scholarly journals The Impact of the ‘Mis-Peptidome’ on HLA Class I-Mediated Diseases: Contribution of ERAP1 and ERAP2 and Effects on the Immune Response

2020 ◽  
Vol 21 (24) ◽  
pp. 9608
Author(s):  
Valentina Tedeschi ◽  
Giorgia Paldino ◽  
Fabiana Paladini ◽  
Benedetta Mattorre ◽  
Loretta Tuosto ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Association Studies ◽  
Strong Association ◽  
Hla Class I ◽  
Class I ◽  
Mass Spectrometry Analysis ◽  
Genome Wide Association Studies ◽  
Spectrometry Analysis ◽  
Hla Class I Molecules ◽  
The Impact

The strong association with the Major Histocompatibility Complex (MHC) class I genes represents a shared trait for a group of autoimmune/autoinflammatory disorders having in common immunopathogenetic basis as well as clinical features. Accordingly, the main risk factors for Ankylosing Spondylitis (AS), prototype of the Spondyloarthropathies (SpA), the Behçet’s disease (BD), the Psoriasis (Ps) and the Birdshot Chorioretinopathy (BSCR) are HLA-B*27, HLA-B*51, HLA-C*06:02 and HLA-A*29:02, respectively. Despite the strength of the association, the HLA pathogenetic role in these diseases is far from being thoroughly understood. Furthermore, Genome-Wide Association Studies (GWAS) have highlighted other important susceptibility factors such as Endoplasmic Reticulum Aminopeptidase (ERAP) 1 and, less frequently, ERAP2 that refine the peptidome presented by HLA class I molecules to CD8+ T cells. Mass spectrometry analysis provided considerable knowledge of HLA-B*27, HLA-B*51, HLA-C*06:02 and HLA-A*29:02 immunopeptidome. However, the combined effect of several ERAP1 and ERAP2 allelic variants could generate an altered pool of peptides accounting for the “mis-immunopeptidome” that ranges from suboptimal to pathogenetic/harmful peptides able to induce non-canonical or autoreactive CD8+ T responses, activation of NK cells and/or garbling the classical functions of the HLA class I molecules. This review will focus on this class of epitopes as possible elicitors of atypical/harmful immune responses which can contribute to the pathogenesis of chronic inflammatory diseases.

Quantitative HLA Class I Expression and KIR-Mismatch between NK-Cell-Donor and Patient Predict NK Cell Mediated Lysis of Leukemic Cells from Children with Acute Lymphatic Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5205-5205
Author(s):  
Matthias M. Pfeiffer ◽  
Michael Schumm ◽  
Klaus Dietz ◽  
Tobias Feuchtinger ◽  
Rupert Handgretinger ◽  
...  
Keyword(s):  
Nk Cells ◽  
Adhesion Molecules ◽  
Nk Cell ◽  
Hla Class I ◽  
Class I ◽  
Leukemic Cells ◽  
Specific Lysis ◽  
Lymphatic Leukemia ◽  
Hla Class I Molecules ◽  
The Impact

Abstract Relapses represent a major problem after transplantations in children with ALL. Natural Killer (NK) cells have been shown to exert remarkable Graft versus Leukemia effects after mismatched stem cell transplantation in myeloic leukemia, whereas the efficacy against lymphatic leukemia is still unclear. We therefore measured intensity of HLA class I expression on leukemic blasts by quantitative FACS analysis and investigated the impact of quantitative HLA class I expression, of several adhesion molecules and of KIR-mismatch on NK cell mediated lysis of the leukemic blasts from 21 pediatric patients with ALL. Expression of HLA class I molecules differed widely from patient to patient (range 5000–500000) and was reduced in comparison to B cells from healthy donors in 70% of cases. NK cells killed leukemic blasts very heterogeneously but a clear association between number of HLA class I molecules per cell and specific lysis (range 13–98%) was found (r2=0.68, p<0.0001). For the subgroup of leukemic blasts without KIR-mismatch, this association was even stronger (r2=0.98), whereas a weak association was found for the subgroup with KIR-mismatch, since most of these targets were lysed more efficiently than one could expect according to HLA class I expression alone. KIR-mismatch alone (t-test, p=0.45) as well as different patterns of adhesion molecules (ICAM1-3, LFA1/3) and CD95 had no significant influence. However, a multivariate model taking both HLA expression and KIR-ligand-mismatch into account, provided an even stronger association (r2=0.87 p<0.0001) for the whole group. Lysis was mainly dependent on HLA class I expression and in addition on KIR-mismatch for these leukemic cells. Assessment of HLA expression on leukemic blasts and KIR-receptor-ligand-mismatch between donor and recipient may be valuable to define patients who will benefit most from a NK mediated GvL effect.

