Considering that the DR immunopeptidome of different antigen presenting cells is naturally a complex mixture of peptides presented by HLA-DRB1 (primary DRB) and DRB3, 4 and 5 (secondary DRB) molecules, besides the distinct roles these molecules play in disease susceptibility or protection, the deconvolution of the peptide repertoire of DRB1 molecules from the DRB3, 4 and 5 is essential for unraveling the function of class II HLA-DR in the course of autoimmune disorder progression and treatment. This evidence concerns the gene HLA-DRB1 and autoimmune disease.