A beta 2-Integrin/MRTF-A/SRF Pathway Regulates Dendritic Cell Gene Expression, Adhesion, and Traction Force Generation

beta 2-integrins are essential for immune system function because they mediate immune cell adhesion and signaling. Consequently, a loss of beta(2)-integrin expression or function causes the immunodeficiency disorders, Leukocyte Adhesion Deficiency (LAD) type I and III. LAD-III is caused by mutations in an important integrin regulator, kindlin-3, but exactly how kindlin-3 regulates leukocyte adhesion has remained incompletely understood. Here we demonstrate that mutation of the kindlin-3 binding site in the beta 2-integrin (TTT/AAA-beta 2-integrin knock-in mouse/KI) abolishes activation of the actin-regulated myocardin related transcription factor A/serum response factor (MRTF-A/SRF) signaling pathway in dendritic cells and MRTF-A/SRF-dependent gene expression. We show that Ras homolog gene family, member A (RhoA) activation and filamentous-actin (F-actin) polymerization is abolished in murine TTT/AAA-beta 2-integrin KI dendritic cells, which leads to a failure of MRTF-A to localize to the cell nucleus to coactivate genes together with SRF. In addition, we show that dendritic cell gene expression, adhesion and integrin-mediated traction forces on ligand coated surfaces is dependent on the MRTF-A/SRF signaling pathway. The participation of beta 2-integrin and kindlin-3-mediated cell adhesion in the regulation of the ubiquitous MRTF-A/SRF signaling pathway in immune cells may help explain the role of beta 2-integrin and kindlin-3 in integrin-mediated gene regulation and immune system function

Increased incidence of Mycoplasma pneumoniae infection in Finland, 2010-2011

Peer reviewe

Cooling Rates of Molecular Clouds Based on Numerical MHD Turbulence and non-LTE Radiative Transfer

We have computed line emission cooling rates for the main cooling species in models of interstellar molecular clouds. The models are based on numerical simulations of super-sonic magneto-hydrodynamic (MHD) turbulence. Non-LTE radiative transfer calculations have been performed to properly account for the complex density and velocity structures in the MHD simulations. Three models are used. Two of the models are based on MHD simulations with different magnetic field strength and the third includes the computation of self-gravity (in the super-Alfvenic regime of turbulence). The density and velocity fields in the simulations are determined self-consistently by the dynamics of super-sonic turbulence. The models are intended to represent molecular clouds with linear size L~6 pc and mean density ~300 cm^-3, with the density exceeding 10^4 cm^-3 in the densest cores. We present 12CO, 13CO, C18O, O2, OI, CI and H2O cooling rates in isothermal clouds with kinetic temperatures 10-80K. Analytical approximations are derived for the cooling rates. The inhomogeneity of the models reduces photon trapping and enhances the cooling in the densest parts of the clouds. Compared with earlier models the cooling rates are less affected by optical depth effects and are therefore higher. The main effects comes, however, from the density variation since cooling efficiency increases with density. This is very important for the cooling of the clouds as a whole since most cooling is provided by gas with density above the average.Comment: AASTeX, 19 pages, 15 figures; final, revised version; accepted to Ap

A Near-Infrared Imaging Survey of Coalsack Globule 2

We describe a near-infrared imaging survey of Globule 2 in the Coalsack. This Bok globule is the highest density region of this southern hemisphere molecular cloud and is the most likely location for young stars in this complex. The survey is complete for K < 14.0, H < 14.5, and J < 15.5, several magnitudes more sensitive than previous observations of this globule. From the large number of background stars, we derive an accurate near-infrared extinction law for the cloud. Our result, E_{J-H}/E_{H-K} = 2.08 \pm 0.03, is significantly steeper than results for other southern clouds. We use the J-H/H-K color-color diagram to identify two potential young stars with K < 14.0 in the region. We apply H-band star counts to derive the density profile of the Coalsack Globule 2 and use a polytropic model to describe the internal structure of this small cloud. For a gas temperature T \sim 15 K, this globule is moderately unstable.Comment: 19 pages, manuscript format; 6 figures -- Accepted by A

Ascitic complement system in ovarian cancer

Ovarian cancer spreads intraperitoneally and forms fluid, whereby the diagnosis and therapy often become delayed. As the complement (C) system may provide a cytotoxic effector arm for both immunological surveillance and mAb-therapy, we have characterised the C system in the intraperitoneal ascitic fluid (AF) from ovarian cancer patients. Most of the AF samples showed alternative and classical pathway haemolytic activity. The levels of C3 and C4 were similar to or in the lower normal range when compared to values in normal sera, respectively. However, elevated levels of C3a and soluble C5b-9 suggested C activation in vivo. Malignant cells isolated from the AF samples had surface deposits of C1q and C3 activation products, but not of C5b-9 (the membrane attack complex; MAC). Activation could have become initiated by anti-tumour cell antibodies that were detected in the AFs and/or by changes on tumour cell surfaces. The lack of MAC was probably due to the expression of C membrane regulators CD46, CD55 and CD59 on the tumour cells. Soluble forms of C1 inhibitor, CD59 and CD46, and the alternative pathway inhibitors factor H and FHL-1 were present in the AF at concentrations higher than in serum samples. Despite the presence of soluble C inhibitors it was possible to use AF as a C source in antibody-initiated killing of ovarian carcinoma cells. These results demonstrate that although the ovarian ascitic C system fails as an effective immunological surveillance mechanism, it could be utilised as an effector mechanism in therapy with intraperitoneally administrated mAbs, especially if the intrinsic C regulators are neutralised

Systemic administration of IL-33 induces a population of circulating KLRG1<SUP>hi</SUP>type 2 innate lymphoid cells and inhibits type 1 innate immunity against multiple myeloma

Type 2 innate lymphoid cells (ILC2s) are important producers of type 2 cytokines whose role in hematological cancers remains unclear. ILC2s are a heterogeneous population encompassing distinct subsets with different tissue localization and cytokine responsiveness. In this study, we investigated the role of bone marrow (BM) ILC2s and interleukin (IL)-33-stimulated ILC2s in multiple myeloma, a plasma cell malignancy that develops in the BM. We found that myeloma growth was associated with phenotypic and functional alterations of BM ILC2s, characterized by an increased expression of maturation markers and reduced cytokine response to IL-2/IL-33. We identified a population of KLRG1hi ILC2s that preferentially accumulated in the liver and spleen of Il2rg-/- Rag2-/- mice reconstituted with BM ILC2s. A similar population of KLRG1hi ILC2s was observed in the blood, liver and spleen of IL-33-treated wild-type mice. The presence of KLRG1hi ILC2s in ILC2-reconstituted Il2rg-/- Rag2-/- mice or in IL-33-treated wild-type mice was associated with increased eosinophil numbers but had no effect on myeloma progression. Interestingly, while decreased myeloma growth was observed following treatment of Rag-deficient mice with the type 1 cytokines IL-12 and IL-18, this protection was reversed when mice received a combined treatment of IL-33 together with IL-12 and IL-18. In summary, our data indicate that IL-33 treatment induces a population of circulating inflammatory KLRG1hi ILC2s and inhibits type 1 immunity against multiple myeloma. These results argue against therapeutic administration of IL-33 to myeloma patients