ERAP1 Research Articles

ERAP, KIR and HLA-C gene interaction in susceptibility to recurrent spontaneous abortion in the Polish population

Endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 trim peptides to generate stable antigenic epitopes for their presentation by HLA class I (HLA-I) molecules to T cell receptor. By influencing the peptide repertoire of HLA-I molecules, they affect also the interactions of HLA-I with killer cell immunoglobulin-like receptors (KIRs) of natural killer (NK) cells. HLA-C is the only polymorphic HLA-I molecule present on the trophoblast.In this study we investigated the role of ERAP1 and ERAP2 polymorphisms in the context of KIR and HLA-C genes in women suffering from recurrent spontaneous abortion (RSA) in the Polish population. We used TaqMan genotyping assays for ERAP1 rs27044, rs30187, rs2287987, rs26618, rs2665 and ERAP2 rs2248374; PCR-SSP methods for KIR and HLA-C genotyping. We tested 285 women who experienced recurrent spontaneous abortion (RSA) and 319 fertile women.We observed a significant association of ERAP1 rs30187TT genotype with RSA (p = 0.02, OR = 1.89, 95%CI = 1.11–3.21), however the most striking association was found in comparison of patients and controls with ERAP1 rs30187TT and KIR Bx genotypes (p = 0.006, pcorr. = 0.036, OR = 2.40, 95%CI = 1.27–4.52). Moreover, this effect was even stronger in HLA-C2 positive patients (p = 0.0031, pcorr. = 0.019, OR = 3.46, 95%CI = 1.48–8.11). Other weaker associations of the remaining tested ERAP single nucleotide polymorphisms with RSA were also presented.In conclusion, ERAP1 rs30187TT genotype itself increased susceptibility to RSA but this effect was much stronger in patients positive for HLA-C2 and KIR Bx genotypes.

ERAP1-ERAP2 haplotypes are associated with ankylosing spondylitis in Polish patients

The objective of this case-control study was to evaluate the role of four single-nucleotide polymorphisms in the ERAP1 (rs2287987, rs30187, rs27044) and ERAP2 (rs2248374) genes and their haplotypes in predicting the risk for ankylosing spondylitis (AS) on a well-defined Polish population. Our study confirmed the strong association between the HLA-B*27 allele and the disease. For all tested ERAP1 SNPs we found significant differences in the minor allele and genotype distribution between patients and controls. The strongest association with AS was observed for rs30187. The minor T allele and homozygous TT genotype of this SNP significantly increased disease risk (OR = 1.56, 95%CI = 1.22–1.99, p = 0.0004 and OR = 2.52, 95%CI = 1.50–4.25, p = 0.001, respectively). In the case of rs2287987, minor C allele exerted a protective effect (OR = 0.64, 95%CI = 0.46–0.88, p = 0.008). In contrast to ERAP1, we observed no effect of rs2248374 in ERAP2 on the disease. We also carried out ERAP1-ERAP2 haplotype analysis to demonstrate a possible association of both genes with AS. Results showed that the haplotype H4, containing ERAP1 SNPs associated with high enzymatic activity, together with the presence of ERAP2 expression, significantly increased the risk of AS (OR = 1.97, 95% CI = 1.21–3.21, pcorr = 0.048). By contrast, the haplotype H5 coding for low activity of ERAP1 and the lack of ERAP2 expression was strongly protective (OR = 0.41, 95% CI = 0.23–0.72, pcorr = 0.008).

