A Lutzomyia longipalpis salivary protein induces cross-reactive antibodies to pemphigus autoantigen desmoglein-1.

Fogo Selvagem (FS) is a blistering skin disease caused by pathogenic IgG4 autoantibodies to desmoglein-1 (Dsg1). Preclinical FS and Leishmaniasis are endemic to certain regions of Brazil and exhibit non-pathogenic anti-Dsg1 antibodies. Recurring bites from Lutzomyia longipalpis (LP), the sand-fly vector of Leishmaniasis, immunize individuals with LP salivary antigens LJM17/LJM11. We measured the antibody responses to LJM17, LJM11, and Dsg1 in normal settlers and FS patients from an endemic focus of FS and non-endemic control populations. We also immunized mice with these antigens and assessed the IgG response. Healthy individuals and FS patients from endemic areas had significantly higher values of IgG4 anti-LJM17 antibodies than non-endemic controls (p<0.001, both). The levels of IgG anti-Dsg1 and IgG4 anti-LJM17/anti-LJM11 antibodies correlated positively in normal settlers and FS. Mice immunized with rLJM17 produced IgG1 antibodies (human IgG4 homolog) that strongly cross-reacted with rDsg1; these IgG1 antibodies were inhibited by LJM17, LJM11, and Dsg1 in a dose-dependent manner. However, they did not bind human or mouse epidermis by indirect immunofluorescence. Lastly, we identified short-sequence homologies of surface exposed residues within the human Dsg1 ectodomain and LJM17. Inoculation by LJM17 from LP elicited Dsg1-cross-reactive IgG4 antibodies may lead to FS in genetically predisposed individuals.