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

Ibuprofen Safety at the Golden Anniversary: Are all NSAIDs the Same? A Narrative Review

Ibuprofen first came to market about 50 years ago and rapidly moved to over-the-counter (OTC) sales. In April 2019, the National Agency for the Safety of Medicines and Health Products (ANSM) of France issued a warning for NSAID uses by patients with infectious diseases based on an analysis of 20 years of real-world safety data on ibuprofen and ketoprofen. Nevertheless, ibuprofen remains a mainstay in the analgesic armamentarium and with numerous randomized clinical trials, head-to-head studies, and decades of clinical experience. The authors offer a review of the safety of ibuprofen and how it may differ from other NSAIDs. Ibuprofen is associated with certain well-known gastrointestinal adverse effects that are related to dose and patient population. Among nonsteroidal anti-inflammatory drugs (NSAIDs), ibuprofen has a comparatively low risk of cardiovascular adverse effects. It has been associated with renal and hepatic adverse effects, which appear to depend on dose, concomitant medications, and patient population. The association of ibuprofen with infections is more complex in that it confers risk in some situations but benefits in others, the latter in cystic fibrosis. Emerging interest in the literature is providing evidence of the role of ibuprofen as a possible endocrine disrupter as well as its potential antiproliferative effects for cancer cells. Taken altogether, ibuprofen has a favorable safety profile and is an effective analgesic for many acute and chronic pain conditions, although it—like other NSAIDs—is not without risk. After 50 years, evidence is still emerging about ibuprofen and its unique safety profile among NSAIDs. The Rapid Service Fee was funded by Abbott Established Pharmaceuticals Division (EPD)

The Porcellini test: a novel test for accurate diagnosis of posterior labral tears of the shoulder: comparative analysis with the established tests

Questions/purposes: Although the posterior labral tears of the shoulder are known for their disabling clinical course, especially in overhead athletes, no clinical test used in isolation can diagnose it accurately in the preoperative period. We wanted to: (1) introduce “Porcellini test” with its radiological verification furnishing the anatomical basis of its mechanism; (2) determine its accuracy; and (3) compare its accuracy with that of the other established tests for diagnosing posterior labral tears of the shoulder. Methods: To determine the anatomical basis, we initially performed radiological verification of our test. Then, we evaluated its accuracy in a retrospective case-controlled study on 310 consecutive patients who underwent shoulder arthroscopic procedures at our hospital between January 2013 and December 2013. All patients were examined preoperatively for Porcellini test, and the presence of posterior labral tear was confirmed on arthroscopy. Later, in a cohort study on 91 consecutive patients who underwent shoulder arthroscopic procedures, we compared its accuracy with O’Brien’s test, the Kim test, the Jerk test, and the Load and Shift test. The accuracy was interpreted in terms of sensitivity, specificity, and predictive values. Results: The radiological verification conferred the anatomical basis for the mechanism of the Porcellini test. This new test showed high accuracy for posterior labral tears with sensitivity of 100 %, specificity of 99.3 %, the positive and negative predictive values of 92.6 and 100 %, respectively. Also, it had superior accuracy results than every other test. The interexaminer reliability for all test results was found to be >0.80. Conclusions: We propose “Porcellini test” as a simple, accurate, reproducible, and reliable test for the preoperative diagnosis of posterior labral tears of shoulder

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

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

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

Recurrent Non-Hodgkin’s lymphoma in the uterine cervix: a case report and a review of the literature

Background. Lymphomas are a heterogeneous group of malignant lymphoproliferative diseases. As primary localization, the most common histological subtype of female genital lymphomas is a Non-Hodgkin Lymphoma (NHL), the diffuse large B-cell type. However cervical relapse of NHL is a very rare condition (0.3%). Case presentation. A 42-year-old Peruvian woman experienced relapse of NHL with uterine localization. She complained at first of abnormal vaginal bleeding and stranguria. The cervical biopsy performed showed a diffuse large B-cell lymphoma in the uterine cervix. The lack of clinical studies on this topic and its rarity make this type of recurrence very difficult to treat. Conclusions. In case of a woman with vaginal bleeding and history of NHL, a disease relapse should always be considered, and a biopsy should be performed to confirm the diagnosis. © 2023, EDRA S.p.A. All rights reserved