Leprosy as a Model of Immunity

Colocalization of T Lymphocytes & M. leprae in the Liver: Is It Well Understood?

Leprosy is thought to be primarily transmitted aerogenically, which means that M. leprae does not just exist in the dermis, and transient or even long-standing bacteremia is required for successful transmission of the pathogen. Hence, locations other than the dermis, such as internal organs, may have some roles in leprosy. For example, the spleen, which filters blood and receives circulating macrophages that may be infected by M. leprae, would likely play an important role in regulating the T-cell and antibody response to the bacillus. Although not many studies have focused on internal organs, one report demonstrates an interesting possibility that the liver plays a pivotal role during the immune response against M. leprae and as a candidate for the reservoir of M. leprae. A histological investigation of the liver tissues of 240 leprosy patients found leprous granulomata in 21% of TT and 62% of LL patients.^[114] Bacteremia is thought to occur in the early period of infection because liver granulomas were found in TT and BT patients within 1 year after diagnosis. Furthermore, bacterial index, determined by a skin smear, correlates well with the existence of acid-fast bacilli stained in the liver. It is important to note that even though the bacilli had been cleared from skin lesions, as shown by negative bacterial indices in skin smears, acid-fast bacilli were still detected in 14% of liver biopsy tissues.^[114,115]

Clearly, M. leprae generally favors the cooler parts of the body rather than internal organs. In addition, the persistence of M. leprae in the liver may be unusual given that the T-cell biology of the liver is unlike that of other organs. However, the liver receives a blood supply from both the hepatic artery and the portal vein. This mixture of blood containing immune cells passes over a large macrophage population (Kupffer cells) with M. leprae infection in sinusoids. Innate lymphocytes, for example, conventional NK cells and NKT cells, which can be activated upon stimulation, are commonly found in the liver.^[116] It is thought that antigens can be presented by sinusoidal endothelial cells, stellate cells and even by liver parenchymal cells with the expression of immunosuppressive cytokines and inhibitory cell surface proteins.^[116,117] As a result, antigens presented by these nonprofessional APCs often result in the induction of immune tolerance. The induction of systemic tolerance by liver APCs has been attributed to both peripheral deletion and the induction of antigen-specific Tregs.^[117]

In addition, the liver might sequester activated T cells in an antigen-independent manner, and the high apoptotic rate of activated T cells has given rise to the idea that the liver might be a 'graveyard' for systemic T cells.^[118] In the natural history of chronic HBV infection, an HBV-specific cellular immune response is absent in the initial immune tolerance phase when the HBV load is high. Liver cell damage induced by cellular immune responses is usually associated with lower HBV load.^[119] This pattern is rather similar to M. leprae infection as described by the Ridley–Jopling model, in which cellular immune response is absent in the LL pole where bacterial load is high, while tuberculoid granuloma is formed in the TT pole of leprosy.

Macrophages and dendritic cells both differentiate from circulating PBMCs, which continue to develop and mature in the blood and can be recruited to the tissue at various points during their maturation continuum.^[1,120] Therefore, macrophages and dendritic cells capable of presenting M. leprae antigens may be newly created in the liver. In fact, granulomas consisting of TACO-positive macrophages engulfing bacteria were induced following Mycobacterium bovis BCG infection in mice.^[73] Owing to the large volume of blood that circulates through the liver, it is possible that communications between such APCs and circulating lymphocytes including those already primed by M. leprae antigens in skin lesions occur. This possibility, in addition to the fact that acid-fast bacilli and histological lesions that correlate with skin lesions of leprosy were identified in the liver biopsies,^[114] suggests an interesting possibility that the liver may have a pivotal role on the clinical manifestations of leprosy.

To demonstrate this hypothesis, re-evaluation of M. leprae persistence with local immunological responses in the liver to demonstrate specific lymphocyte subsets and cytokine profiles, is needed. Although performing the liver biopsy in leprosy patients for this purpose is not appropriate, armadillos or a congenic strain of hypertensive nude rats (SHR/NCrj-rnu) in which M. leprae disseminates throughout internal organs including the liver, spleen and lungs,^[121] will be a useful model for such studies. Since anergy to the M. leprae antigen can be induced by several factors including tolerance to overwhelming number of bacilli,^[122,123] M. leprae-specific, dose-related immunological tolerance in lepromatous patients would thus be an interesting topic for further studies.