Mechanisms of B cell tolerance against peripheral antigen

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It is believed that mechanisms leading self-tolerance are operative in both B and T cells. However, those for B cells are less clarified. In particular, it is largely unknown how B cells acquire tolerance against antigens that are expressed primarily in peripheral organs and tissues. In order to examine the mechanism of such B cell peripheral tolerance, we employed a newly established model mouse system where autoantibody against desmoglein 3 (Dsg3) is continuously produced Dsg3 is a cadherin type cell-to-cell adhesion molecule expressed in stratified squamous epithelia and autoantibody production against Dsg3 leads to a well characterized autoimmune disease, pemphigus vulgaris (PV). We have established a PV model mouse by adoptive transfer of Dsg3^<-/-> splenocytes immunized with recombinant mouse Dsg3 to Rag2^<-/-> recipient mice expressing Dsg3, resulting in the stable production of anti-Dsg3 IgG and development of PV phenotypes including oral erosions with suprabasilar acantholysis … More . We established hybridoma clones producing anti-mouse Dsg3 from these model mice and isolated heavy and light chain genes from one of such hybridomas. We then generated a transgenic mouse by injecting both genes into fertilized eggs. In anti-Dsg3 antoantibody transgenic mice, B cells expressing anti-mouse Dsg3 were readily observed in the bone marrow and peripheral organs, even though Dsg3 is expressed in the stratified squamous epithelia of these mice. These mice do not show any PV phenotypes, indicating that the generation of B cells reactive with Dsg3 alone is not sufficient for the development of PV phenotypes. Our results further suggest that the tolerance against Dsg3 is not established by simple deletion of autoreactive B cells and mechanisms other than deletion are likely involved in the tolerance against Dsg3. Future studies using this model mouse system will help us to understand the molecular mechanisms of establishment of self-tolerance and breakdown of self-tolerance against peripheral antigens in B cells. Less