild-type mice following repeated administration of exogenous recombinant shCD5 protein. These data reveal the relevant role played by CD5/CD5L interactions on the homeostasis of some functionally relevant lymphocyte subpopulations and the modulation of immune responses to autologous antigens

Analysis of ancestral and functionally relevant CD5 variants in systemic lupus erythematosus patients

OBJECTIVE: CD5 plays a crucial role in autoimmunity and is a well-established genetic risk factor of developing RA. Recently, evidence of positive selection has been provided for the CD5 Pro224-Val471 haplotype in East Asian populations. The aim of the present work was to further analyze the functional relevance of non-synonymous CD5 polymorphisms conforming the ancestral and the newly derived haplotypes (Pro224-Ala471 and Pro224-Val471, respectively) as well as to investigate the potential role of CD5 on the development of SLE and/or SLE nephritis. METHODS: The CD5 SNPs rs2241002 (C/T; Pro224Leu) and rs2229177 (C/T; Ala471Val) were genotyped using TaqMan allelic discrimination assays in a total of 1,324 controls and 681 SLE patients of Spanish origin. In vitro analysis of CD3-mediated T cell proliferative and cytokine response profiles of healthy volunteers homozygous for the above mentioned CD5 haplotypes were also analyzed. RESULTS: T-cell proliferation and cytokine release were significantly increased showing a bias towards to a Th2 profile after CD3 cross-linking of peripheral mononuclear cells from healthy individuals homozygous for the ancestral Pro224-Ala471 (CC) haplotype, compared to the more recently derived Pro224-Val471 (CT). The same allelic combination was statistically associated with Lupus nephritis. CONCLUSION: The ancestral Ala471 CD5 allele confers lymphocyte hyper-responsiveness to TCR/CD3 cross-linking and is associated with nephritis in SLE patients

Therapeutic targeting of CK2 in acute and chronic leukemias

Phosphorylation can regulate almost every property of a protein and is involved in all fundamental cellular processes. Thus, proper regulation of phosphorylation events is critical to the homeostatic functions of cell signaling. Indeed, deregulation of signaling pathways underlies many human diseases, including cancer.[1] The importance of phosphorylation makes protein kinases and phosphatases promising therapeutic targets for a wide variety of disorders.[2] CK2, formerly known as casein kinase II, was discovered in 1954, [3] although only recently, and especially over the last two decades, it has become one of the most studied protein kinases, due to its ubiquity, pleiotropy and constitutive activity. In particular, appreciation of its pleiotropy has completely changed our vision of CK2 biology, from an ordinary cell homeostasis-maintaining enzyme to a master kinase potentially implicated in many human physiological and pathological events. CK2 is responsible for about 25% of the phosphoproteome,[4] as it catalyzes the phosphorylation of >300 substrates.[5] This partly explains the CK2 interconnected roles that underlie its involvement in many signaling pathways. However, CK2 prevalent roles are promotion of cell growth and suppression of apoptosis. Accordingly, several lines of evidence support the notion that CK2 is a key player in the pathogenesis of cancer. High levels of CK2 transcript and protein expression, as well as increased kinase activity are associated with the pathological functions of CK2 in a number of neoplasias.[6] It was only over the last decade, after extensive analyses in solid tumors, that basic and translational studies have provided evidence for a pivotal role of CK2 in driving the growth of different blood cancers as well, although the first report demonstrating increased CK2 expression in acute myelogenous leukemia (AML) dates back to 1985.[7] Since then, CK2 overexpression/activity has been demonstrated in other hematological malignancies, including acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL) and chronic myelogenous leukemia (CML). [8] With the notable exceptions of CML and pediatric ALL, many patients with leukemias still have a poor outcome, despite the development of protocols with optimized chemotherapy combinations. Insufficient response to first-line therapy and unsalvageable relapses present major therapeutic challenges. Moreover, chemotherapy, even if successful, could have deleterious long-term biological and psychological effects, especially in children.[9] Furthermore, CML patients can develop resistance to tyrosine kinase inhibitors (TKIs), while both primary chemoresistant and relapsed pediatric ALL cases still remain an unresolved issue.[9

From IR to IE through GL

This paper describes the project MILK (Multilingual Indexing based on Lexical Knowledge), a cooperation between University of Brandeis and CELI (Centro per l'Elaborazione del Linguaggio e dell'Informazione). The project focuses on the interaction between information extraction and information retrieval in a web based multilingual scenario. This paper mainly elaborates on the Italian component of the system

MILK: a Hybrid system for Multilingual Indexing and Information Extraction

Substance Countable Countable Substance Human Animal Inanimate Figure 2: LKML hierarchy: top level. tic typing and recursive typing (identifying larger semantic tags) over a text is a "semi-structured" text, with less structure than a database file, but significantly more information than a text file. LKML-markup is the first step towards delivering automated content-based retrieval over text database. Semantically tagged portions of text will be indexed, together with some statistically inferred information about the document type. In a second phase, the information extraction component will be tailored to capture also individual referring concept, i.e., basically, all kinds of referential noun phrases. In parallel, information retrieval techniques will be applied to learn about the possibility of creating complex concepts in the hierarchy (in the first phase complex concepts are just inferred on a document base and are not driven by semantic inferences). In the last phase the inform..

Perspectives for the High Field Approach in Fusion Research and Advances within the Ignitor Program

The Ignitor Program maintains the objective of approaching D-T ignition conditions by incorporating systematical advances made with relevant high field magnet technology and with experiments on high density well confined plasmas in the present machine design. An additional objective is that of charting the development of the high field line of experiments that goes from the Alcator machine to the ignitor device. The rationale for this class of experiments, aimed at producing poloidal fields with the highest possible values (compatible with proven safety factors of known plasma instabilities) is given. On the basis of the favourable properties of high density plasmas produced systematically by this line of machines, the envisioned future for the line, based on novel high field superconducting magnets, includes the possibility of investigating more advanced fusion burn conditions than those of the D-T plasmas for which Ignitor is designed. Considering that a detailed machine design has been carried out (Coppi et al 2013 Nucl. Fusion 53 104013), the advances made in different areas of the physics and technology that are relevant to the Ignitor project are reported. These are included within the following sections of the present paper: main components issues, assembly and welding procedures; robotics criteria; non-linear feedback control; simulations with three-dimensional structures and disruption studies; ICRH and dedicated diagnostics systems; anomalous transport processes including self-organization for fusion burning regimes and the zero-dimensional model; tridimensional structures of the thermonuclear instability and control provisions; superconducting components of the present machine; envisioned experiments with high field superconducting magnets