Activation of signaling lymphocytic activation molecule triggers a signaling cascade that enhances Th1 responses in human intracellular infection

T cell production of IFN-gamma contributes to host defense against infections by intracellular pathogens, including mycobacteria. Lepromatous leprosy, the dissminated from of infection caused by Mycobacterium leprae, is characterized by loss of cellular response against the pathogen and diminished Th1 cytokine production. Relieving bacterial burden in Ag-unresponsive patients might be achieved through alternative receptors that stimulate IFN-gamma production. We have previously shown that ligation of signaling lymphocytic activation molecule (SLAM) enhances IFN-gamma in mycobacterial infection; therefore, we investigated molecular pathways leading from SLAM activation to IFN-gamma production in human leprosy. The expression of the SLAM-associated protein (an inhibitory factor for IFN-gamma induction) on M. leprae-stimulated cells from leprosy patients was inversely correlated to IFN-gamma production. Howevwe, SLAM ligation or exposure of cell from lepromatous patients to a proinflammatory microenvironment down-regulated SLAM-associated protein expression. Moreover. SALAM activation induced a sequence of signaling proteins, including activation of the NF-kB complex, phosphorylation of Stat1, and induction of T-bet expression, resulting in the promotion a cascade of molecular events during signaling through SLAM in leprosy that cooperate to induce INF-gamma production and strongly suggest that SLAM might be a focal point for therapeutic modulation of the cell cytokine responses in diseases characterized by dysfunctional Th2 responses

Differential sensitivity of peripheral blood lymphocytes of untreated leprosy patients to mitomycin C.

The effects of a bifunctional alkylating agent mitomycin C (MMC), an effective inducer of chromosome aberrations and sister-chromatid exchanges (SCEs), have been studied in untreated leprosy patients. This was done to study the mutagen sensitivity of the leprosy patients. The frequency of chromosomal aberrations induced by MMC (conc. 0.01 microgram/ml) was 2.5% in controls, 3.6% in paucibacillary (PB), and 6.8% in multibacillary (MB) patients. The difference in the frequency of MMC-induced chromosome aberrations between the 3 groups studied was highly significant (p less than 0.01). Cultures grown with MMC showed the frequency of SCEs/cell to be 12.70 +/- 1.19 in controls, 19.97 +/- 3.51 in PB, and 29.66 +/- 5.92 in MB patients. The differences in the frequency of MMC-induced SCEs between the 3 groups were found to be highly significant (p less than 0.01). The enhanced frequencies of spontaneous and MMC-induced chromosome aberrations and SCEs observed in PB and MB patients indicate a clear differential mutagen sensitivity between PB and MB patients who are known to have different immunological status and thereby differ in the severity of the disease.