ERAP1 allotypes shape the epitope repertoire of virus-specific CD8+ T cell responses in acute hepatitis C virus infection

Endoplasmic reticulum aminopeptidase 1 (ERAP1) polymorphisms are linked with human leukocyte antigen (HLA) class I-associated autoinflammatory disorders, including ankylosing spondylitis and Behçet's disease. Disease-associated ERAP1 allotypes exhibit distinct functional properties, but it remains unclear how differential peptide trimming in vivo affects the repertoire of epitopes presented to CD8+ T cells. The aim of this study was to determine the impact of ERAP1 allotypes on the virus-specific CD8+ T cell epitope repertoire in an HLA-B*27:05+ individual with acute hepatitis C virus (HCV) infection. We performed genetic and functional analyses of ERAP1 allotypes and characterized the HCV-specific CD8+ T cell repertoire at the level of fine epitope specificity and HLA class I restriction, in a patient who had acquired an HCV genotype 1a infection through a needle-stick injury. Two hypoactive allotypic variants of ERAP1 were identified in an individual with acute HCV infection. The associated repertoire of virus-derived epitopes recognized by CD8+ T cells was uncommon in a couple of respects. Firstly, reactivity was directed away from classically immunodominant epitopes, preferentially targeting either novel or subdominant epitopes. Secondly, reactivity was biased towards longer epitopes (10-11-mers). Despite the patient exhibiting favorable prognostic indicators, these atypical immune responses failed to clear the virus and the patient developed persistent low-level infection with HCV. ERAP1 allotypes modify the virus-specific CD8+ T cell epitope repertoire in vivo, leading to altered immunodominance patterns that may contribute to the failure of antiviral immunity after infection with HCV. Endoplasmic reticulum aminopeptidase 1 (ERAP1) plays a key role in antigen presentation. Genetic variants of ERAP1 (leading to distinct allotypes) are linked with specific autoinflammatory disorders, such as ankylosing spondylitis and Behçet's disease. We found that ERAP1 allotypes modified the repertoire of virus-specific CD8+ T cell epitopes in a patient with hepatitis C virus, leading to an altered pattern of immunodominance that may have contributed to the failure of antiviral immunity in this patient.

High-Resolution Crystal Structure of Endoplasmic Reticulum Aminopeptidase 1 with Bound Phosphinic Transition-State Analogue Inhibitor.

Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an intracellular enzyme that helps generate peptides presented by Major Histocompatibility Complex Class I (MHC class I) molecules and is an emerging target for immunotherapy applications. Despite almost two decades of research on ERAP1, lack of high-resolution crystal structures has hampered drug-development efforts. By optimizing the protein construct, we obtained a high-resolution (1.60 Å) crystal structure of the closed-conformation of ERAP1 with a potent phosphinic pseudopeptide inhibitor bound in its active site. The structure provides key insight on the mechanism of inhibition as well as selectivity toward homologous enzymes and allows detailed mapping of the internal cavity of the enzyme that accommodates peptide-substrates. Bis-tris propane and malic acid molecules, found bound in pockets in the internal cavity, reveal potential druggable secondary binding sites. The ability to obtain high-resolution crystal structures of ERAP1 removes a major bottleneck in the development of compounds that regulate its activity and will greatly accelerate drug-discovery efforts.

Susceptibility to ERAP1 gene single nucleotide polymorphism modulates the inflammatory cytokine setting in ankylosing spondylitis.

To evaluate the association of ERAP1 gene single nucleotide polymorphisms (SNPs) with the risk of ankylosing spondylitis (AS) and their role in modulation of the inflammatory interleukin (IL)-17/IL-23 axis in the disease. For genotyping, 190 AS cases and 190 healthy controls were enrolled. After DNA extraction, all the subjects were genotyped for rs17482078, rs469876, and rs27038 polymorphisms using single specific primer polymerase chain reaction (PCR) assay. After isolation of peripheral blood mononuclear cells, RNA extraction and complementary DNA synthesis, real-time PCR using SYBR Green master mix was employed to determine messenger RNA (mRNA) expression of IL-17A and IL-23 in PBMCs. Using enzyme-linked immunosorbent assay, the concentration of these cytokines was determined in serum samples. It was observed that the A allele of rs27038 polymorphism significantly increased AS risk (odds ratio [OR] = 1.53, 95% CI =1.11-2.12; P = 0.0096). Moreover, AA and AG genotypes of this SNP were associated with increased (OR = 2.89, 95% CI = 1.42-5.85; P=0.0031) and decreased (OR = 0.57, 95% CI = 0.36-0.92; P=0.021), respectively, risk of the disease. The rs27038 SNP was associated with C-reactive protein level. There were significantly increased mRNA and serum concentrations of both IL-17A and IL-23 in AS patients compared with controls. Furthermore, AS patients with the AA in comparison to other genotypes for rs27038 SNP indicated significantly increased mRNA and serum concentration levels for both cytokines. This study demonstrated the association of ERAP1 gene rs27038 polymorphism with the risk of AS in an Iranian population. Additionally, it seems that rs27038 is involved in the modulation of the inflammatory IL-17/IL-23 axis in AS.

