Cellular mechanisms of tolerance breakdown in autoantibody production

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It is believed that mechanisms leading self-tolerance are operative in both B and T cells although those for B cells are less clarified. Since production of antibodies by B cells generally requires T cell help, breakdown of self-tolerance in both B and T cell compartments is expected to take place. Alternatively, it is possible that self-reactive B cells are widely present in our body and breakdown of T cell tolerance is sufficient to trigger autoimmunity. However, experimental data supporting this notion have rarely been obtained. We have developed a new method to generate active autoimmune disease model by employing autoantigen knockout mice. In a given knockout mice self tolerance against the defective molecule is not acquired. Adoptive transfer of lymphocytes from such autoantigen knockout mice after immunization with antigens into antigen-positive mice should provide an active disease animal model for autoimmune diseases. We have applied this method to a well characterized autoimmune disease, pemphigus vulgaris (PV). It is well established in human PV that IgG antibodies against Dsg3, a cadherin type cell-to-cell adhesion molecule expressed in stratified squamous epithelia, play a pathogenic role to cause blisters in the skin and mucous membranes. Adoptive transfer of Dsg3^<-/-> splenocytes immunized with recombinant mouse Dsg3 to Rag2^<-/-> recipient mice expressing Dsg3 resulted in the stable production of anti-Dsg3 IgG and development of PV phenotypes including oral erosions with suprabasilar acantholysis. When purified T and B cells from Dsg3^<-/->, Dsg3^<+/-> or Dsg3^<+/+> mice were mixed with various combinations and transferred to Rag2^<-/-> mice, pathogenic anti-Dsg3 IgG production was observed only with a combination of Dsg3^<-/-> T and Dsg3^<-/-> B cells but not with the other combinations. These results suggest that loss of tolerance against Dsg3 in both B and T cells is important for the development of autoimmune state of PV.