The putative role of endoplasmic reticulum aminopeptidase in autoimmunity: insights from genomic-wide association studies

Autoimmune diseases represent a heterogeneous group of conditions whose incidence is increasing worldwide. This has propelled studies on their etiopathogenesis, derived from a complex interaction of genetic and environmental factors, aiming to finally improve prevention and treatment of disease. In the autoimmune process, immune responses are generated against self-antigens presented by MHC class I complexes on the cell surface. These peptide/MHC class I complexes are assembled in the endoplasmic reticulum (ER) through MHC class I antigen processing and presentation machinery. In the 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 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. Several recent GWAS provide the importance of ERAP1 and ERAP2 in several autoimmune diseases including ankylosing spondylitis (AS), insulin-dependent diabetes (T1D), psoriasis, multiple sclerosis (MS), Crohn’s disease (CD).In this review we first provide a general overview of ERAP1 and ERAP2 genes, their biological functions and their relevancy in autoimmunity with particular reference to the genomic-wide association studies and the following case-control studies that confirm relevancy of these associations and define linkage with particular MHC class I haplotypes.