ANTIGEN-SPECIFIC IMMUNOADSORPTION OF PATHOGENIC AUTOANTIBODIES IN PEMPHIGUS FOLIACEUS

Patients with the autoimmune blistering disease pemphigus foliaceus (P F) have circulating autoantibodies directed against the desmosomal cad herin desmoglein 1 (Dsg1). Based on the fact that purified IgG fractio ns from PF patients induce loss of cell adhesion in organ culture and in a neonatal mouse model, it has been proposed that these anti-Dsg1 a ntibodies play a pathogenic role in blister formation. To directly add ress whether antibodies in PF sera specific for the Dsg1 extracellular domain are indeed pathogenic in the disease, PFIg, a chimeric protein containing the entire extracellular domain of human Dsg1 and the cons tant region of human IgG1, was produced by baculovirus expression. Inc ubation of PF patients' sera with the PFIg baculoprotein removed the i mmunoreactivity of autoantibodies against keratinocyte cell surfaces i n all 20 PF and eight Brazilian PF patients' sera tested. This adsorpt ion was conformation dependent, because PFIg protein denatured by low pH or heart was no longer able to adsorb the immunoreactivity of PF se ra. Furthermore, the incubation with the PFIg baculoprotein eliminated the pathogenic activity of PF patients' sera and prevented gross blis ter formation in a neonatal mouse model of pemphigus. Anti-Dsg1 antibo dies eluted from the PFIg protein column were pathogenic as they resul ted in the appearance of gross blisters in neonatal mice with typical histologic findings of PF. These observations indicate that the extrac ellular domain of Dsg1 expressed by baculovirus is capable of specific ally immunoadsorbing pathogenic autoantibodies from PF patients' sera and provide direct evidence that the anti-Dsg1 auto-antibodies in PF s era are indeed pathogenic. The availability of this Dsg1 recombinant p rotein may facilitate the development of antigen-specific plasmapheres is as a novel therapeutic strategy in pemphigus.