Genotyping of Italian patients with Behçet syndrome identified two novel ERAP1 polymorphisms using sequencing-based approach

The endoplasmic reticulum aminopeptidase protein 1 gene (ERAP1) is related to several human diseases, including Behçet syndrome (BS), a multisystemic disorder with unknown etiology. ERAP1 is involved in immune response and its role can be influenced by gene single nucleotide variations (SNVs).We genotyped the ERAP1 whole structure in 50 consecutive BS patients and 50 ethnically-matched healthy controls using both bioinformatics and molecular methodologies.We identified two novel heterozygous missense SNVs of ERAP1 exon3 responsible for the p.Glu183Val and p.Phe199Ser changes. The first variation was recognized in 7/50 (14%) BS patients and involved the substrate binding site (p.Glu183) required for the anchorage of the peptide N-terminal group. The SNV was predicted to be a damaging variation, as well as the p.Phe199Ser substitution (PolyPhen-2 and SIFT on line software). 3D protein structure prediction showed a change in energy score when the wild-type and the variant states were compared, probably influencing the substrate binding and the protein folding. The first variation was associated to a more stable protein chain, while the second polymorphism was related to a less stable protein chain.Our data need to be tested in larger genetic studies.

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.

Trimming of MHC Class I Ligands by ERAP Aminopeptidases.

Studies over the last decade on characterization of the major histocompatibility complex (MHC) class I antigen presentation pathway have highlighted the importance of antigen processing, peptide transport, peptide trimming, and peptide selection as key stages for the development of optimal peptide repertoires that are presented by MHC class I molecules to cytotoxic T lymphocytes (CTLs). The study of these stages and how they are regulated, is fundamental for progress in understanding the adaptive immune system. Here we describe an in vitro assay monitoring peptide trimming by the human endoplasmic reticulum amino peptidases 1 (ERAP1) and ERAP2 (ERAPs) as a tool to characterize trimming events and gain a better understanding of the role and function of ERAPs in peptide repertoire development. Specifically, our assay allows for monitoring trimming of free but also of MHC I-bound peptides which may reflect the physiological situation best.

Peptide Trimming for MHC Class I Presentation by Endoplasmic Reticulum Aminopeptidases.

Endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 have recently emerged as important players in regulating innate and adaptive immune responses by trimming peptide ligands for MHC class I molecules. Functional polymorphisms in ERAP1 and ERAP2 genes have been associated with predisposition to several diseases including autoimmune diseases, viral infections, and virally induced cancers. In this chapter, we describe two basic methods for monitoring peptide-trimming activity by ER aminopeptidases and screening potential chemical inhibitors.

