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

Cranial neuralgias: from physiopathology to pharmacological treatment

Cranial neuralgias are paroxysmal painful disorders of the head characterised by some shared features such as unilaterality of symptoms, transience and recurrence of attacks, superficial and "shock-like" quality of pain and the presence of triggering factors. Although rare, these disorders must be promptly recognised as they harbour a relatively high risk for underlying compressive or inflammatory disease. Nevertheless, misdiagnosis is frequent. Trigeminal and glossopharyngeal neuralgias are sustained in most cases by a neurovascular conflict in the posterior fossa resulting in a hyperexcitability state of the trigeminal circuitry. If the aetiology of trigeminal neuralgia (TN) and other typical neuralgias must be brought back to the peripheral injury, their pathogenesis could involve central allodynic mechanisms, which, in patients with inter-critical pain, also engage the nociceptive neurons at the thalamic-cortical level. Currently available medical treatments for TN and other cranial neuralgias are reviewed

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

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

Epitaxial thin films of multiferroic Bi2FeCrO6 with B-site cationic order

Epitaxial thin films of Bi2FeCrO6 have been synthesized by pulsed laser deposition on SrRuO3 on (100)- and (111)-oriented SrTiO3 substrates. Detailed X-ray diffraction and cross-section transmission electron microscopy analysis revealed a double perovskite crystal structure of the Bi2FeCrO6 epitaxial films very similar to that of BiFeO3 along with a particularly noteworthy Fe3+/Cr3+ cation ordering along the [111] direction. The films contain no detectable magnetic iron oxide impurities and have the correct cationic average stoichiometry throughout their thickness. They however exhibit a slight modulation in the Fe and Cr compositions forming complementary stripe patterns, suggesting minor local excess or depletion of Fe and Cr. The epitaxial BFCO films exhibit good ferroelectric and piezoelectric properties, in addition to magnetic properties at room temperature, as well as an unexpected crystallographic orientation dependence of their room temperature magnetic properties. Our results qualitatively confirm the predictions made using the ab-initio calculations: the double-perovskite structure of Bi2FeCrO6 films exhibit a Fe3+/Cr3+ cation ordering and good multiferroic properties, along with the unpredicted existence of magnetic ordering at room temperature.Comment: Accepted for publication in Journal of Materials Researc

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

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

MicroRNAs from saliva of anopheline mosquitoes mimic human endogenous miRNAs and may contribute to vector-host-pathogen interactions

During blood feeding haematophagous arthropods inject into their hosts a cocktail of salivary proteins whose main role is to counteract host haemostasis, inflammation and immunity. However, animal body fluids are known to also carry miRNAs. To get insights into saliva and salivary gland miRNA repertoires of the African malaria vector Anopheles coluzzii we used small RNA-Seq and identified 214 miRNAs, including tissue-enriched, sex-biased and putative novel anopheline miRNAs. Noteworthy, miRNAs were asymmetrically distributed between saliva and salivary glands, suggesting that selected miRNAs may be preferentially directed toward mosquito saliva. The evolutionary conservation of a subset of saliva miRNAs in Anopheles and Aedes mosquitoes, and in the tick Ixodes ricinus, supports the idea of a non-random occurrence pointing to their possible physiological role in blood feeding by arthropods. Strikingly, eleven of the most abundant An. coluzzi saliva miRNAs mimicked human miRNAs. Prediction analysis and search for experimentally validated targets indicated that miRNAs from An. coluzzii saliva may act on host mRNAs involved in immune and inflammatory responses. Overall, this study raises the intriguing hypothesis that miRNAs injected into vertebrates with vector saliva may contribute to host manipulation with possible implication for vector-host interaction and pathogen transmission

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

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