Abstract
BackgroundAlthough immunopathology dictates clinical outcome in leprosy, the dynamics of early and chronic infection are poorly defined. In the tuberculoid region of the spectrum, Mycobacterium leprae growth is restricted yet a severe granulomatous lesion can occur. The evolution and maintenance of chronic inflammatory processes like those observed in the leprosy granuloma involve an ongoing network of communications via cytokines. IL-10 has immunosuppressive properties and IL-10 genetic variants have been associated with leprosy development and reactions.Methodology/Principal FindingsThe role of IL-10 in resistance and inflammation in leprosy was investigated using Mycobacterium leprae infection of mice deficient in IL-10 (IL-10−/−), as well as mice deficient in both inducible nitric oxide synthase (NOS2−/−) and IL-10 (10NOS2−/−). Although a lack of IL-10 did not affect M. leprae multiplication in the footpads (FP), inflammation increased from C57Bl/6 (B6)<IL-10−/−<NOS2−/−<10NOS2−/−. While IL-10−/− mice exhibited modest FP induration compared to B6, NOS2−/− and 10NOS2−/− mice developed markedly enlarged FP marking distinct phases: early (1 month), peak (3–4 months), and chronic (8 months). IFN-γ-producing CD4+CD44+ cells responding to M. leprae cell wall, membrane, and cytosol antigens and ML2028 (Ag85B) were significantly increased in the evolved granuloma in NOS2−/− FP compared to B6 and IL-10−/− during early and peak phases. In 10NOS2−/− FP, CD4+CD44+ and especially CD8+CD44+ responses were augmented even further to these antigens as well as to ML0380 (GroES), ML2038 (bacterioferritin), and ML1877 (EF-Tu). Moreover, fragmented nerves containing CD4+ cells were present in 10NOS2−/− FP.Conclusions/SignificanceThe 10NOS2−/− strain offers insight on the regulation of granuloma formation and maintenance by immune modulators in the resistant forms of leprosy and presents a new model for investigating the pathogenesis of neurological involvement.
Highlights
Leprosy is a neglected tropical disease that is still diagnosed in .200,000 new patients every year [1]
In an effort to investigate this broad range of responses within the lesion, we have evaluated the M. leprae-induced footpad (FP) granuloma in a number of mouse strains with immune defects [12,13,14,15,16], including inducible nitric oxide synthase knockout mice (NOS22/2) [17,18]
Leprosy reactions are a major risk for neuritis that leads to peripheral nerve damage, disfigurement and disability
Summary
Leprosy is a neglected tropical disease that is still diagnosed in .200,000 new patients every year [1]. Its clinical spectrum is associated with a diverse and often dynamic immune response ranging from strong cell mediated immunity (CMI) at one end to complete anergy toward Mycobacterium leprae antigens at the other. The majority of leprosy patients are classified into the borderline area of the spectrum [11] where there appears to be a partial immunity of an undefined nature which allows neither complete anergy nor resolution of disease. NOS22/2 mice respond to M. leprae infection in a manner that resembles borderline tuberculoid disease in that bacterial growth is restricted and they develop a large granulomatous response, composed of epithelioid macro-. IL-10 has immunosuppressive properties and IL-10 genetic variants have been associated with leprosy development and reactions
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