Epistatic Interaction of ERAP1 and HLA-B*51 in Iranian Patients with Beh\xe7et\u2019s Disease

Behçet’s Disease (BD) pathogenesis remains unclear, but some genetic loci and environmental factors are proposed to play a role. Here, we investigate the association of the endoplasmic reticulum aminopeptidase-1 (ERAP1) gene variants and HLA-B*51 with BD susceptibility and clinical manifestations in Iranian patients. In the study, 748 BD patients and 776 healthy individuals were included. The MGB-TaqMan Allelic Discrimination method was used to genotype 10 common missense single nucleotide polymorphisms (SNPs) and one intronic SNP in the ERAP1 gene region. We found no significant association between the 11 SNPs and BD in allelic and genotypic association tests. However, rs30187 showed the strongest association with BD in the recessive genotype model of the risk T allele in HLA-B*51 carriers. Although this became insignificant after correcting for multiple comparisons, the homozygous rs30187 risk allele genotype (TT) increased disease susceptibility in HLA-B*51 carriers in epistasis analysis, and the rs30187 TT recessive genotype showed a significant association with risk of cardiac involvement in the all patients and articular involvements in HLA-B*51 positive patients. Our findings suggest that gene-gene interactions between HLA-B*51 and ERAP1 variants is important for BD development, however, ERAP1 variants which interact with HLA-B*51 may differ among disease phenotypes or populations.

Germline genetic polymorphisms influence tumor gene expression and immune cell infiltration

Cancer immunotherapy has emerged as an effective therapy in a variety of cancers. However, a key challenge in the field is that only a subset of patients who receive immunotherapy exhibit durable response. It has been hypothesized that host genetics influences the inherent immune profiles of patients and may underlie their differential response to immunotherapy. Herein, we systematically determined the association of common germline genetic variants with gene expression and immune cell infiltration of the tumor. We identified 64,094 expression quantitative trait loci (eQTLs) that associated with 18,210 genes (eGenes) across 24 human cancers. Overall, eGenes were enriched for their being involved in immune processes, suggesting that expression of immune genes can be shaped by hereditary genetic variants. We identified the endoplasmic reticulum aminopeptidase 2 (ERAP2) gene as a pan-cancer type eGene whose expression levels stratified overall survival in a subset of patients with bladder cancer receiving anti-PD-L1 (atezolizumab) therapy. Finally, we identified 103 gene signature QTLs (gsQTLs) that were associated with predicted immune cell abundance within the tumor microenvironment. Our findings highlight the impact of germline SNPs on cancer-immune phenotypes and response to therapy; and these analyses provide a resource for integration of germline genetics as a component of personalized cancer immunotherapy.

Evaluation of ERAP1 Gene Single Nucleotide Polymorphism in Impressing the Inflammatory Cytokine Profile of Ankylosing Spondylitis Patients

Ankylosing spondylitis (AS), an autoinflammatory disease, has been associated with impaired Endoplasmic reticulum aminopeptidase (ERAP) 1 activity, which is involved in priming antigenic peptides. The purpose of this study was to evaluate if the genetic variant of ERAP1 gene could impress the inflammation status of the AS patients. For genotyping, 140 AS cases and 140 healthy controls were enrolled. After isolation of peripheral blood mononuclear cells (PBMCs) and DNA extraction, all the subjects were genotyped for rs27044 polymorphism using SSP-PCR assay. Total RNA of PBMCs was isolated, cDNA was synthesized, and quantitative analyses of mRNA expression of cytokines were performed via Real-time PCR using the SYBR Green Gene Expression MasterMix. To measure the concentration of cytokines in serum of subjects, Enzyme-linked immunosorbent assay (ELISA) was used. It was observed that the G allele of rs27044 polymorphism was significantly prevalent in AS patients. Moreover, the GG genotype and the GG+GC dominant model had significantly different distribution between study groups. There was a significant overexpression of mRNAs of IL-17A, IL-6, IL-33, TNF-α, and IFN-γ, while IL-10 was significantly downregulated in AS patients. The ELISA results were in line with that of the gene expression analysis. No significant differences in mRNA expression and concentration of cytokine were identified among AS patients with three genotypes for rs27044 SNP. This study replicated the association of polymorphisms in ERAP1 gene with the risk of AS in a population from Iranian. However, it did not directly determine the inflammatory profile of the AS patients.

How ERAP1 and ERAP2 Shape the Peptidomes of Disease-Associated MHC-I Proteins.