scholarly journals The UFM1 Pathway Impacts HCMV US2-Mediated Degradation of HLA Class I

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 287
Author(s):  
A.B.C. Schuren ◽  
I.G.J. Boer ◽  
E.M. Bouma ◽  
M.L. Van de Weijer ◽  
A.I. Costa ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Ribosomal Proteins ◽  
Hla Class I ◽  
Class I ◽  
Mass Spectrometry Analysis ◽  
Misfolded Proteins ◽  
Immune Recognition ◽  
Post Translational Modification ◽  
Hla Class I Molecules ◽  
A Genome

To prevent accumulation of misfolded proteins in the endoplasmic reticulum, chaperones perform quality control on newly translated proteins and redirect misfolded proteins to the cytosol for degradation by the ubiquitin-proteasome system. This pathway is called ER-associated protein degradation (ERAD). The human cytomegalovirus protein US2 induces accelerated ERAD of HLA class I molecules to prevent immune recognition of infected cells by CD8+ T cells. Using US2-mediated HLA-I degradation as a model for ERAD, we performed a genome-wide CRISPR/Cas9 library screen to identify novel cellular factors associated with ERAD. Besides the identification of known players such as TRC8, p97, and UBE2G2, the ubiquitin-fold modifier1 (UFM1) pathway was found to affect degradation of HLA-I. UFMylation is a post-translational modification resembling ubiquitination. Whereas we observe ubiquitination of HLA-I, no UFMylation was detected on HLA-I or several other proteins involved in degradation of HLA-I, suggesting that the UFM1 pathway impacts ERAD in a different manner than ubiquitin. Interference with the UFM1 pathway seems to specifically inhibit the ER-to-cytosol dislocation of HLA-I. In the absence of detectable UFMylation of HLA-I, UFM1 may contribute to US2-mediated HLA-I degradation by misdirecting protein sorting indirectly. Mass spectrometry analysis of US2-expressing cells showed that ribosomal proteins are a major class of proteins undergoing extensive UFMylation; the role of these changes in protein degradation may be indirect and remains to be established.

scholarly journals Quantifying the impact of genetically regulated expression on complex traits and diseases

2019 ◽  
Author(s):  
Mingxuan Cai ◽  
Lin Chen ◽  
Jin Liu ◽  
Can Yang
Keyword(s):  
Complex Traits ◽  
Wide Spectrum ◽  
Association Studies ◽  
Strong Association ◽  
Significant Proportion ◽  
Reference Panel ◽  
Genome Wide Association Studies ◽  
Regulated Expression ◽  
Phenotypic Variations ◽  
The Impact

About 90% of risk variants identified from genome-wide association studies (GWAS) are located in non-coding regions, highlighting the regulatory role of genetic variants. We propose a unified statistical framework, IGREX, for quantifying the impact of genetically regulated expression (GREX). This is achieved by estimating proportion of phenotypic variations that can be explained by the GREX component. IGREX only requires summary-level GWAS data and a gene expression reference panel as input. In real data analysis, using 48 tissues from the GTEx project as the reference panel, we applied IGREX to a wide spectrum of phenotypes in GWAS, and observed a significant proportion of phenotypic variations could be attributed to the GREX component. In particular, the results given by IGREX revealed tissue-across and tissue-specific patterns of the GREX effects. We also observed strong association between GREX effect and immune-related proteins, further supporting the relevance between GREX and the immune processes.

scholarly journals RAD51B (rs8017304 and rs2588809), TRIB1 (rs6987702, rs4351379, and rs4351376), COL8A1 (rs13095226), and COL10A1 (rs1064583) Gene Variants with Predisposition to Age-Related Macular Degeneration

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Alvita Vilkeviciute ◽  
Loresa Kriauciuniene ◽  
Romanas Chaleckis ◽  
Vytenis Pranas Deltuva ◽  
Rasa Liutkeviciene
Keyword(s):  
Macular Degeneration ◽  
Association Studies ◽  
Strong Association ◽  
Age Related Macular Degeneration ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Exudative Amd ◽  
Age Related ◽  
Significant Difference ◽  
The Impact

