Abnormalities in the regulation of variable region genes that encode for antibodies to DNA may be a central factor in the pathogenesis of systemic lupus erythematosus.

Systemic lupus erythematosus (lupus) is characterised by the excessive and spontaneous production of antibodies to DNA. In animal models of lupus, and in humans, antibodies to DNA have been directly implicated in pathogenesis. The variable region genes that encode for reactivity of antibodies to DNA have, in general, not been regarded as a risk factor in lupus. Recent evidence from several workers, including ourselves, does not sustain this dogma. Individual autoreactive V genes appear to be repeatedly used and to have an affinity for DNA. These genes are present in subjects with the disease and in some, but not all, normal subjects. Presumably, in some subjects carrying autoreactive V genes in their germline, these genes are normally silenced by regulatory factors, including cytokines, and in others with disease there is a breakdown in regulation. Experimental evidence suggests that multiple cytokines may have a role and that this role is complex.