BALB/c mice produce blister-causing antibodies upon immunization with a recombinant human desmoglein 3

Pemphigus vulgaris (PV) is an Ab-mediated autoimmune blistering disease of mucotaneous surfaces, Over 95% of the patients with PV express DR4 or DRw6, and the disease is characterized by the presence of autoantibodies directe d against desmoglein 3 (Dsg 3), a protein expressed on keratinocytes, An ap propriate animal model is required to understand irnmunoregulation and to a ddress the role of immunogenetic components in the production of pathogenic Abs that are characteristic of PV, Therefore, we turned to the development of a mouse model. Four strains of female mice (BALB/c, DBA/1, SJL/J, and H RS/J) were screened for their ability to produce pathogenic anti-Dsg 3 Abs. We demonstrated that only BALB/c mice immunized,vith a full-length Dsg 3 c an produce pathogenic Abs capable of causing acantholysis of human foreskin in culture and blistering in neonatal mice, This observation suggested tha t either H-2(d) or the BALE background contains the immunogenetic makeup ne cessary for the production of pathogenic anti-Dsg 3 Abs, No correlation was noted between a given isotype and the pathogenic potential of autoantibodi es from different strains of mice. Similarly, the pattern of reactivity of Abs with a panel of 46 synthetic peptides that span the entire Dsg 3 failed to reveal any association between binding specificity and the pathogenic p otential, and suggested that pathogenic Abs might recognize conformational epitopes. Moreover, our studies showed that the epitopes recognized by path ogenic Abs are contained within the extracellular Dsg 3.