Background. Age-related macular degeneration (AMD) is a progressive neurodegenerative disease of a central part of the neural retina (macula) and a leading cause of blindness in elderly people. While it is known that the AMD is a multifactorial disease, genetic factors involved in lipid metabolism, inflammation, and neovascularization are currently being widely studied in genome-wide association studies (GWAS). The aim of our study was to evaluate the impact of new single nucleotide polymorphisms (SNPs) in RAD51B, TRIB1, COL8A1, and COL10A1 genes on AMD development. Methods. Case-control study involved 254 patients diagnosed with early AMD, 244 patients with exudative AMD, and 942 control subjects. The genotyping of RAD51B (rs8017304 and rs2588809), TRIB1 (rs6987702, rs4351379, and rs4351376), COL8A1 (rs13095226), and COL10A1 (rs1064583) was carried out using TaqMan assays by a real-time polymerase chain reaction (RT-PCR) method. Results. Statistically significant difference was found in genotype (TT, TC, and CC) distribution of COL8A1 rs13095226 between exudative AMD and control groups (60.2%, 33.6%, and 6.1% vs. 64.9%, 32.3%, and 2.9%, respectively, p=0.036). Also, comparing with TT+TC, rs13095226 CC genotype was associated with 3.5-fold increased odds of exudative AMD development (OR = 3.540; 95% CI: 1.415-8.856; p=0.007). Conclusion. Our study revealed a strong association between a variant in COL8A1 (rs13095226) and exudative AMD development.

scholarly journals ENDOPLASMIC RETICULUM AMINO PEPTIDASE 1 (ERAP1) IN ANKYLOSING SPONDYLITIS

2015 ◽  
Vol 24 (1) ◽  
pp. 27-33
Author(s):  
Marius Cherciu ◽  
◽  
Mihai Bojinca ◽  
Laura Ioana Cherciu ◽  
Constantin Bara ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Ankylosing Spondylitis ◽  
Association Studies ◽  
Hla Class I ◽  
Genome Wide Association Studies ◽  
Antigenic Peptides ◽  
Pathogenic Potential ◽  
Hla Class I Molecules ◽  
Genome Wide ◽  
Different Populations

Recently, endoplasmic reticulum aminopeptidase 1 (ERAP1) gene polymorphisms were associated with ankylosing spondylitis (AS) in genome-wide association studies (GWAS), associations which later were replicated across different populations, including the Romanian population. ERAP1 enzyme was proved to be involved in the final trimming, to the optimal length, of the antigenic peptides before loading them to human leucocyte antigen (HLA) class I molecules, different variants of ERAP1 being able to modify the types of peptides presented by HLA I molecules (including HLA-B27) to the CD8+ T cells. This article presents a detailed description of the functions, structure and the pathogenic potential of ERAP1 in AS.

The impact of peptides on the recognition of HLA class I molecules by human HLA antibodies

2003 ◽  
Vol 64 (10) ◽  
pp. S22
Author(s):  
Arend Mulder ◽  
Chantal Eijsink ◽  
Michel Kester ◽  
Marrie J. Kardol ◽  
Marry E.I. Franke-van Dijk ◽  
...  
Keyword(s):  
Hla Class I ◽  
Class I ◽  
Hla Antibodies ◽  
Hla Class I Molecules ◽  
The Impact

Strong Association between Serotonin Transporter 5-HTTVNTR Variant and Psychoactive Substance (Nicotine) Use in the Turkish Cypriot Population

2020 ◽  
Vol 21 (6) ◽  
pp. 466-470
Author(s):  
Emine Kandemis ◽  
Gulten Tuncel ◽  
Ozen Asut ◽  
Sehime G. Temel ◽  
Mahmut C. Ergoren
Keyword(s):  
Serotonin Transporter ◽  
Association Studies ◽  
Strong Association ◽  
Smoking Behavior ◽  
Population Based ◽  
Genome Wide Association Studies ◽  
Genotype Distribution ◽  
Psychological Traits ◽  
Wide Range ◽  
Turkish Cypriot

Background: The use of psychoactive substances is one of the most dangerous social problems worldwide. Nicotine dependence results from the interaction between neurobiological, environmental and genetic factors. Serotonin is a neurotransmitter that has a wide range of central nervous system activities. The serotonin transporter gene has been previously linked to psychological traits. Objective: A variable number of tandem repeats within the serotonin transporter-linked polymorphic gene region are believed to alter the transcriptional efficiency of the 5-HTT gene. Therefore, we aimed to investigate the association between this polymorphic site and smoking behavior in the Turkish Cypriot population. Methods: A total of 259 (100 smokers, 100 non-smokers and 59 ex-smokers) Turkish Cypriots were included in this population-based cross-sectional study. Genomic DNA was extracted from peripheral blood samples and the 5-HTTVNTR2 polymorphisms were determined by the PCR-RFLP. Results: The allelic frequency and genotype distribution results of this study showed a strong association (P<0.0001) between smokers and non-smokers. No statistical significance was found between non-smokers and ex-smokers. Conclusion: This is the first genetic epidemiology study to investigate the allelic frequencies of 5-HTTVNTR2 polymorphisms associated with smoking behavior in the Turkish Cypriot population. Based on the results of this study, genome-wide association studies should be designed for preventive medicine in this population.

