Somatic DNA mutations in the blood of normal and autoimmune individuals.

We have analyzed blood from normal and autoimmune individuals, finding a previously unrecognized level of somatic DNA mutations. Using a PCR‐cloning technique we have found an average mutational frequency of 10 −3 mutations/bp in two marker genes (a mitochondrial [ND1] and nuclear gene [DLD]). These somatic mutational data from normal and autoimmune individuals suggests a need for re‐evaluation of self tolerance models to incorporate mutated self. Negative selection requires the presentation of self antigens – but what happens when self mutates? Among the possibilities are: a) there may be no B and T cells capable of launching a reaction against the mutated self because no new epitopes were generated by the mutant antigen, b) an immune cell may recognize the mutant antigen as non‐self and react to it but the number of identical mutant antigens may be too small to promote an auto‐immune reaction, or c) the immune cells may bind and react to the mutant antigen and in doing so form a memory response that can cross‐react to the nonmutant self antigen precipitating or supporting autoimmunity. A model of autoimmunity precipitated and/or supported by mutations in self will be presented. Research funded by CIHR.