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

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.

S100A12 Is Part of the Antimicrobial Network against Mycobacterium leprae in Human Macrophages.

Triggering antimicrobial mechanisms in macrophages infected with intracellular pathogens, such as mycobacteria, is critical to host defense against the infection. To uncover the unique and shared antimicrobial networks induced by the innate and adaptive immune systems, gene expression profiles generated by RNA sequencing (RNAseq) from human monocyte-derived macrophages (MDMs) activated with TLR2/1 ligand (TLR2/1L) or IFN-γ were analyzed. Weighed gene correlation network analysis identified modules of genes strongly correlated with TLR2/1L or IFN-γ that were linked by the "defense response" gene ontology term.

IL-27 Suppresses Antimicrobial Activity in Human Leprosy.

The mechanisms by which intracellular pathogens trigger immunosuppressive pathways are critical for understanding the pathogenesis of microbial infection. One pathway that inhibits host defense responses involves the induction of type I interferons and subsequently IL-10, yet the mechanism by which type I IFN induces IL-10 remains unclear. Our studies of gene expression profiles derived from leprosy skin lesions suggested a link between IL-27 and the IFN-β induced IL-10 pathway.

Recognizing and managing the immunologic reactions in leprosy.

Immunologic reactions are an important aspect of leprosy that significantly impacts the course of the disease and the associated disability. Reversal reaction (type 1), erythema nodosum leprosum (type 2), and Lucio phenomenon are the 3 leprosy reactions, and they are most commonly seen in patients with the lepromatous and borderline categories of the disease. Because these forms of leprosy are the most common types seen in the United States, it is particularly important for physicians to be able to recognize and treat them.

A comparison of stigma among patients with leprosy in rural Tanzania and urban United States: a role for public health in dermatology.

Background:   Leprosy is a chronic infection of the skin and peripheral nerves caused by the bacterium Mycobacterium leprae, which causes peripheral insensitivity and disfigurements of the skin, limbs, and digits. Social stigma is a common consequence of leprosy and may differ according to level of physical disfigurement and geographic location. The objective of this study was to assess social stigma encountered by patients with leprosy in clinical settings located in rural Tanzania and urban USA and to compare the social stigma reported in these regions.

Type I interferon suppresses type II interferon-triggered human anti-mycobacterial responses.

Type I interferons (IFN-α and IFN-β) are important for protection against many viral infections, whereas type II interferon (IFN-γ) is essential for host defense against some bacterial and parasitic pathogens. Study of IFN responses in human leprosy revealed an inverse correlation between IFN-β and IFN-γ gene expression programs. IFN-γ and its downstream vitamin D-dependent antimicrobial genes were preferentially expressed in self-healing tuberculoid lesions and mediated antimicrobial activity against the pathogen Mycobacterium leprae in vitro.

Galectin-3 regulates the innate immune response of human monocytes.

Galectin-3 is a β-galactoside-binding lectin widely expressed on epithelial and hematopoietic cells, and its expression is frequently associated with a poor prognosis in cancer. Because it has not been well-studied in human infectious disease, we examined galectin-3 expression in mycobacterial infection by studying leprosy, an intracellular infection caused by Mycobacterium leprae. Galectin-3 was highly expressed on macrophages in lesions of patients with the clinically progressive lepromatous form of leprosy; in contrast, galectin-3 was almost undetectable in self-limited tuberculoid lesions.

NOD2 triggers an interleukin-32-dependent human dendritic cell program in leprosy.

It is unclear whether the ability of the innate immune system to recognize distinct ligands from a single microbial pathogen via multiple pattern recognition receptors (PRRs) triggers common pathways or differentially triggers specific host responses. In the human mycobacterial infection leprosy, we found that activation of monocytes via nucleotide-binding oligomerization domain-containing protein 2 (NOD2) by its ligand muramyl dipeptide, as compared to activation via heterodimeric Toll-like receptor 2 and Toll-like receptor 1 (TLR2/1) by triacylated lipopeptide, preferentially induced differentiation into dendritic cells (DCs), which was dependent on a previously unknown interleukin-32 (IL-32)-dependent mechanism. Notably, IL-32 was sufficient to induce monocytes to rapidly differentiate into DCs, which were more efficient than granulocyte-macrophage colony-stimulating factor (GM-CSF)-derived DCs in presenting antigen to major histocompatibility complex (MHC) class I-restricted CD8(+) T cells.

