Cell-type deconvolution with immune pathways identifies gene networks of host defense and immunopathology in leprosy
Megan S. Inkeles, … , Matteo Pellegrini, Robert L. Modlin
Megan S. Inkeles, … , Matteo Pellegrini, Robert L. Modlin
Published September 22, 2016
Citation Information: JCI Insight. 2016;1(15):e88843. https://doi.org/10.1172/jci.insight.88843.
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Research Article Immunology Infectious disease

Cell-type deconvolution with immune pathways identifies gene networks of host defense and immunopathology in leprosy

Abstract

Transcriptome profiles derived from the site of human disease have led to the identification of genes that contribute to pathogenesis, yet the complex mixture of cell types in these lesions has been an obstacle for defining specific mechanisms. Leprosy provides an outstanding model to study host defense and pathogenesis in a human infectious disease, given its clinical spectrum, which interrelates with the host immunologic and pathologic responses. Here, we investigated gene expression profiles derived from skin lesions for each clinical subtype of leprosy, analyzing gene coexpression modules by cell-type deconvolution. In lesions from tuberculoid leprosy patients, those with the self-limited form of the disease, dendritic cells were linked with MMP12 as part of a tissue remodeling network that contributes to granuloma formation. In lesions from lepromatous leprosy patients, those with disseminated disease, macrophages were linked with a gene network that programs phagocytosis. In erythema nodosum leprosum, neutrophil and endothelial cell gene networks were identified as part of the vasculitis that results in tissue injury. The present integrated computational approach provides a systems approach toward identifying cell-defined functional networks that contribute to host defense and immunopathology at the site of human infectious disease.

Authors

Megan S. Inkeles, Rosane M.B. Teles, Delila Pouldar, Priscila R. Andrade, Cressida A. Madigan, David Lopez, Mike Ambrose, Mahdad Noursadeghi, Euzenir N. Sarno, Thomas H. Rea, Maria T. Ochoa, M. Luisa Iruela-Arispe, William R. Swindell, Tom H.M. Ottenhoff, Annemieke Geluk, Barry R. Bloom, Matteo Pellegrini, Robert L. Modlin

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Figure 8

MMP-12 expression in leprosy lesions.

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MMP-12 expression in leprosy lesions. MMP-12 protein expression was eval...
MMP-12 protein expression was evaluated in leprosy lesions (T-lep, L-lep, RR, and ENL). (A) CD3 expression was used as a marker for T cells, and IgG1 was used as a negative control; 1 representative labeled section is shown of at least 5 (each obtained from a different patient). Scale bar: 40 μm. Original magnification: ×100. (B) Automated image analysis of MMP12 protein expression. Each dot represents the percentage of MMP-12–stained area (diaminobenzidine [DAB]) per nuclear area for each individual photomicrograph (n = 5 for each group). Data represent mean ± SEM, T-lep (77.5 ± 10.7), L-lep (17.8 ± 8), RR (54.76 ± 10.2), and ENL 13 (32.14 ± 10.2). One-way ANOVA analysis was performed (P = 0.0004) using GraphPad Prism software, and post-hoc analysis (Bonferroni test) is indicated (*P < 0.05, **P < 0.01, ***P < 0.001). ENL, erythema nodosum leprosum; L-lep, lepromatous leprosy; RR, reversal reaction; T-lep, tuberculoid leprosy.