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

Friends and Symptom Dimensions in Patients with Psychosis: A Pooled Analysis

PMCID: PMC3503760This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

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

The BIM-based Integrated Design of the SHiP Project Decay Volume

The Search for Hidden Particles (SHiP) experiment is a new general-purpose fixed target facility proposed at the CERN Super Proton Synchrotron accelerator to search for longlived exotic particles associated with Hidden Sectors and Dark Matter. This paper reports on the BIM integrated design of SHiP’s decay volume, a conical steel vessel under vacuum that should host several large particle physics detector systems. The use of BIM characterized the design of the decay volume, both in the modeling and structural design phase, and in the process definition phase for the realization and implementation in the facility of the device. This procedure helps to minimize the risks of incorrect design and construction of the device during the whole process. With the automation of the virtual model and the use of interoperable software, in addition to speeding up the exchange of information, it is possible also to export the detailed information of the structural design directly to the numerical control machines for the prefabrication of the various steel modules. Then, the BIM approach to support the integrated design of the SHiP project decay volume from the conceptual planning to the construction phase is shown in this work

AIF-1 gene does not confer susceptibility to Behçet's disease: Analysis of extended haplotypes in Sardinian population

Background BehcEet's disease (BD) is a polygenic immune-mediated disorder characterized by a close association with the HLA-B∗51 allele. The HLA region has a strong linkage disequilibrium (LD) and carries several genetic variants (e.g. MIC-A, TNF-α genes) identified as associated to BD because of their LD with HLA-B∗51. In fact, the HLA-B∗51 is inherited as part of extended HLA haplotypes which are well preserved in patients with BD. Sardinian population is highly differentiated from other Mediterranean populations because of a distinctive genetic structure with very highly preserved HLA haplotypes. Patients and methods In order to identify other genes of susceptibility to BD within the HLA region we investigated the distribution of human Allograft Inflammatory Factor-1 (AIF-1) gene variants among BD patients and healthy controls from Sardinia. Six (rs2736182; rs2259571; rs2269475; rs2857597; rs13195276; rs4711274) AIF-1 single nucleotide polymorphisms (SNPs) and related extended haplotypes have been investigated as well as their LD within the HLA region and with HLA-B∗51. Overall, 64 BD patients, 43 HLA-B∗51 positive healthy controls (HC) and 70 random HC were enrolled in the study. Results HLA-B∗51 was the only allele with significantly higher frequency (pc = 0.0021) in BD patients (40.6%) than in HC (9.8%). The rs2259571TAIF-1 variant had a significantly reduced phenotypic, but not allelic frequency in BD patients (72.1%; pc = 0.014) compared to healthy population (91.3%). That was likely due to the LD between HLA-B∗51 and rs2259571G(pc= 9E-5), even though the rs2259571Gdistribution did not significantly differ between BD patients and HC. Conclusion No significant difference in distribution of AIF-1 SNPs haplotypes was observed between BD patients and HC and between HLA-B∗51 positive BD patients and HLA-B∗51 positive HC. Taken together, these results suggest that AIF-1 gene is not associated with susceptibility to BD in Sardinia

VUV-Vis optical characterization of Tetraphenyl-butadiene films on glass and specular reflector substrates from room to liquid Argon temperature

The use of efficient wavelength-shifters from the vacuum-ultraviolet to the photosensor's range of sensitivity is a key feature in detectors for Dark Matter search and neutrino physics based on liquid argon scintillation detection. Thin film of Tetraphenyl-butadiene (TPB) deposited onto the surface delimiting the active volume of the detector and/or onto the photosensor optical window is the most common solution in current and planned experiments. Detector design and response can be evaluated and correctly simulated only when the properties of the optical system in use (TPB film + substrate) are fully understood. Characterization of the optical system requires specific, sometimes sophisticated optical methodologies. In this paper the main features of TPB coatings on different, commonly used substrates is reported, as a result of two independent campaigns of measurements at the specialized optical metrology labs of ENEA and University of Tor Vergata. Measured features include TPB emission spectra with lineshape and relative intensity variation recorded as a function of the film thickness and for the first time down to LAr temperature, as well as optical reflectance and transmittance spectra of the TPB coated substrates in the wavelength range of the TPB emission

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

Is idiopathic intracranial hypertension without papilledema a risk factor for migraine progression?

The association of chronic migraine (CM) with an idiopathic intracranial hypertension without papilledema (IIHWOP), although much more prevalent than expected in clinical series of CM sufferers, is not included among the risk factors for migraine progression. We discuss the available evidence supporting the existence of a pathogenetic link between CM and idiopathic intracranial hypertensive disorders and suggest a causative role for IIHWOP in migraine progression

Friends and Symptom Dimensions in Patients with Psychosis: A Pooled Analysis

Background Having friends is associated with more favourable clinical outcomes and a higher quality of life in mental disorders. Patients with schizophrenia have fewer friends than other mentally ill patients. No large scale studies have evaluated so far what symptom dimensions of schizophrenia are associated with the lack of friendships. Methods Data from four multi-centre studies on outpatients with schizophrenia and related disorders (ICD F20-29) were included in a pooled analysis (N = 1396). We established whether patients had close friends and contact with friends by using the equivalent items on friendships of the Manchester Short Assessment of Quality of Life or of the Lancashire Quality of Life Profile. Symptoms were measured by the Brief Psychiatric Rating Scale or by the identical items included in the Positive and Negative Syndrome Scale. Results Seven hundred and sixty-nine patients (55.1%) had seen a friend in the previous week and 917 (65.7%) had someone they regarded as a close friend. Low levels of negative symptoms and hostility were significantly associated with having a close friend and contact with a friend. Overall, almost twice as many patients with absent or mild negative symptoms had met a friend in the last week, compared with those with moderate negative symptoms. Conclusions Higher levels of negative symptoms and hostility are specifically associated with the lack of friendships in patients with psychotic disorders. These findings suggest the importance of developing effective treatments for negative symptoms and hostility in order to improve the probability of patients with schizophrenia to have friends

Frequency of the New HLA-B*2709 Allele in Ankylosing Spondylitis Patients and Healthy Individuals

We have recently described a new HLA-B27 subtype, named HLA-B*2709 (Del Porto et al. 1994). This allele is identical to the subtype most frequently found in Caucasoids, HLA-B*2705, except for a single amino acid substitution (Asp to His) in position 116. This residue, that is part of the F pocket of the molecule, has been shown to be relevant in determining which C-terminal amino acid of HLA-class I-binding peptides can be accomodated into the groove (Elliott, 1993). In nonamer peptides, this aminoacid corresponds to a primary anchor position (P9; Madden et al., 1992). Accordingly, we have previously shown that B2709 molecule hardly accepts nonamer peptides with an Arg or Tyr in P9, while the same amino acids represent good anchors for B2705 molecules (Fiorillo et al., 1995). Special attention is focused on HLA-B27 subtypes because of the strong association of B27 with ankylosing spondylitis (AS). More than 90% of AS patients are B27-positive and, conversely, about 4% of B27-positive individuals in the population are affected. This represents a relative risk over 100, that is the highest in HLA-disease associations. However, little is known on the pathogenic mechanisms of the disease. Following the hypothesis that an antigenic B27-binding peptide is involved in the disease (the so-called arthritogenic peptide), differential association with the different B27 subtypes may give a clue on the nature of such peptide. If two subtypes of partially overlapping peptide binding specificity are found to be both AS-associated, this would restrict the search for peptides that can be bound by both allelic products. Conversely, if a B27 subtype is found to be non AS-associated, this would be even more helpful in eliminating an array of peptides as possible candidates