Ankylosing Spondylitis: a trade Off of HLA-B27, ERAP, and pathogen interconnections? Focus on Sardinia

The frequency of HLA-B27 in patients with Ankylosing Spondylitis (AS) is over 85%. There are more than 170 recognized HLA-B27 alleles but the majority of them is not sufficiently represented for genetic association studies. So far only two alleles, the HLA-B*2706 in Asia and the HLA-B*2709 in Sardinia, have not been found to be associated with AS. The highly homogenous genetic structure of the Sardinian population has favored the search of relevant variants for disease-association studies. Moreover, malaria, once endemic in the island, has been shown to have contributed to shape the native population genome affecting the relative allele frequency of relevant genes. In Sardinia, the prevalence of HLA-B*2709, which differs from the strongly AS-associated B*2705 prototype for one amino acid (His/Asp116) in the F pocket of the peptide binding groove, is around 20% of all HLA-B27 alleles. We have previously hypothesized that malaria could have contributed to the establishment of this allele in Sardinia. Based on our recent findings, in this perspective article we speculate that the Endoplasmic Reticulum Amino Peptidases, ERAP1 and 2, associated with AS and involved in antigen presentation, underwent co-selection by malaria. These genes, besides shaping the immunopeptidome of HLA-class I molecules, have other biological functions that could also be involved in the immunosurveillance against malaria

Expression analysis of HLA-E and NKG2A and NKG2C receptors points at a role for natural killer function in ankylosing spondylitis

Background. Ankylosing Spondylitis (AS) is a complex chronic inflammatory disease strongly associated with the majority of HLA-B27 alleles. HLA-E are non-classical MHC class I molecules that specifically interact with the natural killer receptors NKG2A (inhibitory) and NKG2C (activating), and have been recently proposed to be involved in AS pathogenesis. Objectives: To analyze the expression of HLA-E and the CD94/NKG2 pair of receptors in HLA-B27 positive AS patients and healthy controls (HC) bearing the AS-associated, B*2705 and the non-AS-associated, B*2709 allele. Methods: The level of surface expression of HLA-E molecules on CD14 positive peripheral blood mononuclear cell was evaluated in 21 HLA-B*2705 patients with AS, 12 HLA-B*2705 HC, 12 HLA-B*2709 HC and 6 HLA-B27 negative HC, using the monoclonal antibody MEM-E/08 by quantitative cytofluorimetric analysis. The percentage and density of expression of HLA-E ligands NKG2A and NKG2C were also measured on CD3-CD56+ NK cells. Results. HLA-E expression in CD14 positive cells was significantly higher in AS patients (587.0 IQR 424-830) compared to B*2705 HC (389 IQR 251.3-440.5, p=0.0007), B*2709 HC (294.5 IQR 209.5-422, p=0.0004) and HLA-B27 negative HC (380 IQR 197.3-515.0, p=0.01). A higher number of NK cells expressing NKG2A compared to NKG2C was found in all cohort analysed as well as a higher cell surface density. Conclusion: The higher surface level of HLA-E molecules in AS patients compared to HC, concurrently with a prevalent expression of NKG2A, suggests that the crosstalk between these two molecules might play a role in AS pathogenesis accounting for the previously reported association between HLA-E and AS

Enantioselective HF loss promoted by resonant two photon ionization of supersonically expanded (R)-1-phenyl-2,2,2-trifluoroethanol clusters.

(R)-1-Phenyl-2,2,2-trifluoroethanol and its hydrogen bonded adducts with achiral (water, tetrahydrofuran) and chiral solvent mols. ((R)- and (S)-butan-2-ol, (R)- and (S)-3-hydroxy-tetrahydrofuran) have been ionized by resonant two-photon absorption. The presence of photofragments, attributable to the occurrence of a hydrogen fluoride loss reaction, has been interpreted with the aid of theor. predictions at the DFT level of theory with the inclusion of dispersive terms. The HF elimination process takes place by a mechanism involving the preliminary C.alpha.-H hydrogen transfer to an hydroxyl oxygen assisted by the solvent mol. which is followed by extrusion of the HF mol. The calcd. energy barriers depend on the type of solvent as well as on its configuration and are consistent with the obsd. fragmentation ratios

An allelic variant in the intergenic region between ERAP1 and ERAP2 correlates with an inverse expression of the two genes

The Endoplasmatic Reticulum Aminopeptidases ERAP1 and ERAP2 are implicated in a variety of immune and non-immune functions. Most studies however have focused on their role in shaping the HLA class I peptidome by trimming peptides to the optimal size. Genome Wide Association Studies highlighted non-synonymous polymorphisms in their coding regions as associated with several immune mediated diseases. The two genes lie contiguous and oppositely oriented on the 5q15 chromosomal region. Very little is known about the transcriptional regulation and the quantitative variations of these enzymes. Here, we correlated the level of transcripts and proteins of the two aminopeptidases in B-lymphoblastoid cell lines from 44 donors harbouring allelic variants in the intergenic region between ERAP1 and ERAP2. We found that the presence of a G instead of an A at SNP rs75862629 in the ERAP2 gene promoter strongly influences the expression of the two ERAPs with a down-modulation of ERAP2 coupled with a significant higher expression of ERAP1. We therefore show here for the first time a coordinated quantitative regulation of the two ERAP genes, which can be relevant for the setting of specific therapeutic approaches

