Systemic IgG responses to Leishmania braziliensis–derived extracellular vesicles vary across clinical forms of American tegumentary leishmaniasis and associate with early therapeutic outcome

Background American tegumentary leishmaniasis (ATL) caused by Leishmania braziliensis is characterized by marked clinical and immunopathological heterogeneity. While cellular immune responses have been extensively investigated, the contribution of humoral immunity, particularly against parasite-derived extracellular vesicles (EVs) components, remains poorly understood. Here, we evaluated systemic IgG responses against EVs derived from L. braziliensis isolates associated with distinct clinical forms of ATL and assessed their association with disease presentation and therapeutic outcome. Methods Serum samples from patients with cutaneous leishmaniasis (CL), mucosal leishmaniasis (ML), disseminated leishmaniasis (DL), early cutaneous leishmaniasis (ECL), and healthy subjects were analyzed by ELISA using intact EVs. Results and discussion CL patients exhibited higher anti-EV IgG levels than healthy subjects, confirming the induction of EV reactive humoral responses during active disease. Comparative analysis revealed that CL and DL patients displayed higher anti-EV IgG levels than ML patients, whereas ECL patients exhibited lower levels than classical CL, consistent with reduced systemic humoral responses at early stages of infection. IgG responses against EVs derived from different isolates were strongly correlated, indicating shared antigenic determinants exposed on the vesicle surface. Higher baseline IgG levels against EV surface antigens were associated with clinical cure at day 60 following antimonial therapy but did not predict outcome at day 90, suggesting a relationship with early healing dynamics rather than definitive lesion resolution. Anti-DL EV IgG levels showed a weak correlation with time to lesion healing. In contrast, short-term in vitro stimulation of peripheral blood mononuclear cells with EVs did not alter circulating B cell subset distribution. Together, these findings demonstrate that L. braziliensis–derived EVs are immunologically relevant targets of systemic humoral responses in humans and that IgG reactive to EVs profiles reflect clinical form and early therapeutic response. EV-based serological analyses may therefore provide complementary insights into immune dynamics and disease progression in ATL.