IL-10 and NOS2 modulate antigen-specific reactivity and nerve infiltration by T cells in experimental leprosy.

Abstract

BACKGROUND:

Although 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 FINDINGS:

The 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/SIGNIFICANCE:

The 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.

• Authors: Deanna A Hagge, David M Scollard, Nashone A Ray, Vilma T Marks, Angelina T Deming, John S Spencer, Linda B Adams
• Journal: PLoS neglected tropical diseases (PLoS Negl Trop Dis) Vol. 8 Issue 9 Pg. e3149 (Sep 2014) ISSN: 1935-2735 [Electronic] United States
• PMID: 25210773 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antigens, Bacterial
• Interleukin-10
• Nitric Oxide Synthase Type II
• Nos2 protein, mouse

Topics

• Animals
• Antigens, Bacterial (immunology)
• CD4-Positive T-Lymphocytes (immunology)
• Disease Models, Animal
• Female
• Interleukin-10 (genetics, immunology)
• Leprosy (immunology)
• Mice
• Mice, Knockout
• Mycobacterium leprae (immunology)
• Nitric Oxide Synthase Type II (genetics, immunology)