The role of indoleamine 2, 3-dioxygenase in lepromatous leprosy immunosuppression.

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.

Expression of cyclooxygenase type 2 in lepromatous and tuberculoid leprosy lesions.

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.

Expression of inducible nitric oxide synthase and nitrotyrosine in borderline leprosy lesions.

BACKGROUND: In the response to T-helper cell (Th1)-type cytokines and interactions with pathogens, high levels of nitric oxide (NO) are produced by activated macrophages expressing the inducible NO synthase (iNOS). The role and importance of reactive nitrogen intermediates (RNIs) such as NO and peroxynitrite in the host response to diseases caused by intracellular pathogens such as Mycobacterium leprae and M. tuberculosis is unclear. OBJECTIVES: The aim of this study was to investigate the presence of local production of NO and peroxynitrite in borderline leprosy by using antibodies against iNOS and the product of peroxynitrite, nitrotyrosine (NT). METHODS: We detected the presence of iNOS and NT in skin biopsies from borderline leprosy patients, with and without reversal reaction (RR), by immunohistochemistry (n = 26). RESULTS: In general, the granulomas from borderline leprosy lesions with and without RR showed high and specific expression of iNOS and NT. Moreover, strong immunoreactivity to iNOS and NT was observed in granulomas surrounding and infiltrating dermal nerves. The expression of iNOS and NT was also strong in keratinocytes, fibroblasts and endothelial cells in close relation to the granulomatous reaction. In contrast, normal human skin showed no expression of iNOS and NT in these cells. CONCLUSIONS: We conclude that iNOS and NT are expressed in granulomas from borderline leprosy patients with and without RR and propose that RNIs might be involved in the nerve damage following RR in leprosy.

Adenosine deaminase activity in leprosy.

Serum adenosine deaminase (ADA) was studied in 60 patients of different types of leprosy and 50 healthy control subjects. ADA levels in patients with tuberculoid (50.50 +/- 5.22 U/L), borderline (41.14 +/- 3.89 U/L) and lepromatous leprosy (30.10 +/- .03 U/L) were higher than that in controls (17.84 +/- 2.78 U/L), thus correlating with the immunological status of patients. Patients with lepra reaction showed decreased ADA levels and higher grade of lepromin test positivity was associated with increased ADA activity.

Gamma-glutamyl transpeptidase in leprosy.

Activity of the enzyme-gamma-glutamyl transpeptidase (GGTP) was measured in sera of 20 patients each of paucibacillary and multibacillary leprosy and 20 healthy controls. None of the subjects had any systemic or hepatic disease and none had taken any hepatotoxic or antileprotic drugs in the past 3 months. Mean values in the paucibacillary group (38.62 +/- 1.99 U/L) and in the multibacillary group (59.04 +/- 3.13 U/L) were significantly higher compared to that in controls (32.04 +/- 0.66 U/L). Mean value in the multibacillary group was also significantly higher compared to that in the paucibacillary group.

Adenosine deaminase activity in leprosy.

Adenosine deaminase (ADA) activity was studied in serum and peripheral blood lymphocytes of leprosy patients and healthy controls. Serum ADA levels were found to be elevated in tuberculoid as well as lepromatous cases compared to control subjects. Serum ADA activity was significantly higher in tuberculoid cases than in the lepromatous group. Lymphocyte adenosine deaminase activity showed a similar trend. These results suggest that, since the overall activity of the enzyme is not deficient in leprosy, the cellular immune abberation seen in the different types of leprosy may be due to abnormal proliferation of different subsets of lymphocytes in response to M. leprae.

Lymphocyte arginase activity in leprosy--a preliminary report.

Arginase activity was estimated in serum and lymphocytes of 22 healthy controls and 50 untreated leprosy patients across the spectrum. The patients included 21 lepromatous/borderline lepromatous (LL/BL); 20 borderline borderline/borderline tuberculoid (BB/BT) and 9 tuberculoid (TT) cases. Mean serum arginase levels were 1.51 +/- 0.43, 1.41 +/- 0.43, 1.24 +/- 0.43 and 1.10 +/- 0.026 mu moles/min/ml in LL/BL, BB/BT and TT patients and healthy controls respectively. The lymphocyte arginase activity showed a similar increasing trend from TT to LL/BL. The mean lymphocyte arginase levels were 0.87 +/- 0.31 mu moles/min/10(6) cells in healthy controls and 1.81 +/- 0.40, 2.54 +/- 0.60 and 5.48 +/- 0.56 mu moles/min/10(6) cells in TT, BB/BT and LL/BL patients respectively. The increasing trend specially in lymphocyte arginase levels across the spectrum of leprosy correlated with the degree of impairment in the protective cell mediated immune response and also the extent of disease. The role of these pathophysiological alterations in relation to defect in immune response calls for investigation.

Adenosine deaminase activity in leprosy (a preliminary study).

Adenosine deaminase (ADA) activity was studied in 25 patients having different types of leprosy and 25 healthy volunteer as control. There was definite rise of ADA activity in BL (72.9 +/- 6.85), LL (56.7 +/- 3.35) and BT (39.1 +/- 8.28) which was statistically significant when compared to ADA activity in healthy control (9.7 +/- 0.53).