042 The sand fly Lutzomyia longipalpis LJM17 protein induces cross-reactive antibodies against desmoglein-1 in Fogo Selvagem

Fogo Selvagem (FS) is a lethal skin disease mediated by pathogenic IgG4 autoantibodies to desmoglein-1 (Dsg1). FS is prevalent in certain regions of Brazil, where Leishmaniasis and Chagas disease are endemic. Normal individuals and leishmaniasis patients from these regions possess non-pathogenic anti-Dsg1 antibodies. They are chronically exposed to bites of the sand fly Lutzomyia longipalpis (LL), which elicits an IgG response to LL salivary proteins LJM17 and LJM11 and could contribute to the development of FS. We tested the antibody response to rDsg1 (IgG), and rLJM17 (IgG4) in normal settlers (n=100), FS patients (n=68) from Limao Verde (LV), an endemic focus of FS, and distinct non-endemic control populations [Brazil (n=33), USA (n=111) and Japan (n=70)]. We also studied the antibody response in mice to these antigens and assessed the protein sequence homology between LJM17 and human Dsg1. We demonstrate that healthy individuals and FS from LV had higher values of IgG4 anti-LJM17 antibodies than control groups from non-endemic areas (p<0.001, both). Levels of IgG anti-Dsg1 and IgG4 anti-LJM17 antibodies were positively correlated in normal settlers (r= 0.56) and FS (r= 0.38). Mice immunized with rLJM17 produce IgG1 antibodies (human IgG4 homolog) that strongly cross-react with rDsg1. These cross-reactive antibodies were purified by rDsg1-Ni-agarose media and were inhibited by rDsg1 and rLJM17 in a dose-dependent manner. In contrast, rLJM11 immunized mice did not generate cross-reactive antibodies. In addition, we identified short regions of sequence homology between the ectodomain of human Dsg1 and LJM17. Inoculation of LJM17 from LL may elicit anti-Dsg1 cross-reactive IgG4 antibodies that lead to FS in a subset of genetically predisposed individuals