The role of polymorphic ERAP1 in autoinflammatory disease

Abstract

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.

Pathogenesis and clinical perspectives of extraintestinal manifestations in inflammatory bowel diseases

“…ERAP1 variant K528R associated with CD has involved in aberrant peptide production resulting in suboptimal peptide MHC I complex. 43 The CD risk gene, NOD2/CARD15, which encodes a pattern recognition receptor, is also associated with sacroiliitis and uveitis. 44,45 STAT4 is also responsible for the expansion of Th17 cells activated by IL-23, which promotes chronic inflammation in innate and adaptive immunity and is considerably associated with the development of EIMs involving the joints and eyes in patients with IBD.…”

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

“…ERAP1, and perhaps also ERAP2, may have additional functions besides antigen processing ( 38 , 39 ). For instance, ERAP1 can be secreted from macrophages in response to lipopolyssacharide and interferon-gamma by a TLR-dependent mechanism ( 40 ), which enhances their phagocytic activity ( 41 ).…”

Impact of Natural Occurring ERAP1 Single Nucleotide Polymorphisms within miRNA-Binding Sites on HCMV Infection

“…ERAP1 is highly polymorphic, with variants that alter the peptide trimming activity, specificity, and expression, even if they reside far from the active site region. Several ERAP1 genetic variants have been associated with multiple human leukocyte antigen (HLA) class I autoinflammatory disorders, including ankylosing spondylitis (AS), BD, psoriasis, multiple sclerosis (MS), and type I diabetes, as well as essential hypertension and susceptibility to infectious disease, such as human papilloma virus (HPV)-induced cancer, HIV, hepatitis C virus (HCV), and HCMV infection [55][56][57]. In the context of autoimmune diseases, these genetic changes contribute to immune dysregulation in individuals with a specific HLA class I background [57].…”

“…Several ERAP1 genetic variants have been associated with multiple human leukocyte antigen (HLA) class I autoinflammatory disorders, including ankylosing spondylitis (AS), BD, psoriasis, multiple sclerosis (MS), and type I diabetes, as well as essential hypertension and susceptibility to infectious disease, such as human papilloma virus (HPV)-induced cancer, HIV, hepatitis C virus (HCV), and HCMV infection [55][56][57]. In the context of autoimmune diseases, these genetic changes contribute to immune dysregulation in individuals with a specific HLA class I background [57]. Indeed, changes in the immunopeptidome due to ERAP1 SNPs are exacerbated in the individuals carrying HLA class I loci conferring risks to disease-HLA-B27 for AS, HLA-Cw*06 for psoriasis, and HLA-B*51 for BD.…”