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Over the past decade the type I interferon cytokine family has been postulated to play a central role in SLE pathogenesis, by promoting feedback loops progressively disrupting peripheral immune tolerance and driving disease activity. The identification of key molecules involved in the pathogenesis of SLE will not only improve our understanding of this complex disease, but also help to identify novel targets for biological intervention.

The pathogenesis of systemic lupus erythematosus SLE is incompletely understood. Even though the hallmark of the disease is a loss of tolerance to nuclear antigens, clinical manifestations as well as disease severity and course vary from patient to patient. This most likely reflects the heterogeneous genetic background that underlies disease susceptibility.

The past few years have witnessed an explosion of SLE genomic studies. Here we summarize recent genetic and transcriptome data that are helping to reconstruct the puzzle of SLE pathogenesis. However, many questions remain to be addressed, including the factors governing disease expression in specific organs, which, with the exception of congenital heart block, remain largely unknown. Presentation of epitopes within the grooves of MHC-I or MHC-II defines the choice of targets for the adaptive immune system and thereby explains the towering dominance of MHC in determining genetic susceptibility, not only in SLE but also in many other autoimmune disorders.