Detection and characterization of a 500 μm dust emissivity excess in the Galactic plane using Herschel/Hi-GAL observations

Context. Past and recent observations have revealed unexpected variations in the far-infrared – millimeter (FIR-mm) dust emissivity in the interstellar medium. In the Herschel spectral range, those are often referred to as a 500 μm emission excess. Several dust emission models have been developed to interpret astrophysical data in the FIR-mm domain. However, these are commonly unable to fully reconcile theoretical predictions with observations. In contrast, the recently revised two level system (TLS) model, based on the disordered internal structure of amorphous dust grains, seems to provide a promising way of interpreting existing data. Aims. The newly available Herschel infrared GALactic (Hi-GAL) data, which covers most of the inner Milky Way, offers a unique opportunity to investigate possible variations in the dust emission properties both with wavelength and environment. The goal of our analysis is to constrain the internal structure of the largest dust grains on Galactic scales, in the framework of the TLS model. Methods. By combining the IRIS (Improved Reprocessing of the IRAS Survey) 100 μm with the Hi-GAL 160, 250, 350, and 500 μm data, we model the dust emission spectra in each pixel of the Hi-GAL maps, using both the TLS model and, for comparison, a single modified black-body fit. The effect of temperature mixing along the line of sight is investigated to test the robustness of our results. Results. We find a slight decrease in the dust temperature with distance from the Galactic center, confirming previous results. We also report the detection of a significant 500 μm emissivity excess in the peripheral regions of the plane (35° < |l| < 70°) of about 13–15% of the emissivity, which can reach up to 20% in some HII regions. We present the spatial distributions of the best-fit values for the two main parameters of the TLS model, i.e. the charge correlation length, lc, used to characterize the disordered charge distribution (DCD) part of the model, and the amplitude A of the TLS processes with respect to the DCD effect. These distributions illustrate the variations in the dust properties with environment, in particular the plausible existence of an overall gradient with distance to the Galactic center. A comparison with previous findings in the solar neighborhood shows that the local value of the excess is less than expected from the Galactic gradient observed here

The MIPSGAL View of Supernova Remnants in the Galactic Plane

We report the detection of Galactic supernova remnants (SNRs) in the mid-infrared (at 24 and 70 μm), in the coordinate ranges 10° < l < 65° and 285° < l < 350°, |b| < 1°, using MIPS aboard the Spitzer Space Telescope. We search for infrared counterparts to SNRs in Green's catalog and identify 39 out of 121, i.e., a detection rate of about 32%. Such a relatively low detection fraction is mainly due to confusion with nearby foreground/background sources and diffuse emission. The SNRs in our sample show a linear trend in [F_8/F_(24)] versus [F_(70)/F_(24)]. We compare their infrared fluxes with their corresponding radio flux at 1.4 GHz and find that most remnants have a ratio of 70 μm to 1.4 GHz which is similar to those found in previous studies of SNRs (with the exception of a few that have ratios closer to those of H II regions). Furthermore, we retrieve a slope close to unity when correlating infrared (24 and 70 μm) with 1.4 GHz emission. Our survey is more successful in detecting remnants with bright X-ray emission, which we find is well correlated with the 24 μm morphology. Moreover, by comparing the power emitted in the X-ray, infrared, and radio, we conclude that the energy released in the infrared is comparable to the cooling in the X-ray range

Tracing the energetics and evolution of dust with Spitzer : a chapter in the history of the Eagle Nebula

