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Article ; Online: HPV16

Konstantopoulos, Georgios / Leventakou, Danai / Saltiel, Despoina-Rozi / Zervoudi, Efthalia / Logotheti, Eirini / Pettas, Spyros / Karagianni, Korina / Daiou, Angeliki / Hatzistergos, Konstantinos E / Dafou, Dimitra / Arsenakis, Minas / Kottaridi, Christine

Viruses

2024 Volume 16, Issue 1

Abstract: Human Papillomaviruses have been associated with the occurrence of cervical cancer, the fourth most common cancer that affects women globally, while 70% of cases are caused by infection with the high-risk types HPV16 and HPV18. The integration of these ... ...

Abstract	Human Papillomaviruses have been associated with the occurrence of cervical cancer, the fourth most common cancer that affects women globally, while 70% of cases are caused by infection with the high-risk types HPV16 and HPV18. The integration of these viruses' oncogenes
MeSH term(s)	Female ; Humans ; B7-H1 Antigen/genetics ; Human papillomavirus 16/genetics ; Immune Evasion ; MicroRNAs/genetics ; Uterine Cervical Neoplasms/genetics ; Uterine Cervical Neoplasms/virology ; Oncogene Proteins, Viral/genetics
Chemical Substances	B7-H1 Antigen ; MicroRNAs ; MIRN143 microRNA, human ; E6 protein, Human papillomavirus type 16 ; Oncogene Proteins, Viral ; HIF1A protein, human
Language	English
Publishing date	2024-01-12
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v16010113
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: A role for naturally occurring alleles of endoplasmic reticulum aminopeptidases in tumor immunity and cancer pre-disposition.

Stratikos, Efstratios / Stamogiannos, Athanasios / Zervoudi, Efthalia / Fruci, Doriana

Frontiers in oncology

2014 Volume 4, Page(s) 363

Abstract: Endoplasmic reticulum aminopeptidase 1 and 2 (ERAP1 and ERAP2) are key components on the pathway that generates antigenic epitopes for presentation to cytotoxic T-lymphocytes (CTLs). Coding single nucleotide polymorphisms (SNPs) in these enzymes have ... ...

Abstract	Endoplasmic reticulum aminopeptidase 1 and 2 (ERAP1 and ERAP2) are key components on the pathway that generates antigenic epitopes for presentation to cytotoxic T-lymphocytes (CTLs). Coding single nucleotide polymorphisms (SNPs) in these enzymes have been associated with pre-disposition to several major human diseases including inflammatory diseases with autoimmune etiology, viral infections, and virally induced cancer. The function of these enzymes has been demonstrated to affect CTL and natural killer cell responses toward healthy and malignant cells as well as the production of inflammatory cytokines. Recent studies have demonstrated that SNPs in ERAP1 and ERAP2 can affect their ability to generate or destroy antigenic epitopes and define the immunopeptidome. In this review, we examine the potential role of these enzymes and their polymorphic states on the generation of cytotoxic responses toward malignantly transformed cells. Given the current state-of-the-art, it is possible that polymorphic variation in these enzymes may contribute to the individual's pre-disposition to cancer through altered generation or destruction of tumor antigens that can facilitate tumor immune evasion.
Language	English
Publishing date	2014-12-19
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2014.00363
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Article: Novel selective inhibitors of aminopeptidases that generate antigenic peptides

Papakyriakou, Athanasios / Zervoudi, Efthalia / Theodorakis, Emmanuel A / Saveanu, Loredana / Stratikos, Efstratios / Vourloumis, Dionisios

Bioorganic & medicinal chemistry letters. 2013 Sept. 1, v. 23, no. 17

2013

Abstract: Endoplasmic reticulum aminopeptidases, ERAP1 and ERAP2, as well as Insulin regulated aminopeptidase (IRAP) play key roles in antigen processing, and have recently emerged as biologically important targets for manipulation of antigen presentation. Taking ... ...

Abstract	Endoplasmic reticulum aminopeptidases, ERAP1 and ERAP2, as well as Insulin regulated aminopeptidase (IRAP) play key roles in antigen processing, and have recently emerged as biologically important targets for manipulation of antigen presentation. Taking advantage of the available structural and substrate-selectivity data for these enzymes, we have rationally designed a new series of inhibitors that display low micromolar activity. The selectivity profile for these three highly homologous aminopeptidases provides a promising avenue for modulating intracellular antigen processing.
Keywords	aminopeptidases ; antigen presentation ; antigens ; chemistry ; endoplasmic reticulum ; insulin ; peptides
Language	English
Dates of publication	2013-0901
Size	p. 4832-4836.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2013.07.024
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Article ; Online: Novel selective inhibitors of aminopeptidases that generate antigenic peptides.