Four inflammatory diseases are strongly associated with Major Histocompatibility Complex class I (MHC-I) molecules: birdshot chorioretinopathy (HLA-A*29:02), ankylosing spondylitis (HLA-B*27), Behçet's disease (HLA-B*51), and psoriasis (HLA-C*06:02). The endoplasmic reticulum aminopeptidases (ERAP) 1 and 2 are also risk factors for these diseases. Since both enzymes are involved in the final processing steps of MHC-I ligands it is reasonable to assume that MHC-I-bound peptides play a significant pathogenetic role. This review will mainly focus on recent studies concerning the effects of ERAP1 and ERAP2 polymorphism and expression on shaping the peptidome of disease-associated MHC-I molecules in live cells. These studies will be discussed in the context of the distinct mechanisms and substrate preferences of both enzymes, their different patterns of genetic association with various diseases, the role of polymorphisms determining changes in enzymatic activity or expression levels, and the distinct peptidomes of disease-associated MHC-I allotypes. ERAP1 and ERAP2 polymorphism and expression induce significant changes in multiple MHC-I-bound peptidomes. These changes are MHC allotype-specific and, without excluding a degree of functional inter-dependence between both enzymes, reflect largely separate roles in their processing of MHC-I ligands. The studies reviewed here provide a molecular basis for the distinct patterns of genetic association of ERAP1 and ERAP2 with disease and for the pathogenetic role of peptides. The allotype-dependent alterations induced on distinct peptidomes may explain that the joint association of both enzymes and unrelated MHC-I alleles influence different pathological outcomes.

Acute-phase protein-like properties of endoplasmic reticulum aminopeptidase 1

Endoplasmic reticulum aminopeptidase 1 (ERAP1) is a multi-functional enzyme. In this study, we analysed its role in lipopolysaccharide-induced inflammatory response in wild-type and ERAP1-knockout mice. Following lipopolysaccharide injection, ERAP1 was secreted into the blood, increasing leucine aminopeptidase activity and NO synthesis therein. Among the amino acids tested, arginine concentration was significantly increased in wild-type mice compared to ERAP1-knockout mice. These results suggest that ERAP1 behaves similar to acute-phase proteins, which are secreted into the blood in response to infectious/inflammatory stimuli and are involved in enhancing NO synthesis as a host defense mechanism.

Behçet's disease: An immunogenetic perspective.

Behçet's disease (BD) is a chronic and rare multisystemic disorder defined byautoimmunity and inflammatory characteristics, manifested by ocular lesions, recurrent genital and oral ulcers, skin symptoms and arthritis as well as neurological, intestinal, and vascular involvement. Despite the unknown cause of BD, there issome strong documentationfor immunological, genetic, environmental, and infectious factors playing a role in the pathogenesis of BD. While the nature of the genetic variants remains unidentified, many genetic risk factors are considered to contribute to BD susceptibility. Along with human leukocyte antigen gene encoding B*51 (HLA-B*51) and areas including the major histocompatibility complex class I, genome-wide association studies have recognized numerous other BD susceptibility genes including those encoding interleukin (IL)-10, IL-12 receptor β 2 (IL-12RB2), IL-23 receptor (IL-23R), C-C chemokine receptor 1 gene, signal transducer and activator of transcription 4 (STAT4), endoplasmic reticulum aminopeptidase (ERAP1), and genes encoding killer cell lectin-like receptor family members (KLRC4-KLRK1). It is believed that BD could be considered as a disorder lyingin between autoimmune and autoinflammatory syndromes. The positive responses to classical immunosuppressive agents like azathioprine and cyclosporineand involvement of autoantigens in the initiation of the disorder are the main BD features that reflect the autoimmune nature of the disorder. In this review, we address recent findings on the role of common cytokines, antibodies and immunogenetic factors in BD.

Association of ERAP1 gene polymorphisms with the susceptibility to psoriasis vulgaris: A case-control study.