Context. The Spitzer GLIMPSE and MIPSGAL surveys have revealed a wealth of details about the Galactic plane in the infrared (IR)with orders of magnitude higher sensitivity, higher resolution, and wider coverage than previous IR observations. The structure of the interstellar medium (ISM) is tightly connected to the countless star-forming regions. We use these surveys to study the energetics and dust properties of the Eagle Nebula (M16), one of the best known star-forming regions. Aims. We present MIPSGAL observations of M16 at 24 and 70 μm and combine them with previous IR data. The mid-IR image shows a shell inside the well-known molecular borders of the nebula, as in the ISO and MSX observations from 15 to 21 μm. The morphologies at 24 and 70 μm are quite different, and its color ratio is unusually warm. The far-IR image resembles the one at 8 μm that enhances the structure of the molecular cloud and the "pillars of creation". We use this set of IR data to analyze the dust energetics and properties within this template for Galactic star-forming regions. Methods. We measure IR spectral energy distributions (SEDs) across the entire nebula, both within the inner shell and the photodissociation regions (PDRs).We use the DUSTEM model to fit these SEDs and constrain the dust temperature, the dust-size distribution, and the radiation field intensity relative to that provided by the star cluster NGC 6611 (χ/χ0). Results. Within the PDRs, the inferred dust temperature (~35 K), the dust-size distribution, and the radiation field intensity (χ/χ0 < 1) are consistent with expectations. Within the inner shell, the dust is hotter (~70 K). Moreover, the radiation field required to fit the SED is larger than that provided by NGC 6611 (χ/χ0 > 1). We quantify two solutions to this problem: (1) The size distribution of the dust in the shell is not that of interstellar dust. There is a significant enhancement of the carbon dust-mass in stochastically heated very small grains. (2) The dust emission arises from a hot (~10^6 K) plasma where both UV and collisions with electrons contribute to the heating. Within this hypothesis, the shell SED may be fit for a plasma pressure p/k ~ 5 × 10^7 K cm^(−3). Conclusions. We suggest two interpretations for the M16 inner shell: (1) The shell matter is supplied by photo-evaporative flows arising from dense gas exposed to ionized radiation. The flows renew the shell matter as it is pushed out by the pressure from stellar winds. Within this scenario, we conclude that massive-star forming regions such as M16 have a major impact on the carbon dustsize distribution. The grinding of the carbon dust could result from shattering in grain-grain collisions within shocks driven by the dynamical interaction between the stellar winds and the shell. (2) We also consider a more speculative scenario where the shell is a supernova remnant. In this case, we would be witnessing a specific time in the evolution of the remnant where the plasma pressure and temperature would enable the remnant to cool through dust emission

Grain size limits derived from 3.6 {\mu}m and 4.5 {\mu}m coreshine

Recently discovered scattered light from molecular cloud cores in the wavelength range 3-5 {\mu}m (called "coreshine") seems to indicate the presence of grains with sizes above 0.5 {\mu}m. We aim to analyze 3.6 and 4.5 {\mu}m coreshine from molecular cloud cores to probe the largest grains in the size distribution. We analyzed dedicated deep Cycle 9 Spitzer IRAC observations in the 3.6 and 4.5 {\mu}m bands for a sample of 10 low-mass cores. We used a new modeling approach based on a combination of ratios of the two background- and foreground-subtracted surface brightnesses and observed limits of the optical depth. The dust grains were modeled as ice-coated silicate and carbonaceous spheres. We discuss the impact of local radiation fields with a spectral slope differing from what is seen in the DIRBE allsky maps. For the cores L260, ecc806, L1262, L1517A, L1512, and L1544, the model reproduces the data with maximum grain sizes around 0.9, 0.5, 0.65, 1.5, 0.6, and > 1.5 {\mu}m, respectively. The maximum coreshine intensities of L1506C, L1439, and L1498 in the individual bands require smaller maximum grain sizes than derived from the observed distribution of band ratios. Additional isotropic local radiation fields with a spectral shape differing from the DIRBE map shape do not remove this discrepancy. In the case of Rho Oph 9, we were unable to reliably disentangle the coreshine emission from background variations and the strong local PAH emission. Considering surface brightness ratios in the 3.6 and 4.5 {\mu}m bands across a molecular cloud core is an effective method of disentangling the complex interplay of structure and opacities when used in combination with observed limits of the optical depth.Comment: 23 pages, 18 figures, accepted for publication in A&

Modeling and predicting the shape of the far-infrared to submillimeter emission in ultra-compact HII regions and cold clumps

Dust properties are very likely affected by the environment in which dust grains evolve. For instance, some analyses of cold clumps (7 K- 17 K) indicate that the aggregation process is favored in dense environments. However, studying warm (30 K-40 K) dust emission at long wavelength ($\lambda$$>$300 $\mu$m) has been limited because it is difficult to combine far infared-to-millimeter (FIR-to-mm) spectral coverage and high angular resolution for observations of warm dust grains. Using Herschel data from 70 to 500 $\mu$m, which are part of the Herschel infrared Galactic (Hi-GAL) survey combined with 1.1 mm data from the Bolocam Galactic Plane Survey (BGPS), we compared emission in two types of environments: ultra-compact HII (UCHII) regions, and cold molecular clumps (denoted as cold clumps). With this comparison we tested dust emission models in the FIR-to-mm domain that reproduce emission in the diffuse medium, in these two environments (UCHII regions and cold clumps). We also investigated their ability to predict the dust emission in our Galaxy. We determined the emission spectra in twelve UCHII regions and twelve cold clumps, and derived the dust temperature (T) using the recent two-level system (TLS) model with three sets of parameters and the so-called T-$\beta$ (temperature-dust emissvity index) phenomenological models, with $\beta$ set to 1.5, 2 and 2.5. We tested the applicability of the TLS model in warm regions for the first time. This analysis indicates distinct trends in the dust emission between cold and warm environments that are visible through changes in the dust emissivity index. However, with the use of standard parameters, the TLS model is able to reproduce the spectral behavior observed in cold and warm regions, from the change of the dust temperature alone, whereas a T-$\beta$ model requires $\beta$ to be known.Comment: Accepted for publication in A&A. 19 pages, 8 figures, 7 table