Antigen Selection of Anti-DSG1 Autoantibodies During and Before the Onset of Endemic Pemphigus Foliaceus

Fogo selvagem (FS), the endemic form of pemphigus foliaceus (PF), is characterized by pathogenic anti-desmoglein 1 (Dsg1) autoantibodies. To study the etiology of FS, hybridomas that secrete either IgM or IgG (predominantly IgG1 subclass) autoantibodies were generated from the B cells of eight FS patients and of one individual four years prior to FS onset, and the H and L chain V genes of anti-Dsg1 autoantibodies analyzed. Multiple lines of evidence suggest that these anti-Dsg1 autoantibodies in FS are antigen selected. First, clonally related sets of anti-Dsg1 hybridomas characterize the response in individual FS patients. Second, H and L chain V gene use appears to be biased, particularly among IgG hybridomas, and third, most hybridomas are mutants and exhibit a bias in favor of CDR amino acid replacement (R) mutations. Strikingly, pre-FS hybridomas also exhibit evidence of antigen selection, including an overlap in VH gene use and shared multiple R mutations with anti-Dsg1 FS hybridomas, suggesting selection by the same or a similar antigen. We conclude that the anti-Dsg1 response in FS is antigen driven, and that selection for mutant anti-Dsg1 B cells begins well before the onset of disease