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Emma Reeves, Edward James
Autoimmune and autoinflammatory conditions represent a group of disorders characterized by self-directed tissue damage due to aberrant changes in innate and adaptive immune responses. These disorders possess widely varying clinical phenotypes and etiology, however they share a number of similarities in genetic associations and environmental influences. Whilst the pathogenic mechanisms of disease remain poorly understood, genome wide association studies (GWAS) have implicated a number of genetic loci that are shared between several autoimmune and autoinflammatory conditions...
July 27, 2018: Bioscience Reports
Chenchen Feng, Guanxiong Ding, Qiang Ding, Hui Wen
AIM: Clear-cell renal cell carcinoma (ccRCC) is characterized with underlying genetic disorders and the role of low density lipoprotein receptor-related protein 1 (LRP1) in ccRCC is unknown. METHOD: An in silico exploratory analysis using multiple public genetic datasets was used to establish association between LRP1 expression and clinicopathological parameters. Associations of interest were validated using 155 ccRCC samples using immunohistochemistry. RESULTS: LRP1 was overexpressed in tumor compared with normal kidney tissue...
July 19, 2018: Biochemical and Biophysical Research Communications
Marta Stawczyk-Macieja, Aneta Szczerkowska-Dobosz, Krzysztof Rębała, Magdalena Gabig-Cimińska, Roman J Nowicki, Agnieszka Haraś, Lidia Cybulska, Ewa Kapińska
Introduction: HLA-C*06 is a major psoriasis genetic risk marker. Recent reports have been focused on the role of different polymorphisms within genes involved in the functioning of the epidermal barrier and antigen processing in the pathogenesis of psoriasis. Data on the association between genetic variants of LCE3B_LCE3C, CSTA, ERAP1 , ZAP70 and this dermatosis in the population from Eastern Europe are lacking. Aim: To compare the association between known genetic risk markers and psoriasis in a cohort of northern Polish patients with psoriasis and healthy controls...
June 2018: Postȩpy Dermatologii i Alergologii
Fabiana Paladini, Maria Teresa Fiorillo, Carolina Vitulano, Valentina Tedeschi, Matteo Piga, Alberto Cauli, Alessandro Mathieu, Rosa Sorrentino
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...
July 10, 2018: Scientific Reports
Zhiping Tan, Hui Zeng, Zhaofa Xu, Qi Tian, Xiaoyang Gao, Chuanman Zhou, Yu Zheng, Jian Wang, Guanghui Ling, Bing Wang, Yifeng Yang, Long Ma
BACKGROUND: Ankylosing spondylitis (AS) is a debilitating autoimmune disease affecting tens of millions of people in the world. The genetics of AS is unclear. Analysis of rare AS pedigrees might facilitate our understanding of AS pathogenesis. METHODS: We used genome-wide linkage analysis and whole-exome sequencing in combination with variant co-segregation verification and haplotype analysis to study an AS pedigree and a sporadic AS patient. RESULTS: We identified a missense variant in the ankyrin repeat and death domain containing 1B gene ANKDD1B from a Han Chinese pedigree with dominantly inherited AS...
July 5, 2018: BMC Medical Genetics
Robert Y L Zee, Alicia Rivera, Yaritza Inostroza, Paul M Ridker, Daniel I Chasman, Jose R Romero
Recent studies have demonstrated the importance of endoplasmic reticulum aminopeptidase (ERAP) in blood pressure (BP) homeostasis. To date, no large prospective, genetic-epidemiological data are available on genetic variation within ERAP and hypertension risk. The association of 45 genetic variants of ERAP1 and ERAP2 was investigated in 17,255 Caucasian female participants from the Women's Genome Health Study. All subjects were free of hypertension at baseline. During an 18-year follow-up period, 10,216 incident hypertensive cases were identified...
2018: International Journal of Genomics
Navid Dashti, Mahdi Mahmoudi, Saeed Aslani, Ahmadreza Jamshidi
Ankylosing spondylitis (AS) is a highly heritable kind of arthritis that affects the vertebral column. AS risk has been associated strongly with Human leukocyte antigen (HLA)-B*27. In fact, some HLA-B*27 subtypes have been associated with the increased disease risk, although some specific subtypes have not shown such associations. It is supposed that HLA-B*27 plays a major role in the etiopathogenesis of the disease. However, the difference in pathogenic outcomes of HLA-B*27 certain subtypes needs to be clarified...
September 5, 2018: Gene
Marcelina E Janik, Sabina Szwed, Paweł Grzmil, Radosław Kaczmarek, Marcin Czerwiński, Dorota Hoja-Łukowicz
The objective of this study was to identify a normalizer or combination of normalizers for quantitative evaluation of the expression of a target gene of interest during melanoma progression. Adult melanocytes, uveal primary melanoma cells and cutaneous primary and metastatic melanoma cells were used to construct a panel of 14 experimental models reflecting cancer promotion and progression. Hypoxanthine phosphoribosyltransferase 1 (HPRT1), glucuronidase beta (GUSB), ribosomal protein S23 (RPS23), phosphoglycerate kinase 1 (PGK1) and small nuclear ribonucleoprotein progression...
