sq-23377 and Leprosy

Present study investigates the role of Mycobacterium leprae (M. leprae) antigens on TCR- and TCR/CD28-induced signalling leading to T-cell activation and further correlates these early biochemical events with T-cell anergy, as prevailed in advanced stages of leprosy. We observed that both whole cell lystae (WCL) and soluble fraction of M. leprae sonicate (MLSA) not only inhibited TCR, thapsigargin and ionomycin induced calcium fluxes by diminishing the opening of calcium channels, but also TCR- or TCR/CD28-induced proximal signalling events like phosphorylation of Zap-70 and protein kinase-C (PKC) activity. Study of TCR- and TCR/CD28-induced downstream signals revealed that M. leprae antigens curtail phosphorylation of both Erk1/2 and p38MAPK, consequently altering terminal signalling events like reduced binding of NFAT on IL-2 promoter and transcription of IL-2 gene, diminished expression of activation markers (CD25 and CD69). Furthermore, M. leprae fractions significantly inhibited IL-2 secretion and T-cell blastogenesis in healthy individuals. Altogether, results suggest that M. leprae interferes with TCR/CD28-induced upstream as well as downstream signalling events resulting in reduced IL-2 production and thus inhibition in T-cell proliferation, which might be responsible for T-cell unresponsiveness leading to stage of immunosuppression and consequently, for the progression of disease.

Topics: Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, T-Lymphocyte; Calcium; CD28 Antigens; Cell Proliferation; Clonal Anergy; Enzyme Inhibitors; Gene Expression Regulation; Humans; Interleukin-2; Interleukin-2 Receptor alpha Subunit; Ionomycin; Ionophores; Jurkat Cells; Lectins, C-Type; Leprosy; Lymphocyte Activation; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 3; Mycobacterium leprae; NFATC Transcription Factors; p38 Mitogen-Activated Protein Kinases; Promoter Regions, Genetic; Protein Kinase C; Receptors, Antigen, T-Cell; T-Lymphocytes; Thapsigargin; ZAP-70 Protein-Tyrosine Kinase

Peripheral blood mononuclear cells from leprosy patients underwent spontaneous apoptosis upon culture for 24 h. The apoptosis was inhibited by anti-TNFalpha antibodies and to a certain extent by anti-IL-1alpha and IL-6, thus showing that T(H)2-type cytokines (mainly TNFalpha) are responsible for inducing apoptosis. This cytokine-mediated apoptosis could be inhibited by ionomycin and zinc, thereby suggesting that these metal ions can be used to decrease the levels of these inflammatory cytokines in various diseases.

Topics: Antibodies; Antibody Specificity; Apoptosis; CD28 Antigens; Cells, Cultured; Cytokines; Humans; Interleukin-1; Interleukin-6; Ionomycin; Leprosy; Leukocytes, Mononuclear; Tumor Necrosis Factor-alpha; Zinc

PBMC from tuberculoid (BT/TT) and lepromatous leprosy (BL/LL) leprosy patients showed spontaneous apoptosis when cultured in the absence of mitogen for 24 h, which was inhibited by anti-tumour necrosis factor-alpha (TNF-alpha) antibodies. Apoptosis was also inhibited by ionomycin and zinc, which also increased IL-2 and decreased TNF-alpha production. The increase in IL-2 production suggests a mechanism whereby dietary supplements with zinc might alter the cell-mediated immunity response in leprosy patients.

Topics: Antibodies; Apoptosis; Calcium Signaling; Cells, Cultured; Humans; Interleukin-2; Ionomycin; Leprosy; Leprosy, Lepromatous; Leprosy, Tuberculoid; Leukocytes, Mononuclear; Monensin; Tumor Necrosis Factor-alpha; Zinc