HLA Class I or Class II and Disease Association: Catch the Difference if You Can

The association of autoimmune diseases with HLA has been known for many decades. To date, however, the underlying mechanisms have not been fully understood. The recently introduced genome-wide association studies (GWAS) have suggested that several genes converging in common pathways contribute to the genetic susceptibility in such disorders. Nevertheless, for most autoimmune/autoinflammatory diseases, the HLA genes are by far the strongest risk factors. The basis of some associations has now been elucidated, particularly in those cases in which exogenous factors are involved

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

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

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

Evaluation of Psychometric and Linguistic Properties of the Italian Adolescent Pain Assessment Scales: A Systematic Review

Introduction: Adolescents’ pain experiences are complex and multidimensional, and evaluating pain only from a sensory and affective point of view may be in many instances limiting and inadequate; this is the reason why it is of paramount importance to identify the tools which can better assess the pain experienced by young patients. A person-oriented approach is highly encouraged, as it may better investigate the cognitive and behavioral development typical of this age group. The aim of this review paper is to describe the available tools which are able to adequately assess pain intensity in adolescents, in particular those validated in Italian. Methods: We conducted a systematic review using four databases: CINAHL, PsycINFO, PubMed and Cochrane, and selected all the articles published between January 1970 and November 2017. We selected all the papers reporting the validation process of pain assessment tools specifically tailored for adolescent patients (age range 10–18 years) and based on psychometric and linguistic parameters, and focused especially on the tools available in Italian and able to measure acute and chronic pain. Results: The results of our investigation have revealed the existence of 40 eligible tools, 17 of which are monodimensional and the remaining 23 multidimensional, more specifically tailored to assess both acute and chronic pain. Some of the instruments (26) were self-reports while others were classified as behavioral (13) and/or mixed. Only one tool turned out to be suitable for fragile adolescents, while six adopted a person-oriented approach that better emphasized the cognitive and behavioral process typical of the adolescent population. None of them has ever been validated in Italian. Conclusion: Valid and reliable psychometric tools specifically organized to provide a cultural and linguistic evaluation of the patient are indeed the most recommended instruments to assess the intensity of the pain experienced by the patient, as they may provide useful information to implement a health policy aimed at identifying the best assistance programs

A Broadband Study of Galactic Dust Emission

We have combined infrared data with HI, H2 and HII surveys in order to spatially decompose the observed dust emission into components associated with different phases of the gas. An inversion technique is applied. For the decomposition, we use the IRAS 60 and 100 micron bands, the DIRBE 140 and 240 micron bands, as well as Archeops 850 and 2096 micron wavelengths. In addition, we apply the decomposition to all five WMAP bands. We obtain longitude and latitude profiles for each wavelength and for each gas component in carefully selected Galactic radius bins.We also derive emissivity coefficients for dust in atomic, molecular and ionized gas in each of the bins.The HI emissivity appears to decrease with increasing Galactic radius indicating that dust associated with atomic gas is heated by the ambient interstellar radiation field (ISRF). By contrast, we find evidence that dust mixed with molecular clouds is significantly heated by O/B stars still embedded in their progenitor clouds. By assuming a modified black-body with emissivity law lambda^(-1.5), we also derive the radial distribution of temperature for each phase of the gas. All of the WMAP bands except W appear to be dominated by emission from something other than normal dust, most likely a mixture of thermal bremstrahlung from diffuse ionized gas, synchrotron emission and spinning dust. Furthermore, we find indications of an emissivity excess at long wavelengths (lambda > 850 micron) in the outer Galaxy (R > 8.9 kpc). This suggests either the existence of a very cold dust component in the outer Galaxy or a temperature dependence of the spectral emissivity index. Finally, it is shown that ~ 80% of the total FIR luminosity is produced by dust associated with atomic hydrogen, in agreement with earlier findings by Sodroski et al. (1997).Comment: accepted for publication by A&

New ATCA, ALMA and VISIR observations of the candidate LBV SK-67266 (S61): the nebular mass from modelling 3D density distributions