August 2018: International Journal of Biochemistry & Cell Biology
Alejandro Sanz-Bravo, Adrian Martin-Esteban, Jonas J W Kuiper, Marina García-Peydró, Eilon Barnea, Arie Admon, José A López de Castro
Virtually all patients of the rare inflammatory eye disease birdshot chorioretinopathy (BSCR) carry the HLA-A*29:02 allele. BSCR is also associated with endoplasmic reticulum aminopeptidase 2 (ERAP2), an enzyme involved in processing HLA class I ligands, thus implicating the A*29:02 peptidome in this disease. To investigate the relationship between both risk factors we employed label-free quantitative mass spectrometry to characterize the effects of ERAP2 on the A*29:02-bound peptidome. An ERAP2-negative cell line was transduced with lentiviral constructs containing GFP-ERAP2 or GFP alone, and the A*29:02 peptidomes from both transduced cells were compared...
May 16, 2018: Molecular & Cellular Proteomics: MCP
Anastasia Mpakali, Zachary Maben, Lawrence J Stern, Efstratios Stratikos
Endoplasmic Reticulum aminopeptidase 1 (ERAP1) is an intracellular enzyme that can generate or destroy potential peptide ligands for MHC class I molecules. ERAP1 activity influences the cell-surface immunopeptidome and epitope immunodominance patterns but in complex and poorly understood manners. Two main distinct pathways have been proposed to account for ERAP1's effects on the nature and quantity of MHCI-bound peptides: i) ERAP1 trims peptides in solution, generating the correct length for binding to MHCI or overtrimming peptides so that they are too short to bind, and ii) ERAP1 trims peptides while they are partially bound onto MHCI in manner that leaves the peptide amino terminus accessible...
April 17, 2018: Molecular Immunology
Athanasios Papakyriakou, Emma Reeves, Mary Beton, Halina Mikolajek, Leon Douglas, Grace Cooper, Tim Elliott, Jörn M Werner, Edward James
Endoplasmic reticulum aminopeptidase 1 (ERAP1) and ERAP2 process N-terminally extended antigenic precursors for optimal loading onto major histocompatibility complex class I (MHC I) molecules. We and others have demonstrated that ERAP1 processes peptides bound to MHC I, but the underlying mechanism is unknown. To this end, we utilized single-chain trimers (SCT) of the ovalbumin-derived epitope SIINFEKL (SL8) tethered to the H2-Kb MHC I determinant from mouse and introduced three substitutions, E63A, K66A, and W167A, at the A-pocket of the peptide-binding groove in the MHC I heavy chain, which interact with the N termini of peptides...
May 18, 2018: Journal of Biological Chemistry
M C Padula, P Leccese, A A Padula, S D'Angelo, G Martelli
The novel ERAP1 allelic variant is a missense polymorphism leading to the Arg53Pro substitution.
March 26, 2018: HLA
Yoshikuni Goto, Yuko Ogawa, Hiroki Tsumoto, Yuri Miura, Takahiro J Nakamura, Kenji Ogawa, Yoshihiro Akimoto, Hayato Kawakami, Tamao Endo, Ryohei Yanoshita, Masafumi Tsujimoto
Macrophages secrete endoplasmic reticulum aminopeptidase 1 (ERAP1) in response to lipopolysaccharide (LPS) and interferon (IFN)-γ to enhance their phagocytic and nitric oxide (NO) synthetic activities. In this study, we found that a subset of secreted ERAP1 bound to exosomes released from LPS/IFN-γ-treated murine RAW264.7 macrophages compared to untreated cells. ERAP1-bound exosomes enhanced phagocytic and NO synthetic activities of macrophages more efficiently than free ERAP1 and exosomes derived from untreated cells...
June 2018: Biochimica et Biophysica Acta
Karin Schmidt, Christin Keller, Anja A Kühl, Ana Textor, Ulrike Seifert, Thomas Blankenstein, Gerald Willimsky, Peter-Michael Kloetzel
Cytotoxic T lymphocytes can reject established tumors if their target peptide is efficiently presented by MHC class I molecules (pMHC-I) on the surface of cancerous cells. Therapeutic success upon adoptive T-cell transfer (ATT), however, requires additional cross-presentation of the same pMHC-I on noncancerous cells. Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an enzyme that customizes the N-terminus of proteasome-generated peptides so they can be loaded onto MHC-I molecules in the endoplasmic reticulum (ER)...