Psoriasis vulgaris (PsV), also known as plaque psoriasis, is a life-threatening autoimmune skin disease. Inflammatory factors may contribute to the development of PsV. Present study aimed to explore the association of endoplasmic reticulum aminopeptidase 1 (ERAP1) gene polymorphisms (rs26653 and rs27524) with PsV susceptibility in a Chinese Han population. Subgroup analysis was also performed based on the onset of PsV.Present case–control study included 143 patients with PsV and 149 healthy controls. Direct sequencing method was used for genotyping ERAP1 polymorphisms. Chi-squared test was used to estimate the association between ERAP1 polymorphisms and PsV susceptibility. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess association strength.The polymorphism rs26653 was positively correlated with PsV susceptibility (CC vs GG, P = .047, OR = 1.964, 95% CI = 1.006–3.834; C vs G, P = .042, OR = 1.403, 95% CI = 1.011–1.946). Meanwhile, its CC genotype and C allele were positively associated with the early onset of PsV (P = .036, OR = 2.080, 95% CI = 1.044–4.145; P = .034, OR = 1.443, 95% CI = 1.028–2.024) and increased PsV risk in the subgroup with family history (P = .029, OR = 2.149, 95% CI = 1.075–4.296; P = .027, OR = 1.466, 95% CI = 1.044–2.059).ERAP1 gene rs26653 polymorphism may increase the risk of PsV in Chinese Han population.

Functionally distinct ERAP1 and ERAP2 are a hallmark of HLA-A29-(Birdshot) Uveitis.

Birdshot Uveitis (Birdshot) is a rare eye condition that affects HLA-A29-positive individuals and could be considered a prototypic member of the recently proposed ‘MHC-I (major histocompatibility complex class I)-opathy’ family. Genetic studies have pinpointed the endoplasmic reticulum aminopeptidase (ERAP1) and (ERAP2) genes as shared associations across MHC-I-opathies, which suggests ERAP dysfunction may be a root cause for MHC-I-opathies. We mapped the ERAP1 and ERAP2 haplotypes in 84 Dutch cases and 890 controls. We identified association at variant rs10044354, which mediated a marked increase in ERAP2 expression. We also identified and cloned an independently associated ERAP1 haplotype (tagged by rs2287987) present in more than half of the cases; this ERAP1 haplotype is also the primary risk and protective haplotype for other MHC-I-opathies. We show that the risk ERAP1 haplotype conferred significantly altered expression of ERAP1 isoforms in transcriptomic data (n = 360), resulting in lowered protein expression and distinct enzymatic activity. Both the association for rs10044354 (meta-analysis: odds ratio (OR) [95% CI]=2.07[1.58–2.71], P = 1.24 × 10(−7)) and rs2287987 (OR[95% CI]: =2.01[1.51–2.67], P = 1.41 × 10(−6)) replicated and showed consistent direction of effect in an independent Spanish cohort of 46 cases and 2103 controls. In both cohorts, the combined rs2287987-rs10044354 haplotype associated with Birdshot more strongly than either variant alone [meta-analysis: P=3.9 × 10(−9)]. Finally, we observed that ERAP2 protein expression is dependent on the ERAP1 background across three European populations (n = 3353). In conclusion, a functionally distinct combination of ERAP1 and ERAP2 are a hallmark of Birdshot and provide rationale for strategies designed to correct ERAP function for treatment of Birdshot and MHC-I-opathies more broadly.

