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.
Highlights
Autoimmune and autoinflammatory diseases are a leading cause of mortality and morbidity worldwide
The aminopeptidase was first shown to be significant in regulating the peptide repertoire at the cell surface in 2002, where two independent studies investigating human endoplasmic reticulum aminopeptidase 1 (ERAP1) and the mouse homolog, endoplasmic reticulum aminopeptidase associated with antigen processing (ERAAP), revealed that they were responsible for N-terminal trimming of peptide precursors to generate stable peptide major histocompatibility complex (MHC) I complexes [6,7]
The diseases largely associated with MHC class I (MHC I) are largely innate immune mediated and fall into the autoinflammatory end of the spectrum, whereas those that convey a strong MHC II association are most associated with the adaptive immune response [2]
Summary
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; they share a number of similarities in genetic associations and environmental influences. 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.
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