Role of interleukin-15 and nitric oxide expression in chronic inflammatory disease

Interleukin-15 (IL-15) is a pleiotropic cytokine produced by macrophages and fibroblasts, which mediates biological activities primarily through binding to the beta and gamma components of the IL-2 receptor, together with its own unique a chain. IL-15 induces T cell migration and activation, NK cell activation, B cell maturation and antibody production and monocyte activation. IL-15 mRNA is widely expressed in both immune and non-immune tissues and cells lines. However, the role of IL-15 in the context of any pathological situation remains unclear. Therefore, the role of IL-15 in a T helper-1 (Th1) disease prototype, rheumatoid arthritis (RA), and a Th2 disease prototype, asthma, was investigated in the present study. IL-15 was identified in RA synovial fluids. Following IL-15-mediated activation, peripheral blood (PB) T cells were capable of inducing TNF-alpha production from a macrophage cell line, from syngeneic PB monocytes, and from synovial macrophage / synoviocyte co-cultures, through a cell-contact dependent mechanism which required no T cell cytokine synthesis. RA synovial fluid (SF) T cells exhibited similar properties, which were IL-15-dependent in vitro. IL-15 up-regulated CD69 expression on CD45RO+ T cells and neutralisation studies determined that such CD69 expression, in combination with LFA-1 and ICAM-1, was partly responsible for cell- contact mediated macrophage activation by T cells. Furthermore, a similar mechanism operated in regulating cell-contact-induced IL-15 production by monocytes. Thus, activated T cells appeared to be effective costimulators of TNF-alpha and IL-15 production by monocytes via cell-cell contact, thereby generating a positive feedback loop. IL-15 also modulated cytokine production and adhesion molecule expression by RA neutrophils. Finally, in a murine model, IL-15 blockade profoundly suppressed the development of collagen-induced arthritis (CIA). This was accompanied in vitro by marked reductions in antigen-specific proliferation and interferon-gamma (IFN-y) synthesis by spleen cells from treated compared with control mice and in vivo by 4 significant reduction in serum anti-collagen antibody levels. Taken together, these data clearly demonstrated an important role for IL-15 in the development of inflammatory arthritis. Parallel studies established that epithelial cells and inflammatory leukocytes from the respiratory tract of asthma patients expressed IL-15. Moreover, such cells also expressed high levels of inducible nitric oxide synthase and produced NO in vitro. Expression of both IL-15 and iNOS was significantly suppressed in patients receiving inhaled corticosteroid therapy. In vitro studies demonstrated synergistic upregulation of TNF-alpha by IL-15 and NO providing evidence for interactions between radical inflammatory mediators and cytokines in chronic inflammatory responses

Cell-cell interactions in synovitis: Interactions between T lymphocytes and synovial cells

Mechanisms whereby T lymphocytes contribute to synovial inflammation in rheumatoid arthritis are poorly understood. Here we review data that indicate an important role for cell contact between synovial T cells, adjacent macrophages and fibroblast-like synoviocytes (FLS). Thus, T cells activated by cytokines, endothelial transmigration, extracellular matrix or by auto-antigens can promote cytokine, particularly TNFα, metalloproteinase production by macrophages and FLS through cell-membrane interactions, mediated at least through β-integrins and membrane cytokines. Since soluble factors thus induced may in turn contribute directly to T cell activation, positive feedback loops are likely to be created. These novel pathways represent exciting potential therapeutic targets

Symmetries of Lagrangian fibrations

We construct fiber-preserving anti-symplectic involutions for a large class of symplectic manifolds with Lagrangian torus fibrations. In particular, we treat the K3 surface and the quintic threefold. We interpret our results as corroboration of the view that in homological mirror symmetry, an anti-symplectic involution is the mirror of duality. In the same setting, we construct fiber-preserving symplectomorphisms that can be interpreted as the mirror to twisting by a holomorphic line bundle.Comment: 45 page

Preparation and Characterization of Monoclonal Antibodies Directed Against Antigenic Determinants of Recombinant Human Tumour Necrosis Factor (rTNF)

A large number of monoclonal antibodies (McAb) binding to antigenic determinants of human tumour necrosis factor (TNF) were prepared from two fusions of mouse myeloma NSO cells with spleen cells from Balb/c mice immunized with highly purified recombinant (r)TNF. Several of these McAbs were highly neutralizing with respect to the biological activity (cytotoxicity) of TNF manifested in L-929 C1.10 cells. Antibody competition experiments suggested the presence of at least two antigenic determinants on the rTNF molecule through which binding of McAb effects neutralization of biological activity. Some of these McAbs were shown to be suitable for the development of immuoassays to quantify rTNF

Dense and accurate motion and strain estimation in high resolution speckle images using an image-adaptive approach

