Leprosy in the 21st century: a comprehensive review of immunological mechanisms, diagnosis, and treatment

Leprosy remains a significant public health challenge, with approximately 182,815 new cases annually. This review synthesizes current knowledge on pathogenesis, diagnosis, and treatment, emphasizing recent advances. We discuss the immunological spectrum, ranging from Th1-dominant tuberculoid forms to Th2/regulatory-dominant lepromatous forms, and highlight the roles of B-lymphocyte, inflammasome activation, and Schwann cell antigen presentation in granuloma formation and neural damage. Leprosy reactions—type 1 and 2—arise from distinct immunopathological mechanisms triggered by various factors, with emerging evidence pointing to the involvement of Th17 and regulatory B cells. Diagnostic advances include molecular techniques, nerve ultrasonography, monofilament testing, and serological assays that complement traditional approaches. Treatment is based on multidrug therapy, with country-specific adaptations such as Brazil’s PQT-U, although challenges with adherence and resistance persist. Alternative regimens may include minocycline, clarithromycin, and fluoroquinolones, with bedaquiline showing promising results. Prophylactic strategies include BCG vaccination and the debated use of single-dose rifampicin for contacts. Management of reactional states employs corticosteroids, thalidomide, with biologics and JAK inhibitors reserved for refractory cases. Genetic and epigenetic factors, including TLR polymorphisms and HLA variants, influence susceptibility and outcomes. Despite recent progress, delayed detection, stigma, and inadequate follow-up remain barriers. Comprehensive approaches integrating early diagnosis, active case finding, chemoprophylaxis, stigma reduction, and rehabilitation are essential. The elimination of leprosy requires sustained commitment, improved resource access, and ongoing research into host-pathogen interactions. This review offers clinicians and researchers an updated understanding to support global control strategies.