TARGETED DISRUPTION OF THE PEMPHIGUS-VULGARIS ANTIGEN (DESMOGLEIN-3) GENE IN MICE CAUSES LOSS OF KERATINOCYTE CELL-ADHESION WITH A PHENOTYPE SIMILAR TO PEMPHIGUS-VULGARIS

In patients with pemphigus vulgaris (PV), autoantibodies against desmo glein 3 (Dsg3) cause loss of cell-cell adhesion of keratinocytes in th e basal and immediate suprabasal layers of stratified squamous epithel ia. The pathology, at least partially, may depend on protease release from keratinocytes, but might also result from antibodies interfering with an adhesion function of Dsg3. However, a direct role of desmoglei ns in cell adhesion has not been shown. To test whether Dsg3 mediates adhesion, we genetically engineered mice with a targeted disruption of the DSG3 gene. DSG3 -/- mice had no DSG3 mRNA by RNase protection ass ay and no Dsg3 protein by immunofluorescence (IF) and immunoblots. The se mice were normal at birth, but by 8-10 d weighed less than DSG3 +/- or +/+ litter-mates, and at around day 18 were grossly runted. We spe culated that oral lesions (typical in PV patients) might be inhibiting food intake, causing this runting. Indeed, oropharyngeal biopsies sho wed erosions with histology typical of PV, including suprabasilar acan tholysis and ''tombstoning'' of basal cells. EM showed separation of d esmosomes. Traumatized skin also had crusting and suprabasilar acantho lysis. Runted mice showed hair loss at weaning. The runting and hair l oss phenotype of DSG3 -/- mice is identical to that of a previously re ported mouse mutant, balding (bal). Breeding indicated that bal is coa llelic with the targeted mutation. We also showed that bal mice lack D sg3 by IF, have typical PV oral lesions, and have a DSG3 gene mutation . These results demonstrate the critical importance of Dsg3 for adhesi on in deep stratified squamous epithelia and suggest that pemphigus au toantibodies might interfere directly with such a function.