Editors' ChoiceLeprosy

Separate But Not Equal: Giving the NOD to Innate Immunity in Leprosy

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Science Translational Medicine  25 Apr 2012:
Vol. 4, Issue 131, pp. 131ec70
DOI: 10.1126/scitranslmed.3004178

Cells of the innate immune system respond to foreign microbial cues through pattern-recognition receptors, which detect pathogen-specific molecules such as bacterial cell wall components. Signaling via these receptors causes various immune responses; for example, blood monocytes give rise to specialized immune cells, such as dendritic cells (DCs)—which present foreign proteins to T cells—and macrophages. It is not known whether recognition of distinct ligands from one pathogen by different pattern recognition receptors, such as the transmembrane Toll-like receptors (TLRs) and the cytoplasmic nucleotide-binding oligomerization domain-containing (NOD)–like receptors, triggers different immune responses in the host. Schenk et al. investigated this question in the case of Mycobacterium leprae, the intracellular pathogen that causes leprosy.

The authors tested the effects of two mycobacterial ligands—one of which activates NOD2 and the other TLR2/1—on blood monocytes from healthy donors. The NOD2-induced DCs were better able to present tetanus toxoid to T cells as compared with those triggered by TLR2/1 signaling. NOD2-induced DC differentiation, unlike TLR2/1-induced differentiation, was partly independent of the growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF), a finding of clinical interest because most efforts to expand human DCs ex vivo to fight tumors depend on GM-CSF. Furthermore, GM-CSF and GM-CSF receptor were not induced by NOD2 signaling. Instead, the cytokine interleukin-32 (IL-32) was strongly induced by NOD2 signaling and was necessary for differentiation, as shown by knockdown of IL-32 expression by means of small interfering RNA. Infection of monocytes with M. leprae also induced IL-32. Furthermore, IL-32 was sufficient to cause monocytes to differentiate into DCs.

The key observation linking these studies to human disease came from an examination of skin lesions from individuals with a limited form of leprosy versus those with a progressive form. DC frequency and IL-32 and NOD2 expression were greater in skin lesions in patients with the limited form of the disease; patients with progressive disease had defects in the induction of DCs through NOD2. The addition of IL-32 overcame this deficit, suggesting that differences in this pathway may relate to different clinical outcomes. Further work will likely address the causal relationship of differential innate immune signaling to clinical outcomes and a potential role for IL-32 as a therapeutic strategy to differentiate monocyte-derived DCs.

M. Schenk et al., NOD2 triggers an interleukin-32–dependent human dendritic cell program in leprosy. Nat. Med. 18, 555–563 (2012). [Abstract]

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