Seeking better understanding of the functional role of HLA molecules in SLE, we examined an antigen presentation-independent mechanism, modeled after the ‘MHC Cusp’ theory10,11, which postulates that in addition to presenting antigenic peptides to T cells, major histocompatibility complex (MHC) molecules express signal transducing ligands that, upon binding to non-MHC receptors trigger allele-specific cell activation events. Here, HLA-C is linked to systemic lupus erythematosus.