We have shown that although the
IgG response in fogo selvagem (FS) is mainly restricted to
desmoglein (Dsg) 1, other keratinocyte
cadherins are also targeted by FS patients and healthy control subjects living in the endemic region of Limão Verde, Brazil (endemic controls). Evaluating nonpathogenic
IgG1 and pathogenic
IgG4 subclass responses to desmosomal
proteins may reveal important differences between pathogenic and nonpathogenic responses, and how these differences relate to the pathogenic
IgG4 response and resultant FS. In this study, we tested by ELISA >100 sera from each FS patient, endemic control, and nonendemic control for
IgG1 and
IgG4 autoantibodies to keratinocyte
cadherins besides Dsg1.
IgG1 and
IgG4 subclass responses in endemic controls are highly correlated between Dsg1 and other keratinocyte
cadherins. This correlation persists in the
IgG1 response among FS patients, but diminishes in
IgG4 response, suggesting that
IgG1 binds highly conserved linear
epitopes among
cadherins, whereas
IgG4 binds mainly specific conformational
epitopes on Dsg1. A confirmatory test comparing serum samples of 11 individuals before and after their FS onset substantiated our findings that
IgG1 recognizes primarily linear
epitopes on Dsg1 both before and after disease onset, whereas
IgG4 recognizes primarily linear
epitopes before disease onset, but recognizes more conformational
epitopes on Dsg1 after the onset of disease. This study may provide a mechanism by which a specificity convergence of the
IgG4 response to unique Dsg1
epitopes, most likely conformational pathogenic
epitopes, leads to the onset of FS disease.