Leprosy as a Model of Immunity

Yang Degang; Kazuaki Nakamura; Takeshi Akama; Yuko Ishido; Yuqian Luo; Norihisa Ishii; Koichi Suzuki


Future Microbiol. 2014;9(1):43-54. 

In This Article

The Host Immune Response in Leprosy: Does It Conform to the Model of Bipolar Spectrum?

M. leprae in itself has been suggested as a rather innocuous organism. The fact that approximately 95% of patients infected with the bacterium do not develop overt disease[83] may suggest the importance of the host immune response in controlling disease progression as well as the inappropriate immune response in the pathology of leprosy as evidenced by lepra reactions. The cytokines generated by the innate immune response have been known to play a role as conductors to orchestrate the adaptive immune response. It has been reported that IL-15, which is associated with proliferation of NK and T cells, is preferably produced in TT and BT lesions, while IL-10, which is associated with reduced expression of costimulators and class II MHC molecules, is preferably produced in LL and BL lesions.[84,85] Thus, the production of these key cytokines by the innate immune system might be an essential factor that determines distinct macrophage function upon infection.[86]

It has been demonstrated that host immune responses to M. leprae correlate with the distribution of macrophages expressing TLR1 and TLR2.[54] In fact, polymorphisms within the TLR1 and TLR2 genes were shown to be associated with the development of leprosy as well as its diversity of immune reactions to M. leprae.[87–90] The expression of TLR2 and TLR1 is much stronger in macrophages obtained from TT compared with LL patients.[54] By contrast, macrophages from MB lesions expressed higher levels of DC-SIGN, which may be associated with Th2 immune responses.[91] When naive CD4+ T cells differentiate into Th2 cells instead of Th1 cells, they could inhibit macrophage activation, the microbicidal activity of macrophage and the subsequent cell-mediated immunity. Thus, MB lesions represent a progressive reduction of Th1 activation, resulting in a state of antigen-specific tolerance. Furthermore, macrophages in LL lesions may downregulate cellular immunity by reducing antigen-presenting function and secreting Th2 cytokines or by secreting other suppressive factors, such as IL-10 and prostaglandin E2.[92,93] Mimicking the Th1–Th2 paradigm of the T cells, activated macrophages develop either a proinflammatory phenotype (M1 macrophage), characterized by secretion of IL-23, or an anti-inflammatory phenotype (M2 macrophage), characterized by IL-10 secretion, depending on the triggers.[94]M. leprae-infected macrophages are also refractory to IFN-γ-induced activation and manifest aberrant functions including impaired bactericidal capacity, such as a decreased oxidative state.[95,96] Although attempts to induce macrophage activation in LL patients by local administration of antigens or IFN-γ have been ineffective,[97] a significant type II reaction has been induced by intradermally injecting IFN-γ in to LL and BL patients.[98]

NK cells are involved in the early (within 24 h) IFN-γ response, while CTLs play a more significant role at later intervals (48 h to 5 days).[99,100] Intradermal administration of IL-2 to LL patients resulted in an eightfold increase in NK cells, along with increased T-cell and monocyte infiltration and upgradation of the lesional infiltrate to a granulomatous TT type.[101] However, interleukins produced by NK and T cells in MB patients induced a much lower level of CTL activity and IFN-γ production. It could be proposed that the presence of IL-4 and IL-13, usually generated by Th2 cells in MB patients, leads to accumulation of immature NK cells.[100] Tregs with the CD4+CD25+ phenotype are involved in the suppression of immune reactions, and have been demonstrated to have important roles in various immunological disorders.[102] Although an increase in Tregs was reported in both lepromatous patients[103] and in TT patients,[104] a recent study clearly demonstrated an association of Tregs with immune suppression and disease progression of leprosy.[105] Therefore, Tregs may have important roles on the transition of clinical phenotypes and the occurrence of lepra reactions.

The ability of the innate immune system to instruct a cell-mediated immune response against M. leprae could be also mediated by dendritic cells.[106–108] Reduction of dendritic cells in lepromatous lesions has been considered as a potential mechanism to explain the poor cell-mediated immune responses against M. leprae.[109,110] It was shown that monocytes differentiate into macrophages and dendritic cells after TLR activation.[111,112] In contrast to the effect of other mycobacteria, Murray et al. revealed that M. leprae infection could inhibit maturation of dendritic cells and the subsequent activation of T cells,[113] suggesting that the pathogen specifically subverts the generation of functional APCs. It has been proposed that M. leprae induces specific receptor in order to reduce TLR-mediated activation against mannose-capped lipoarabinomannan, and that the cell wall components of M. leprae modulate APC activation. Thus, the components of various cell wall lipids and the corresponding expression of their recognition systems within dendritic cells might be the factors that determine the immune reaction.[113] Further investigation is needed to determine the effect of live and killed bacilli on immune suppression and activation.