Association analysis of ERAP1 gene single nucleotide polymorphism in susceptibility to ankylosing spondylitis in Iranian population

Background Ankylosing spondylitis (AS) is a debilitating spondyloarthropathy that has been associated with variation in several genes. Human leukocyte antigen (HLA)-B27 constructs an impaired structure, culminating in recognition and activation of immune system. Impaired function of Endoplasmic reticulum aminopeptidase (ERAP) 1, which primes peptides to be loaded in HLA molecules, has strongly been associated with AS proneness. Here, we intended to investigate the possible association of ERAP1 gene single nucleotide polymorphisms (SNPs) with AS susceptibility in Iranian patients.Methods Two-hundred and twenty AS patients and 220 healthy controls were enrolled in this study. DNA was extracted from blood samples and then was genotyped for rs27044, rs17482078, and rs10050860 polymorphism by SSP-PCR approach.Results It was seen that G allele and GG genotype of rs27044 SNP significantly increased the risk of AS that was even stronger in HLA-B27 positive patients. Moreover, the T allele and TT genotype of rs10050860 polymorphism were associated with increased risk of the disease in both all and HLA-B27 positive AS group. Two haplotypes were associated with the risk of AS and there was linkage disequilibrium between SNPs. Two SNPs were associated with clinicopathological manifestations of AS subjects.Conclusions This association study replicated the role ofERAP1 gene polymorphisms with the risk of AS in an Iranian population.

Beyond the TNF-α Inhibitors: New and Emerging Targeted Therapies for Patients with Axial Spondyloarthritis and their Relation to Pathophysiology.

Axial spondyloarthritis (axSpA) is a complex disease that affects the joints and entheses of axial and peripheral joints, and is associated with inflammation in extra-articular sites such as the gut. Improved knowledge on genetics and immunology has improved treatment options with the availability of treatments targeting tumor necrosis factor-α (TNF-α) and interleukin (IL)-17. However, these agents do not provide clinical benefit for about 40% of patients, and additional therapeutic options are necessary. Theories on pathogenesis includes misfolding of HLA-B*27 during its assembly leading to endoplasmic reticulum stress and autophagy/unfolded protein response (UPR). HLA-B*27 may express free heavy chain on the cell surface, which activates innate immune receptors on T, natural killer, and myeloid cells with pro-inflammatory effects. Activation of UPR genes is associated with increased TNF-α, interleukin-23 (IL-23), IL-17, interferon-γ expression, and expansion of T helper (Th)-17 cells. Certain genotypes of endoplasmic reticulum aminopeptidase (ERAP) 1 and 2 are associated with ankylosing spondylitis (AS) and functionally interact with the HLA-B27 peptidome. Innate immune cells type 3, which express RORγt, regulate expression of IL-17 and IL-22 in T cells. Stimulation of gamma-delta T cells with IL-23 also induces IL-17. Mucosa-associated invariant T cells residing in the gut mucosa express IL-17 in AS patients after stimulation with IL-7. Prostaglandin E2 induces IL-17A independent of IL-23 via IL-1β and IL-6. The pathogenic role of gut inflammation, zonulin and microbiota, which has a different composition in AS patients, remains to be elucidated. This article also includes a comprehensive review on the mechanism of action and efficacy of the biological treatments currently approved for axSpA (TNF-α inhibitors and IL-17 inhibitors) and future targets for treatment (other IL-17 family member (s), Janus kinase, IL-23, and phosphodiesterase 4).

The role of polymorphic ERAP1 in autoinflammatory disease.

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. Association of particular HLA alleles with disease susceptibility represents one of the strongest genetic associations. Furthermore, recent GWAS findings reveal strong associations with single nucleotide polymorphisms in the endoplasmic reticulum aminopeptidase 1 (ERAP1) gene and susceptibility to a number of these HLA-associated conditions. ERAP1 plays a major role in regulating the repertoire of peptides presented on HLA class I alleles at the cell surface, with the presence of single nucleotide polymorphisms in ERAP1 having a significant impact on peptide processing function and the repertoire of peptides presented. The impact of this dysfunctional peptide generation on CD8+ T-cell responses has been proposed as a mechanism of pathogenesis diseases where HLA and ERAP1 are associated. More recently, studies have highlighted a role for ERAP1 in innate immune-mediated pathways involved in inflammatory responses. Here, we discuss the role of polymorphic ERAP1 in various immune cell functions, and in the context of autoimmune and autoinflammatory disease pathogenesis.