We present new observations of the nebula around the Magellanic candidate Luminous Blue Variable S61. These comprise high-resolution data acquired with the Australia Telescope Compact Array (ATCA), the Atacama Large Millimetre/Submillimetre Array (ALMA), and VISIR at the Very Large Telescope (VLT). The nebula was detected only in the radio, up to 17 GHz. The 17 GHz ATCA map, with 0.8 arcsec resolution, allowed a morphological comparison with the H$\alpha$ Hubble Space Telescope image. The radio nebula resembles a spherical shell, as in the optical. The spectral index map indicates that the radio emission is due to free-free transitions in the ionised, optically thin gas, but there are hints of inhomogeneities. We present our new public code RHOCUBE to model 3D density distributions, and determine via Bayesian inference the nebula's geometric parameters. We applied the code to model the electron density distribution in the S61 nebula. We found that different distributions fit the data, but all of them converge to the same ionised mass, ~0.1 $\rm M\odot$, which is an order of magnitude smaller than previous estimates. We show how the nebula models can be used to derive the mass-loss history with high-temporal resolution. The nebula was probably formed through stellar winds, rather than eruptions. From the ALMA and VISIR non-detections, plus the derived extinction map, we deduce that the infrared emission observed by space telescopes must arise from extended, diffuse dust within the ionised region.Comment: 17 pages, 9 figures. Authors list corrected. In press in MNRAS. RHOCUBE code available online ( https://github.com/rnikutta/rhocube

Trade-off between angular resolution and straylight contamination in CMB anisotropy experiments. II. Straylight evaluation

Satellite CMB anisotropy missions and new generation of balloon-borne and ground experiments, make use of complex multi-frequency instruments at the focus of a meter class telescope. Between 70 GHz and 300 GHz, where foreground contamination is minimum, it is extremely important to reach the best trade-off between the improvement of the angular resolution and the minimization of the straylight contamination mainly due to the Galactic emission. We focus here, as a working case, on the 30 and 100 GHz channels of the Planck Low Frequency Instrument (LFI). We evaluate the GSC introduced by the most relevant Galactic foreground components for a reference set of optical configurations. We show that it is possible to improve the angular resolution of 5-7% by keeping the overall GSC below the level of few microKelvin. A comparison between the level of straylight introduced by the different Galactic components for different beam regions is presented. Simple approximate relations giving the rms and peak-to-peak levels of the GSC are provided. We compare the results obtained at 100 GHz with those at 30 GHz, where GSC is more critical. Finally, we compare the results based on Galactic foreground templates derived from radio and IR surveys with those based on WMAP maps including CMB and extragalactic source fluctuations.Comment: Submitted to A&A. Quality of the figures was degraded for size-related reason

The multifaceted nature of aminopeptidases ERAP1, ERAP2, and LNPEP: from evolution to disease

In the human genome, the aminopeptidases ERAP1, ERAP2 and LNPEP lie contiguously on chromosome 5. They share sequence homology, functions and associations with immune-mediated diseases. By analyzing their multifaceted activities as well as their expression in the zoological scale, we suggest here that the progenitor of the three aminopeptidases might be LNPEP from which the other two aminopeptidases could have derived by gene duplications. We also propose that their functions are partially redundant. More precisely, the evolutionary story of the three aminopeptidases might have been dictated by their role in regulating the renin–angiotensin system, which requires their controlled and coordinated expression. This hypothesis is supported by the many species that lack one or the other gene as well as by the lack of ERAP2 in rodents and a null expression in 25% of humans. Finally, we speculate that their role in antigen presentation has been acquired later on during evolution. They have therefore been diversified between those residing in the ER, ERAP1 and ERAP2, whose role is to refine the MHC-I peptidomes, and LNPEP, mostly present in the endosomal vesicles where it can contribute to antigen cross-presentation or move to the cell membrane as receptor for angiotensin IV. Their association with autoinflammatory/autoimmune diseases can therefore be two-fold: as “contributors” to the shaping of the immune-peptidomes as well as to the regulation of the vascular response