Papakyriakou, Athanasios / Zervoudi, Efthalia / Theodorakis, Emmanuel A / Saveanu, Loredana / Stratikos, Efstratios / Vourloumis, Dionisios

Bioorganic & medicinal chemistry letters

2013 Volume 23, Issue 17, Page(s) 4832–4836

Abstract	Endoplasmic reticulum aminopeptidases, ERAP1 and ERAP2, as well as Insulin regulated aminopeptidase (IRAP) play key roles in antigen processing, and have recently emerged as biologically important targets for manipulation of antigen presentation. Taking advantage of the available structural and substrate-selectivity data for these enzymes, we have rationally designed a new series of inhibitors that display low micromolar activity. The selectivity profile for these three highly homologous aminopeptidases provides a promising avenue for modulating intracellular antigen processing.
MeSH term(s)	Aminopeptidases/antagonists & inhibitors ; Cystinyl Aminopeptidase/antagonists & inhibitors ; Drug Design ; Endoplasmic Reticulum/enzymology ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Humans ; Models, Molecular
Chemical Substances	Enzyme Inhibitors ; Aminopeptidases (EC 3.4.11.-) ; Cystinyl Aminopeptidase (EC 3.4.11.3) ; leucyl-cystinyl aminopeptidase (EC 3.4.11.3)
Language	English
Publishing date	2013-09-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2013.07.024
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Article: Optimized Peptide-MHC Multimer Protocols for Detection and Isolation of Autoimmune T-Cells.

Dolton, Garry / Zervoudi, Efthalia / Rius, Cristina / Wall, Aaron / Thomas, Hannah L / Fuller, Anna / Yeo, Lorraine / Legut, Mateusz / Wheeler, Sophie / Attaf, Meriem / Chudakov, Dmitriy M / Choy, Ernest / Peakman, Mark / Sewell, Andrew K

Frontiers in immunology

2018 Volume 9, Page(s) 1378

Abstract: Peptide-MHC (pMHC) multimers have become the "gold standard" for the detection and isolation of antigen-specific T-cells but recent evidence shows that normal use of these reagents can miss fully functional T-cells that bear T-cell receptors (TCRs) with ... ...

Abstract	Peptide-MHC (pMHC) multimers have become the "gold standard" for the detection and isolation of antigen-specific T-cells but recent evidence shows that normal use of these reagents can miss fully functional T-cells that bear T-cell receptors (TCRs) with low affinity for cognate antigen. This issue is particularly pronounced for anticancer and autoimmune T-cells as self-reactive T-cell populations are enriched for low-affinity TCRs due to the removal of cells with higher affinity receptors by immune tolerance mechanisms. Here, we stained a wide variety of self-reactive human T-cells using regular pMHC staining and an optimized technique that included: (i) protein kinase inhibitor (PKI), to prevent TCR triggering and internalization, and (ii) anti-fluorochrome antibody, to reduce reagent dissociation during washing steps. Lymphocytes derived from the peripheral blood of type 1 diabetes patients were stained with pMHC multimers made with epitopes from preproinsulin (PPI), insulin-β chain, glutamic acid decarboxylase 65 (GAD65), or glucose-6-phospate catalytic subunit-related protein (IGRP) presented by disease-risk allelles HLA A02:01 or HLA24:02. Samples from ankylosing spondylitis patients were stained with a multimerized epitope from vasoactive intestinal polypeptide receptor 1 (VIPR1) presented by HLA B*27:05. Optimized procedures stained an average of 40.5-fold (
Language	English
Publishing date	2018-06-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2018.01378
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Article: Dual Molecular Mechanisms Govern Escape at Immunodominant HLA A2-Restricted HIV Epitope.

Cole, David K / Fuller, Anna / Dolton, Garry / Zervoudi, Efthalia / Legut, Mateusz / Miles, Kim / Blanchfield, Lori / Madura, Florian / Holland, Christopher J / Bulek, Anna M / Bridgeman, John S / Miles, John J / Schauenburg, Andrea J A / Beck, Konrad / Evavold, Brian D / Rizkallah, Pierre J / Sewell, Andrew K

Frontiers in immunology

2017 Volume 8, Page(s) 1503

Abstract: Serial accumulation of mutations to fixation in the SLYNTVATL (SL9) immunodominant, HIV p17 Gag-derived, HLA A2-restricted cytotoxic T lymphocyte epitope produce the SLFNTIAVL triple mutant "ultimate" escape variant. These mutations in solvent-exposed ... ...

