ERAP1 and HLA-C interaction in inflammatory bowel disease in the Spanish population

Castro‐Santos, Patricia; Moro-García, Marco Antonio; Marcos-Fernández, Raquel; Alonso-Arias, Rebeca

doi:10.1177/1753425917716527

Cited by 21 publications

(10 citation statements)

References 33 publications

(50 reference statements)

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“…The distribution of the age at onset of isolated AS ( 24 ) is very similar to that of AS with inflammatory bowel disease ( 24 ) and to that of isolated Crohn’s disease ( 145 , 146 ): risk is low before puberty, increases sharply around the age of 15 years, peaks during young adulthood (age: 18–29 years), and tapers off over the following 30 years ( 146 ). Though Crohn’s disease is not as strongly associated with an MHC class I allele as AS, associations with ERAP alleles and interactions between ERAP alleles and MHC class I alleles have also been reported in Crohn’s disease ( 72 , 73 ). It is thus plausible that exposure to the same sexually acquired intracellular fungal infection is necessary for both spondyloarthritis and isolated Crohn’s disease, and that genetic predisposition determines which symptoms appear following exposure to this environmental factor.…”

Section: Links With Fungimentioning

confidence: 99%

Spondyloarthritis, Acute Anterior Uveitis, and Fungi: Updating the Catterall–King Hypothesis

Laurence¹,

Asquith

Rosenbaum

2018

Front. Med.

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Spondyloarthritis is a common type of arthritis which affects mostly adults. It consists of idiopathic chronic inflammation of the spine, joints, eyes, skin, gut, and prostate. Inflammation is often asymptomatic, especially in the gut and prostate. The HLA-B*27 allele group, which presents intracellular peptides to CD8+ T cells, is by far the strongest risk factor for spondyloarthritis. The precise mechanisms and antigens remain unknown. In 1959, Catterall and King advanced a novel hypothesis explaining the etiology of spondyloarthritis: an as-yet-unrecognized sexually acquired microbe would be causing all spondyloarthritis types, including acute anterior uveitis. Recent studies suggest an unrecognized sexually acquired fungal infection may be involved in prostate cancer and perhaps multiple sclerosis. This warrants reanalyzing the Catterall–King hypothesis based on the current literature. In the last decade, many links between spondyloarthritis and fungal infections have been found. Antibodies against the fungal cell wall component mannan are elevated in spondyloarthritis. Functional polymorphisms in genes regulating the innate immune response against fungi have been associated with spondyloarthritis (CARD9 and IL23R). Psoriasis and inflammatory bowel disease, two common comorbidities of spondyloarthritis, are both strongly associated with fungi. Evidence reviewed here lends credence to the Catterall–King hypothesis and implicates a common fungal etiology in prostate cancer, benign prostatic hyperplasia, multiple sclerosis, psoriasis, inflammatory bowel disease, and spondyloarthritis. However, the evidence available at this time is insufficient to definitely confirm this hypothesis. Future studies investigating the microbiome in relation to these conditions should screen specimens for fungi in addition to bacteria. Future clinical studies of spondyloarthritis should consider antifungals which are effective in psoriasis and multiple sclerosis, such as dimethyl fumarate and nystatin.

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Section: Links With Fungimentioning

confidence: 99%

Spondyloarthritis, Acute Anterior Uveitis, and Fungi: Updating the Catterall–King Hypothesis

Laurence¹,

Asquith

Rosenbaum

2018

Front. Med.

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“…ERAP1 is a peptidase that functions to cleave peptides for presentation via HLA class I complexes, subsequent regulation of Natural Killer (NK) cells is dependent on KIR and HLA class I interaction, and failure of normal NK inhibition or anomalous activation can lead to NK mediated cell death . A recent study described the IBD risk conferred by ERAP1 as being dependant on the HLA‐C*07 genotype, presenting a possible novel regulatory interaction . The interaction between KIRs and HLA‐Cw (and HLA‐Bw) serotypes has been implicated as both a risk and protective factor for IBD depending on the KIR genotype expressed .…”

Section: The Role Of Hla In Disease Pathogenesismentioning

confidence: 99%

“…95 A recent study described the IBD risk conferred by ERAP1 as being dependant on the HLA-C*07 genotype, presenting a possible novel regulatory interaction. 96 The interaction between KIRs and HLA-Cw (and HLA-Bw) serotypes has been implicated as both a risk and protective factor for IBD depending on the KIR genotype expressed. 95,97,98 This effect is thought to be primarily due to variation at the KIR locus but the HLA genotype influences (and may regulate) the relative effect of the genetic risk.…”

Section: Interaction With Killer Immunoglobulin-like Receptors and mentioning

confidence: 99%

Review article: the genetics of the human leucocyte antigen region in inflammatory bowel disease

Ashton

Latham

Beattie

et al. 2019

Aliment Pharmacol Ther

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Summary Background The human leucocyte antigen (HLA) complex, located at chromosome 6p21.3 is a highly polymorphic region containing the classical class I and II HLA genes. The region is highly associated with inflammatory bowel disease (IBD), largely through genome‐wide association studies (GWAS). Aims To review the role of HLA in immune function, summarise data on risk/protective HLA genotypes for IBD, discuss the role of HLA in IBD pathogenesis, treatment and examine limitations that might be addressed by future research. Methods An organised search strategy was used to collate articles describing HLA genes in IBD, including Crohn's disease and ulcerative colitis. Results All classical HLA genes with variation (including HLA‐A, B, C, DRB1, DQA1, DQB1, DPA1 and DPB1) harbour IBD‐associated genotypes. The most implicated gene is HLA‐DRB1, with HLA‐DRB1*03:01 the most associated risk allele in both Crohn's disease and ulcerative colitis. Elucidating precise disease associations is challenging due to high linkage disequilibrium between HLA genotypes. The mechanisms by which risk alleles cause disease are multifactorial, with the best evidence indicating structural and electrostatic alteration impacting antigen binding and downstream signalling. Adverse medication events have been associated with HLA genotypes including with thiopurines (pancreatitis) and anti‐TNF agents (antibody formation). Conclusions The HLA complex is associated with multiple risk/protective alleles for IBD. Future research utilising long‐read technology, ascertainment of zygosity and integration in disease modelling will improve the functional understanding and clinical translation of genetic findings.

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“…The functional variant rs30187 (K528R) ERAP1 confers disease susceptibility to CD and IBD [ 86 ]. More recently, there has been reports of an association between ERAP1 K528R and the expression of HLA-C*07 allele in patients with IBD ( Table 1 ) [ 88 ]. Interestingly, AS and CD have a close clinical relationship, with approximately 10% of individuals with AS presenting with IBD [ 89 ].…”

Section: Inflammatory Bowel Diseasementioning

confidence: 99%

The role of polymorphic ERAP1 in autoinflammatory disease

Reeves

James

2018

Bioscience Reports

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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.

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ERAP1 and HLA-C interaction in inflammatory bowel disease in the Spanish population

Cited by 21 publications

References 33 publications

Spondyloarthritis, Acute Anterior Uveitis, and Fungi: Updating the Catterall–King Hypothesis

Spondyloarthritis, Acute Anterior Uveitis, and Fungi: Updating the Catterall–King Hypothesis

Review article: the genetics of the human leucocyte antigen region in inflammatory bowel disease

The role of polymorphic ERAP1 in autoinflammatory disease

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