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

To Activate or to Suppress? Viable & Intact Versus Killed & Degraded M. leprae?

M. leprae bacilli can parasitize macrophages in large numbers without being killed in vivo. However, the ability to evade the immune system is reversed in the case of a type I reaction, in which the immune response shifts to the TT pole. The high incidence of leprosy reactions shortly after MDT suggests a role of bacilli viability or associated cell wall intactness in effective M. leprae recognition. In vitro studies with live and intact M. leprae often demonstrate evasion or suppression of immune systems, while killed M. leprae or fragmented cell components are well recognized by the immune system. Viable M. leprae confer protection against NK cell-mediated killing in macrophages and Schwann cells, while dead M. leprae was lyzed in affected host cells.[49] Interestingly, apoptosis of macrophages was observed when cells were infected with irradiated M. leprae; however, it was not evident when live M. leprae was used.[50]In vitro cultured live M. leprae caused downregulation of MHC class I and II molecules on dendritic cells, and could only induce expression of the maturation marker CD83 at very high bacterial doses.[51] By contrast, fractionated M. leprae cell membrane upregulates MHC class II and CD86 expression in dendritic cells.[52] These incomplete membrane fractions have also induced strong IFN-γ production in CD4+ and CD8+ T cells and perforin (a microbicidal protein found in the granules of cytotoxic T lymphocytes [CTLs]), production in M. leprae-specific CD8+ CTLs. LipoK, a lipopeptide consisting of the N-terminal 13 amino acids of the 33-kD lipoprotein of M. leprae, can assist in the processing and presentation of M. leprae antigens and, thereby, the high activation of T cells to facilitate M. leprae killing.[53] Triacylated lipopeptides, representing the 19- and 33-kDa lipoproteins of M. leprae, can activate dendritic cells through Toll-like receptor (TLR)2–TLR1 heterodimers.[54]

The innate immune response to M. leprae infection involves both TLR2 and NOD-like receptors.[55,56] Peptidoglycan and its fragment, muramyl dipeptide, are ligands for TLR2 and NOD-2. Peptidoglycan is the primary component of the M. leprae cell wall and is normally shielded by redundant mycolic acid units in a viable bacterium. M. leprae is believed to be damaged shortly after the initiation of MDT and, in response, changes its morphology, as demonstrated by acid-fast staining and electron micrographs that suggest that cell wall structure is significantly modified.[57–59] These data, along with the abruptly elevated incidence of leprosy reactions, indicate a trigger for leprosy reactions: a decrease in bacilli viability and a damaged cell wall structure, either from MDT or normal bacilli degeneration, may be key events in effective immunological recognition.