Abstract	Serial accumulation of mutations to fixation in the SLYNTVATL (SL9) immunodominant, HIV p17 Gag-derived, HLA A2-restricted cytotoxic T lymphocyte epitope produce the SLFNTIAVL triple mutant "ultimate" escape variant. These mutations in solvent-exposed residues are believed to interfere with TCR recognition, although confirmation has awaited structural verification. Here, we solved a TCR co-complex structure with SL9 and the triple escape mutant to determine the mechanism of immune escape in this eminent system. We show that, in contrast to prevailing hypotheses, the main TCR contact residue is 4N and the dominant mechanism of escape is not
Language	English
Publishing date	2017-11-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2017.01503
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Article ; Online: Autoimmune disease-associated variants of extracellular endoplasmic reticulum aminopeptidase 1 induce altered innate immune responses by human immune cells.

Aldhamen, Yasser A / Pepelyayeva, Yuliya / Rastall, David P W / Seregin, Sergey S / Zervoudi, Efthalia / Koumantou, Despoina / Aylsworth, Charles F / Quiroga, Dionisia / Godbehere, Sarah / Georgiadis, Dimitris / Stratikos, Efstratios / Amalfitano, Andrea

Journal of innate immunity

2015 Volume 7, Issue 3, Page(s) 275–289

Abstract: Endoplasmic reticulum aminopeptidase 1 (ERAP1) gene polymorphisms have been linked to several autoimmune diseases; however, the molecular mechanisms underlying these associations are not well understood. Recently, we demonstrated that ERAP1 regulates key ...

Abstract	Endoplasmic reticulum aminopeptidase 1 (ERAP1) gene polymorphisms have been linked to several autoimmune diseases; however, the molecular mechanisms underlying these associations are not well understood. Recently, we demonstrated that ERAP1 regulates key aspects of the innate immune response. Previous studies show ERAP1 to be endoplasmic reticulum-localized and secreted during inflammation. Herein, we investigate the possible roles that ERAP1 polymorphic variants may have in modulating the innate immune responses of human peripheral blood mononuclear cells (hPBMCs) using two experimental methods: extracellular exposure of hPBMCs to ERAP1 variants and adenovirus (Ad)-based ERAP1 expression. We found that exposure of hPBMCs to ERAP1 variant proteins as well as ERAP1 overexpression by Ad5 vectors increased inflammatory cytokine and chemokine production, and enhanced immune cell activation. Investigating the molecular mechanisms behind these responses revealed that ERAP1 is able to activate innate immunity via multiple pathways, including the NLRP3 (NOD-like receptor, pyrin domain-containing 3) inflammasome. Importantly, these responses varied if autoimmune disease-associated variants of ERAP1 were examined in the assay systems. Unexpectedly, blocking ERAP1 cellular internalization augmented IL-1β production. To our knowledge, this is the first report identifying ERAP1 as being involved in modulating innate responses of human immune cells, a finding that may explain why ERAP1 has been genetically associated with several autoimmune diseases.
MeSH term(s)	Adenoviridae ; Aminopeptidases/genetics ; Aminopeptidases/immunology ; Animals ; Autoimmune Diseases/genetics ; Autoimmune Diseases/immunology ; Autoimmune Diseases/pathology ; Carrier Proteins/genetics ; Carrier Proteins/immunology ; Cell Line ; Humans ; Immunity, Innate ; Inflammation/genetics ; Inflammation/immunology ; Inflammation/pathology ; Interleukin-1beta/genetics ; Interleukin-1beta/immunology ; Leukocytes, Mononuclear/immunology ; Leukocytes, Mononuclear/pathology ; Mice ; Minor Histocompatibility Antigens ; NLR Family, Pyrin Domain-Containing 3 Protein ; Transduction, Genetic
Chemical Substances	Carrier Proteins ; IL1B protein, human ; IL1B protein, mouse ; Interleukin-1beta ; Minor Histocompatibility Antigens ; NLR Family, Pyrin Domain-Containing 3 Protein ; NLRP3 protein, human ; Nlrp3 protein, mouse ; Aminopeptidases (EC 3.4.11.-) ; ERAP1 protein, human (EC 3.4.11.-) ; ERAP1 protein, mouse (EC 3.4.11.-)
Language	English
Publishing date	2015
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2454158-8
ISSN	1662-8128 ; 1662-811X
ISSN (online)	1662-8128
ISSN	1662-811X
DOI	10.1159/000368899
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Article ; Online: 3,4-diaminobenzoic acid derivatives as inhibitors of the oxytocinase subfamily of M1 aminopeptidases with immune-regulating properties.