Digital image processing methods represent a viable and well acknowledged alternative to strain gauges and interferometric techniques for determining full-field displacements and strains in materials under stress. This paper presents an image adaptive technique for dense motion and strain estimation using high-resolution speckle images that show the analyzed material in its original and deformed states. The algorithm starts by dividing the speckle image showing the original state into irregular cells taking into consideration both spatial and gradient image information present. Subsequently the Newton-Raphson digital image correlation technique is applied to calculate the corresponding motion for each cell. Adaptive spatial regularization in the form of the Geman-McClure robust spatial estimator is employed to increase the spatial consistency of the motion components of a cell with respect to the components of neighbouring cells. To obtain the final strain information, local least-squares fitting using a linear displacement model is performed on the horizontal and vertical displacement fields. To evaluate the presented image partitioning and strain estimation techniques two numerical and two real experiments are employed. The numerical experiments simulate the deformation of a specimen with constant strain across the surface as well as small rigid-body rotations present while real experiments consist specimens that undergo uniaxial stress. The results indicate very good accuracy of the recovered strains as well as better rotation insensitivity compared to classical techniques

Damage Spreading in a Driven Lattice Gas Model

We studied damage spreading in a Driven Lattice Gas (DLG) model as a function of the temperature $T$, the magnitude of the external driving field $E$, and the lattice size. The DLG model undergoes an order-disorder second-order phase transition at the critical temperature $T_c(E)$, such that the ordered phase is characterized by high-density strips running along the direction of the applied field; while in the disordered phase one has a lattice-gas-like behaviour. It is found that the damage always spreads for all the investigated temperatures and reaches a saturation value $D_{sat}$ that depends only on $T$. $D_{sat}$ increases for $TT_c(E=\infty)$ and is free of finite-size effects. This behaviour can be explained as due to the existence of interfaces between the high-density strips and the lattice-gas-like phase whose roughness depends on $T$. Also, we investigated damage spreading for a range of finite fields as a function of $T$, finding a behaviour similar to that of the case with $E=\infty$.Comment: 13 pages, 7 figures. Submitted to "Journal of Statistical Mechanics: Theory and Experiment

Expression profile of immune response genes in patients with Severe Acute Respiratory Syndrome

BACKGROUND: Severe acute respiratory syndrome (SARS) emerged in later February 2003, as a new epidemic form of life-threatening infection caused by a novel coronavirus. However, the immune-pathogenesis of SARS is poorly understood. To understand the host response to this pathogen, we investigated the gene expression profiles of peripheral blood mononuclear cells (PBMCs) derived from SARS patients, and compared with healthy controls. RESULTS: The number of differentially expressed genes was found to be 186 under stringent filtering criteria of microarray data analysis. Several genes were highly up-regulated in patients with SARS, such as, the genes coding for Lactoferrin, S100A9 and Lipocalin 2. The real-time PCR method verified the results of the gene array analysis and showed that those genes that were up-regulated as determined by microarray analysis were also found to be comparatively up-regulated by real-time PCR analysis. CONCLUSIONS: This differential gene expression profiling of PBMCs from patients with SARS strongly suggests that the response of SARS affected patients seems to be mainly an innate inflammatory response, rather than a specific immune response against a viral infection, as we observed a complete lack of cytokine genes usually triggered during a viral infection. Our study shows for the first time how the immune system responds to the SARS infection, and opens new possibilities for designing new diagnostics and treatments for this new life-threatening disease

SYZ mirror symmetry for hypertoric varieties

We construct a Lagrangian torus fibration on a smooth hypertoric variety and a corresponding SYZ mirror variety using $T$-duality and generating functions of open Gromov-Witten invariants. The variety is singular in general. We construct a resolution using the wall and chamber structure of the SYZ base.Comment: v_2: 31 pages, 5 figures, minor revision. To appear in Communications in Mathematical Physic

The Equivalence Theorem and Effective Lagrangians

We point out that the equivalence theorem, which relates the amplitude for a process with external longitudinally polarized vector bosons to the amplitude in which the longitudinal vector bosons are replaced by the corresponding pseudo-Goldstone bosons, is not valid for effective Lagrangians. However, a more general formulation of this theorem also holds for effective interactions. The generalized theorem can be utilized to determine the high-energy behaviour of scattering processes just by power counting and to simplify the calculation of the corresponding amplitudes. We apply this method to the phenomenologically most interesting terms describing effective interactions of the electroweak vector and Higgs bosons in order to examine their effects on vector-boson scattering and on vector-boson-pair production in $f\bar{f}$ annihilation. The use of the equivalence theorem in the literature is examined.Comment: 20 pages LaTeX, BI-TP 94/1

Hamiltonian Quantization of Effective Lagrangians with Massive Vector Fields

Effective Lagrangians containing arbitrary interactions of massive vector fields are quantized within the Hamiltonian path integral formalism. It is proven that correct Hamiltonian quantization of these models yields the same result as naive Lagrangian quantization (Matthews's theorem). This theorem holds for models without gauge freedom as well as for (linearly or nonlinearly realized) spontaneously broken gauge theories. The Stueckelberg formalism, a procedure to rewrite effective Lagrangians in a gauge invariant way, is reformulated within the Hamiltonian formalism as a transition from a second class constrained theory to an equivalent first class constrained theory. The relations between linearly and nonlinearly realized spontaneously broken gauge theories are discussed. The quartically divergent Higgs self interaction is derived from the Hamiltonian path integral.Comment: 16 pages LaTeX, BI-TP 93/1