Lupus erythematosus is a prototypic autoimmune disease that can be triggered in genetically predisposed individuals by environmental exposures. The disease is based on an uncontrolled activation of the immune system that recognizes self antigens and induces inflammatory disease flares. The multifactorial pathogenesis is based on a polygenic model of inheritance with multiple various susceptibility genes elevating the disease risk. Many of these polymorphisms have been recently identified by genome-wide association studies. Monogenic forms of lupus erythematosus are rare. The identification of their underlying pathogenesis is important for the recognition of main mechanistic pathways in lupus as demonstrated by the history of defects in the complement system. The monogenic, autosomal dominant inherited familial chilblain lupus is characterized by cold-induced infiltrates on acral locations occurring in early childhood. Molecular exploration of the disease pathogenesis revealed that autoimmunity and especially lupus erythematosus can be induced by defects in intracellular elimination of nucleic acids and the subsequent type I-IFN-dependent activation of the innate immune system.