RESUMEN
To elucidate further the possible role of the tryptophan, rate-limiting enzyme indoleamine 2, 3-dioxygenase (IDO) in leprosy, the distribution of IDO-positive cells and IDO activity in the skin biopsies and sera of these patients representing the entire spectrum of the disease were studied. An increased number of macrophages/dendritic cells (DC-lineage IDO(+) cells were found in lepromatous (LL) compared to tuberculoid (BT) and reversal reaction (RR) patients. IDO-positive cells showing CD68 and CD86 surface markers predominated in LL lesions, while higher levels of IDO activity were observed in the sera of LL versus BT patients. Tests revealed an increased IDO message in Mycobacterium leprae-stimulated peripheral blood mononuclear cells (PBMC) by real-time polymerase chain reaction (PCR) and increased IDO expression in M. leprae-stimulated CD14(+) cells of both healthy controls (HC) and LL patients, as evaluated via flow cytometry. Increased M. leprae-induced IDO-protein synthesis was also confirmed by Western blot. Based on our in vitro studies, it was confirmed that M. leprae up-regulated IDO expression and activity in HC and LL monocytes. Interferon (IFN)-γ synergized with M. leprae in promoting IDO expression and activity in monocytes. IDO expression induced by both IFN-γ and M. leprae was abrogated by 1-methyltryptophan (1-MT). Our data suggest that M. leprae chronic infection activates the suppressive molecule IDO which, in turn, contributes to the specific immunosuppression observed in LL leprosy.
Asunto(s)
Tolerancia Inmunológica , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Lepra Lepromatosa/inmunología , Antígenos CD/análisis , Antígenos de Diferenciación Mielomonocítica/análisis , Antígeno B7-2/análisis , Western Blotting , Células Cultivadas , Células Dendríticas/inmunología , Activación Enzimática , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Humanos , Immunoblotting , Indolamina-Pirrol 2,3,-Dioxigenasa/sangre , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Interferón gamma/inmunología , Lepra Lepromatosa/enzimología , Lepra Tuberculoide/enzimología , Lepra Tuberculoide/inmunología , Leucocitos Mononucleares/inmunología , Receptores de Lipopolisacáridos , Macrófagos/inmunología , Monocitos/enzimología , Monocitos/inmunología , Mycobacterium leprae/inmunología , Reacción en Cadena de la Polimerasa , Piel/enzimología , Piel/inmunología , Piel/patología , Triptófano/análogos & derivados , Triptófano/farmacologíaRESUMEN
BACKGROUND: Leprosy is an infectious disease with two polar forms, tuberculoid leprosy (TL) and lepromatous leprosy (LL), which are dominated by T-helper (Th) 1 and Th2 cells, respectively. High concentrations of prostaglandin E2 produced by the inducible enzyme cyclooxygenase type 2 (COX-2) in LL could inhibit Th1 cytokine production, contributing to T-cell anergy. OBJECTIVES: To compare the COX-2 expression in LL and TL. METHODS: Skin biopsies from 40 leprosy patients (LL, n = 20; TL, n = 20) were used to determine by immunohistochemistry and automated morphometry the percentage of COX-2 immunostained cells. RESULTS: Most COX-2-positive cells were macrophages; their percentages in the inflammatory infiltrate located in the papillary dermis, reticular dermis and periadnexally were significantly higher in LL than TL (P < 0.001 by Student's t-test). CONCLUSIONS: The high expression of COX-2 in LL may be related to high prostaglandin production contributing to T-cell anergy.