June 15, 2018: Cancer Research
W Su, L Du, S Liu, J Deng, Q Cao, G Yuan, A Kijlstra, P Yang
Previous studies show that endoplasmic reticulum-associated aminopeptidase (ERAP1/ERAP2) and runt-related transcription factor 3 (RUNX3) gene polymorphisms are associated with AS (ankylosing spondylitis) in European Caucasians. However, contradictory results were reported in different Asian populations. The purpose of this study was to determine whether eleven candidate single nucleotide polymorphisms (SNPs) in ERAP1/ERAP2 and six in RUNX3 genes confer susceptibility to AS with or without acute anterior uveitis (AAU) [AS+ AAU+ or AS+ AAU- ] in Chinese Han...
July 2018: Clinical and Experimental Immunology
Dimitris Georgiadis, Anastasia Mpakali, Despoina Koumantou, Efstratios Stratikos
Endoplasmic Reticulum aminopeptidase 1 and 2 are two homologous enzymes that help generate peptide ligands for presentation by Major Histocompatibility Class I molecules. Their enzymatic activity influences the antigenic peptide repertoire and indirectly controls adaptive immune responses. Accumulating evidence suggests that these two enzymes are tractable targets for the regulation of immune responses with possible applications ranging from cancer immunotherapy to treating inflammatory autoimmune disease. Here, we review the state-of-the-art in the development of inhibitors of ERAP1 and ERAP2 as well as their potential and limitations for clinical applications...
February 13, 2018: Current Medicinal Chemistry
Farhad Babaie, Milad Hasankhani, Hamed Mohammadi, Elham Safarzadeh, Alireza Rezaiemanesh, Reza Salimi, Behzad Baradaran, Zohreh Babaloo
Ankylosing spondylitis (AS) is a type of arthritis that is referred to a group of chronic immune-mediated inflammatory diseases termed as seronegative spondyloarthropathies or spondyloarthritides. It typically affects the joints of the spinal and axial skeleton and exhibits common clinical features and genetic factors such as human leukocyte antigen class I allele HLA-B27, the Endoplasmic Reticulum Aminopeptidase 1 (ERAP1), and environmental factors such as microbial triggers. Although the precise etiopathogenic mechanisms that implicate the pathogenesis of AS have still remained to be clarified, the IL-23/IL-17 immune axis has been detected as an important factor in the immunopathogenesis of AS...
April 2018: Immunology Letters
Deborah Kronenberg-Versteeg, Martin Eichmann, Mark A Russell, Arnoud de Ru, Beate Hehn, Norkhairin Yusuf, Peter A van Veelen, Sarah J Richardson, Noel G Morgan, Marius K Lemberg, Mark Peakman
The signal peptide region of preproinsulin (PPI) contains epitopes targeted by HLA-A-restricted (HLA-A0201, A2402) cytotoxic T cells as part of the pathogenesis of β-cell destruction in type 1 diabetes. We extended the discovery of the PPI epitope to disease-associated HLA-B*1801 and HLA-B*3906 (risk) and HLA-A*1101 and HLA-B*3801 (protective) alleles, revealing that four of six alleles present epitopes derived from the signal peptide region. During cotranslational translocation of PPI, its signal peptide is cleaved and retained within the endoplasmic reticulum (ER) membrane, implying it is processed for immune recognition outside of the canonical proteasome-directed pathway...
April 2018: Diabetes
Yin Tang, Ping Yang, Fang Wang, Hui Xu, Shou-Yang Zong
To explore the association between five polymorphisms in endoplasmic reticulum associated aminopeptidase 1 (ERAP1) gene and risk of ankylosing spondylitis (AS) in a Chinese population. A case-control study enrolled 250 AS patients and 250 healthy controls was carried out. The genotypes of involved polymorphisms (rs27037, rs27038, rs469876, rs27044 and rs27980) in ERAP1 were detected by Sequenom Mass-Array platform. There were significant differences of the level of WBC (white blood cell), Platelets, CRP (C-reactive protein) and ESR (erythrocyte sedimentation rate) between AS patients and controls (Pall <0...
March 10, 2018: Gene
Andrzej Wiśniewski, Łukasz Matusiak, Aneta Szczerkowska-Dobosz, Izabela Nowak, Wioleta Łuszczek, Piotr Kuśnierczyk
The aim of this case-control study was to elucidate the role of some single nucleotide polymorphisms (SNPs) in the ERAP1 (rs27524, rs27044, rs30187, rs2287987 and rs26653) and ERAP2 (rs2248374) genes in predicting the risk for psoriasis vulgaris in the Polish population. ERAP1, ERAP2 and HLA-C*06:02 typing was done using the TaqMan SNP genotyping assays. We confirmed a strong association of the HLA-C*06:02 allele with early-onset psoriasis. In ERAP1, rs30187T increased the risk of psoriasis in HLA-C*06:02-positive patients, most strongly in late onset psoriasis, whereas it was protective when the HLA-C*06:02 allele was absent...
February 2018: Human Immunology
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