Studying mouse and human macrophage cell lines stimulated with short synthetic peptides corresponding to the TAHR coded by three DRB1 alleles, as well as BMDMs derived from transgenic mouse lines that express physiologically folded distinct allelic HLA-DR molecules, we demonstrated allele-specific activation of a cascade of pathogenic events that includes transcriptional, cellular and disease phenomes that closely resemble human SLE and its experimental mouse models. The gene discussed is HLA-DRB1; the disease is systemic lupus erythematosus.