In this review, we will focus on the so-called “mis-peptidome” by discussing a potential harmful role of the suboptimal and self-immunopeptidome in the “MHC-I-opathies”, the influence of ERAP1 and ERAP2 allelic variants and the implication in the onset of AS and related SpA, BD, Ps and BSCR. This evidence concerns the gene ERAP2 and Behcet disease.