Visceral leishmaniasis (VL) is a parasitic disease characterized by immune suppression. Successful treatment is usually followed by immune reconstitution and a dermatosis called post-Kala-azar dermal leishmaniasis (PKDL). Recently, PKDL was described as one of the immune reconstitution syndromes (IRISs) in HIV/VL patients on HAART. This study aimed to present PKDL as a typical example of paradoxical IRIS in non-HIV/AIDS individuals. Published and new data on the pathogenesis and healing of PKDL was reviewed and presented. The data suggested that PKDL is a typical example of paradoxical IRIS, being a new disease entity that follows VL successful treatment and immune recovery. PKDL lesions are immune inflammatory in nature with granuloma, adequate response to immunochemotherapy, and an ensuing hypersensitivity reaction, the leishmanin skin test (LST). The data also suggested that the cytokine patterns of PKDL pathogenesis and healing are probably as follows: an active disease state dominated by IL-10 followed by spontaneous/treatment-induced IL-12 priming, IL-2 stimulation, and INF-γ production. INF-γ-activated macrophages eliminate the Leishmania parasites/antigen to be followed by LST conversion and healing. In conclusion, PKDL is a typical example of paradoxical IRIS in non-HIV/AIDS individuals with anti-inflammatory cytokine patterns that are superseded by treatment-induced proinflammatory cytokines and lesions healing. 1. Introduction L. donovani infections are widely prevalent in East Africa and the Indian subcontinent manifesting as a wide spectrum of clinical phenotypes ranging from subclinical infections to a potentially fatal visceral disease. Visceral leishmaniasis (VL) is a parasitic febrile illness with a transient immune suppression state with leucopenia and increased IL-10 secretion [1–4]. In the HIV/AIDS era, VL is considered an opportunistic infection as evidenced by emergence of HIV/VL coinfections [5–10]. VL successful treatment is characterized by improvement of the leucopenia with a decline in CD4+ T cells and conversion in the leishmanin skin test (LST), a probable immunity surrogate marker. LST conversion probably indicates (re) constitution of transiently lost cell-mediated immunity against Leishmania antigens [1, 11–16]. In VL, IL-4 stimulation with IL-10 overproduction leads to reciprocal inhibition of INF-γ production and polyclonal B-cells stimulation (Th2 immune response) [17–20]. More than fifty percent of successfully treated Sudanese VL patients develop an inflammatory skin rash, called postkala-azar dermal leishmaniasis
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