scholarly journals TCF19 Impacts a Network of Inflammatory and DNA Damage Response Genes in the Pancreatic β-Cell

Metabolites ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 513
Author(s):  
Grace H. Yang ◽  
Danielle A. Fontaine ◽  
Sukanya Lodh ◽  
Joseph T. Blumer ◽  
Avtar Roopra ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Association Studies ◽  
Cell Cycle Gene ◽  
Genome Wide Association Studies ◽  
Β Cell ◽  
Nucleotide Incorporation ◽  
Damage Response ◽  
The Impact

Transcription factor 19 (TCF19) is a gene associated with type 1 diabetes (T1DM) and type 2 diabetes (T2DM) in genome-wide association studies. Prior studies have demonstrated that Tcf19 knockdown impairs β-cell proliferation and increases apoptosis. However, little is known about its role in diabetes pathogenesis or the effects of TCF19 gain-of-function. The aim of this study was to examine the impact of TCF19 overexpression in INS-1 β-cells and human islets on proliferation and gene expression. With TCF19 overexpression, there was an increase in nucleotide incorporation without any change in cell cycle gene expression, alluding to an alternate process of nucleotide incorporation. Analysis of RNA-seq of TCF19 overexpressing cells revealed increased expression of several DNA damage response (DDR) genes, as well as a tightly linked set of genes involved in viral responses, immune system processes, and inflammation. This connectivity between DNA damage and inflammatory gene expression has not been well studied in the β-cell and suggests a novel role for TCF19 in regulating these pathways. Future studies determining how TCF19 may modulate these pathways can provide potential targets for improving β-cell survival.

scholarly journals Molecular Mechanisms of ZC3H12C/Reg-3 Biological Activity and Its Involvement in Psoriasis Pathology

2021 ◽  
Vol 22 (14) ◽  
pp. 7311
Author(s):  
Mateusz Wawro ◽  
Jakub Kochan ◽  
Weronika Sowinska ◽  
Aleksandra Solecka ◽  
Karolina Wawro ◽  
...  
Keyword(s):  
Family Member ◽  
Cellular Localization ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Association Studies ◽  
Psoriasis Patient ◽  
Genome Wide Association Studies ◽  
Mrna Levels ◽  
Transcript Levels

The members of the ZC3H12/MCPIP/Regnase family of RNases have emerged as important regulators of inflammation. In contrast to Regnase-1, -2 and -4, a thorough characterization of Regnase-3 (Reg-3) has not yet been explored. Here we demonstrate that Reg-3 differs from other family members in terms of NYN/PIN domain features, cellular localization pattern and substrate specificity. Together with Reg-1, the most comprehensively characterized family member, Reg-3 shared IL-6, IER-3 and Reg-1 mRNAs, but not IL-1β mRNA, as substrates. In addition, Reg-3 was found to be the only family member which regulates transcript levels of TNF, a cytokine implicated in chronic inflammatory diseases including psoriasis. Previous meta-analysis of genome-wide association studies revealed Reg-3 to be among new psoriasis susceptibility loci. Here we demonstrate that Reg-3 transcript levels are increased in psoriasis patient skin tissue and in an experimental model of psoriasis, supporting the immunomodulatory role of Reg-3 in psoriasis, possibly through degradation of mRNA for TNF and other factors such as Reg-1. On the other hand, Reg-1 was found to destabilize Reg-3 transcripts, suggesting reciprocal regulation between Reg-3 and Reg-1 in the skin. We found that either Reg-1 or Reg-3 were expressed in human keratinocytes in vitro. However, in contrast to robustly upregulated Reg-1 mRNA levels, Reg-3 expression was not affected in the epidermis of psoriasis patients. Taken together, these data suggest that epidermal levels of Reg-3 are negatively regulated by Reg-1 in psoriasis, and that Reg-1 and Reg-3 are both involved in psoriasis pathophysiology through controlling, at least in part different transcripts.

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