title: The putative role of endoplasmic reticulum aminopeptidases in autoimmunity: insights from genomic-wide association studies.
abstract: Autoimmune diseases represent a heterogeneous group of conditions whose incidence is increasing worldwide. This has stimulated studies on their etiopathogenesis, derived from a complex interaction between genetic and environmental factors, aimed at finally improving prevention and treatment of these diseases. In the autoimmune process, immune responses are generated against self antigens presented by Major Histocompatibility Complex (MHC) class I on the cell surface. These peptide/MHC class I complexes are generated and assembled through MHC class I antigen processing and presentation machinery. In the endoplasmic reticulum (ER), aminopeptidases ERAP1 and ERAP2 display distinct trimming activity before antigenic peptides are loaded onto MHC class I molecules. The advent of new tools such as genome-wide association studies (GWAS) has provided evidence for new susceptibility loci and candidate genes playing a role in the autoimmune process for the recognized immune function of their transcripts. Genetic linkage has been discovered with MHC antigens and various autoimmune conditions. Recent GWAS showed the importance of ERAP1 and ERAP2 in several autoimmune diseases, including ankylosing spondylitis, insulin-dependent diabetes mellitus, psoriasis, multiple sclerosis, Crohn's disease. In this review, we first provide a general overview of ERAP1 and ERAP2 genes, their biological functions and their relevancy in autoimmunity. We then discuss the importance of GWAS and the case-control studies that confirm the relevancy of ERAP single-nucleotide polymorphism associations and their linkage with particular MHC class I haplotypes, supporting a putative functional role in the autoimmune process.
authors.affiliation: Immunology Area, Bambino Gesù Children's Hospital IRCCS, Rome, Italy. alessandra.fierabracci@opbg.net
authors.forename: Alessandra
authors.initials: A
authors.lastname: Fierabracci
authors.forename: Annamaria
authors.initials: A
authors.lastname: Milillo
authors.forename: Franco
authors.initials: F
authors.lastname: Locatelli
authors.forename: Doriana
authors.initials: D
authors.lastname: Fruci
mesh_terms: D000626:Aminopeptidases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics; D015551:Autoimmunity / Q000235:genetics* / Q000276:immunology*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015778:Minor Histocompatibility Antigens
chemical_list: D015778:Minor Histocompatibility Antigens; D000626:Aminopeptidases; C464841:ERAP1 protein, human; C503944:ERAP2 protein, human