Papakyriakou, Athanasios / Zervoudi, Efthalia / Tsoukalidou, Sofia / Mauvais, Francois-Xavier / Sfyroera, Georgia / Mastellos, Dimitrios C / van Endert, Peter / Theodorakis, Emmanuel A / Vourloumis, Dionisios / Stratikos, Efstratios

Journal of medicinal chemistry

2015 Volume 58, Issue 3, Page(s) 1524–1543

Abstract: Members of the oxytocinase subfamily of M1 aminopeptidases (ERAP1, ERAP2, and IRAP) play important roles in both the adaptive and innate human immune responses. Their enzymatic activity can contribute to the pathogenesis of several major human diseases ... ...

Abstract	Members of the oxytocinase subfamily of M1 aminopeptidases (ERAP1, ERAP2, and IRAP) play important roles in both the adaptive and innate human immune responses. Their enzymatic activity can contribute to the pathogenesis of several major human diseases ranging from viral and parasitic infections to autoimmunity and cancer. We have previously demonstrated that diaminobenzoic acid derivatives show promise as selective inhibitors for this group of aminopeptidases. In this study, we have thoroughly explored a series of 3,4-diaminobenzoic acid derivatives as inhibitors of this class of enzymes, achieving submicromolar inhibitors for ERAP2 (IC50 = 237 nM) and IRAP (IC50 = 105 nM). Cell-based analysis indicated that the lead compounds can be effective in downregulating macrophage activation induced by lipopolysaccharide and interferon-γ as well as cross-presentation by bone marrow-derived dendritic cells. Our results indicate that this class of inhibitors may be useful for the targeted downregulation of immune responses.
MeSH term(s)	Aminobenzoates/chemical synthesis ; Aminobenzoates/chemistry ; Aminobenzoates/pharmacology ; Aminopeptidases/antagonists & inhibitors ; Aminopeptidases/immunology ; Aminopeptidases/metabolism ; Animals ; Cell Line ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/chemical synthesis ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Mice ; Models, Molecular ; Molecular Structure ; Structure-Activity Relationship
Chemical Substances	Aminobenzoates ; Enzyme Inhibitors ; 3,4-diaminobenzoic acid (2H2G880K12) ; Aminopeptidases (EC 3.4.11.-)
Language	English
Publishing date	2015-02-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/jm501867s
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Article ; Online: Rationally designed inhibitor targeting antigen-trimming aminopeptidases enhances antigen presentation and cytotoxic T-cell responses.

Zervoudi, Efthalia / Saridakis, Emmanuel / Birtley, James R / Seregin, Sergey S / Reeves, Emma / Kokkala, Paraskevi / Aldhamen, Yasser A / Amalfitano, Andrea / Mavridis, Irene M / James, Edward / Georgiadis, Dimitris / Stratikos, Efstratios

Proceedings of the National Academy of Sciences of the United States of America

2013 Volume 110, Issue 49, Page(s) 19890–19895

Abstract: Intracellular aminopeptidases endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and ERAP2), and as well as insulin-regulated aminopeptidase (IRAP) process antigenic epitope precursors for loading onto MHC class I molecules and regulate the adaptive ... ...

Abstract	Intracellular aminopeptidases endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and ERAP2), and as well as insulin-regulated aminopeptidase (IRAP) process antigenic epitope precursors for loading onto MHC class I molecules and regulate the adaptive immune response. Their activity greatly affects the antigenic peptide repertoire presented to cytotoxic T lymphocytes and as a result can regulate cytotoxic cellular responses contributing to autoimmunity or immune evasion by viruses and cancer cells. Therefore, pharmacological regulation of their activity is a promising avenue for modulating the adaptive immune response with possible applications in controlling autoimmunity, in boosting immune responses to pathogens, and in cancer immunotherapy. In this study we exploited recent structural and biochemical analysis of ERAP1 and ERAP2 to design and develop phosphinic pseudopeptide transition state analogs that can inhibit this family of enzymes with nM affinity. X-ray crystallographic analysis of one such inhibitor in complex with ERAP2 validated our design, revealing a canonical mode of binding in the active site of the enzyme, and highlighted the importance of the S2' pocket for achieving inhibitor potency. Antigen processing and presentation assays in HeLa and murine colon carcinoma (CT26) cells showed that these inhibitors induce increased cell-surface antigen presentation of transfected and endogenous antigens and enhance cytotoxic T-cell responses, indicating that these enzymes primarily destroy epitopes in those systems. This class of inhibitors constitutes a promising tool for controlling the cellular adaptive immune response in humans by modulating the antigen processing and presentation pathway.
MeSH term(s)	Aminopeptidases/antagonists & inhibitors ; Aminopeptidases/chemistry ; Aminopeptidases/metabolism ; Animals ; Antigen Presentation/drug effects ; Antigen Presentation/immunology ; Binding Sites/immunology ; Cell Line, Tumor ; Crystallography, X-Ray ; Cystinyl Aminopeptidase/metabolism ; HeLa Cells ; Humans ; Mice ; Minor Histocompatibility Antigens ; Models, Molecular ; Molecular Structure ; Phosphinic Acids ; Protein Engineering ; T-Lymphocytes, Cytotoxic/drug effects ; T-Lymphocytes, Cytotoxic/immunology
Chemical Substances	Minor Histocompatibility Antigens ; Phosphinic Acids ; Aminopeptidases (EC 3.4.11.-) ; ERAP1 protein, human (EC 3.4.11.-) ; ERAP2 protein, human (EC 3.4.11.-) ; Cystinyl Aminopeptidase (EC 3.4.11.3) ; leucyl-cystinyl aminopeptidase (EC 3.4.11.3)
Language	English
Publishing date	2013-11-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1309781110
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Article ; Online: A common single nucleotide polymorphism in endoplasmic reticulum aminopeptidase 2 induces a specificity switch that leads to altered antigen processing.

Evnouchidou, Irini / Birtley, James / Seregin, Sergey / Papakyriakou, Athanasios / Zervoudi, Efthalia / Samiotaki, Martina / Panayotou, George / Giastas, Petros / Petrakis, Olivia / Georgiadis, Dimitris / Amalfitano, Andrea / Saridakis, Emmanuel / Mavridis, Irene M / Stratikos, Efstratios

Journal of immunology (Baltimore, Md. : 1950)

2012 Volume 189, Issue 5, Page(s) 2383–2392

Abstract: Endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and ERAP2) cooperate to trim antigenic peptide precursors for loading onto MHC class I molecules and help regulate the adaptive immune response. Common coding single nucleotide polymorphisms in ERAP1 ... ...

Abstract	Endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and ERAP2) cooperate to trim antigenic peptide precursors for loading onto MHC class I molecules and help regulate the adaptive immune response. Common coding single nucleotide polymorphisms in ERAP1 and ERAP2 have been linked with predisposition to human diseases ranging from viral and bacterial infections to autoimmunity and cancer. It has been hypothesized that altered Ag processing by these enzymes is a causal link to disease etiology, but the molecular mechanisms are obscure. We report in this article that the common ERAP2 single nucleotide polymorphism rs2549782 that codes for amino acid variation N392K leads to alterations in both the activity and the specificity of the enzyme. Specifically, the 392N allele excises hydrophobic N-terminal residues from epitope precursors up to 165-fold faster compared with the 392K allele, although both alleles are very similar in excising positively charged N-terminal amino acids. These effects are primarily due to changes in the catalytic turnover rate (k(cat)) and not in the affinity for the substrate. X-ray crystallographic analysis of the ERAP2 392K allele suggests that the polymorphism interferes with the stabilization of the N terminus of the peptide both directly and indirectly through interactions with key residues participating in catalysis. This specificity switch allows the 392N allele of ERAP2 to supplement ERAP1 activity for the removal of hydrophobic N-terminal residues. Our results provide mechanistic insight to the association of this ERAP2 polymorphism with disease and support the idea that polymorphic variation in Ag processing enzymes constitutes a component of immune response variability in humans.
MeSH term(s)	Amino Acid Sequence ; Aminopeptidases/genetics ; Antigen Presentation/genetics ; Antigen Presentation/immunology ; Crystallography, X-Ray ; Endoplasmic Reticulum/enzymology ; Endoplasmic Reticulum/genetics ; Endoplasmic Reticulum/immunology ; Enzyme Activation/genetics ; Enzyme Activation/immunology ; Genetic Variation/immunology ; HeLa Cells ; Humans ; Immunoglobulin Class Switching/genetics ; Immunoglobulin Class Switching/immunology ; Molecular Sequence Data ; Polymorphism, Single Nucleotide/immunology ; Substrate Specificity/genetics ; Substrate Specificity/immunology
Chemical Substances	Aminopeptidases (EC 3.4.11.-) ; ERAP2 protein, human (EC 3.4.11.-)
Language	English
Publishing date	2012-07-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.1200918
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