MicroRNA-21 targets the vitamin D-dependent antimicrobial pathway in leprosy.

Leprosy provides a model to investigate mechanisms of immune regulation in humans, given that the disease forms a spectrum of clinical presentations that correlate with host immune responses. Here we identified 13 miRNAs that were differentially expressed in the lesions of subjects with progressive lepromatous (L-lep) versus the self-limited tuberculoid (T-lep) disease. Bioinformatic analysis revealed a significant enrichment of L-lep-specific miRNAs that preferentially target key immune genes downregulated in L-lep versus T-lep lesions.

A role for interleukin-5 in promoting increased immunoglobulin M at the site of disease in leprosy.

Leprosy is an infectious disease in which the clinical manifestations correlate with the type of immune response mounted to the pathogen, Mycobacterium leprae. To investigate which biological pathways or gene sets are over-represented in lepromatous (L-Lep) versus tuberculoid (T-Lep) patients that might be relevant in disease pathogenesis, we compared the gene expression profiles of L-lep versus T-lep skin lesions using knowledge-guided bioinformatic analysis, incorporating data on likely biological functions, including gene ontology information and regulatory data. Analysis of probe sets comparatively increased in expression in L-lep versus T-lep revealed multiple pathways and functional groups involving B-cell genes (P values all < 0.

Integrated pathways for neutrophil recruitment and inflammation in leprosy.

Neutrophil recruitment is pivotal to the host defense against microbial infection, but it also contributes to the immunopathology of disease. We investigated the mechanism of neutrophil recruitment in human infectious disease by means of bioinformatic pathways analysis of the gene expression profiles in the skin lesions of leprosy. In erythema nodosum leprosum (ENL), which occurs in patients with lepromatous leprosy and is characterized by neutrophil infiltration in lesions, the most overrepresented biological functional group was cell movement, including E-selectin, which was coordinately regulated with interleukin 1beta (IL-1beta).

Comparative genomic and phylogeographic analysis of Mycobacterium leprae.

Reductive evolution and massive pseudogene formation have shaped the 3.31-Mb genome of Mycobacterium leprae, an unculturable obligate pathogen that causes leprosy in humans. The complete genome sequence of M.

Divergence of macrophage phagocytic and antimicrobial programs in leprosy.

Effective innate immunity against many microbial pathogens requires macrophage programs that upregulate phagocytosis and direct antimicrobial pathways, two functions generally assumed to be coordinately regulated. We investigated the regulation of these key functions in human blood-derived macrophages. Interleukin-10 (IL-10) induced the phagocytic pathway, including the C-type lectin CD209 and scavenger receptors, resulting in phagocytosis of mycobacteria and oxidized low-density lipoprotein.

Activation of Fc gamma RI on monocytes triggers differentiation into immature dendritic cells that induce autoreactive T cell responses.

The formation of immune complexes results in activation of the innate immune system and subsequent induction of host inflammatory responses. In particular, the binding of IgG immune complexes to FcgammaR on monocytes triggers potent inflammatory responses leading to tissue injury in disease. We investigated whether activation of monocytes via FcgammaR induced cell differentiation, imparting specific inflammatory functions of the innate immune response.

Host-derived oxidized phospholipids and HDL regulate innate immunity in human leprosy.

Intracellular pathogens survive by evading the host immune system and accessing host metabolic pathways to obtain nutrients for their growth. Mycobacterium leprae, the causative agent of leprosy, is thought to be the mycobacterium most dependent on host metabolic pathways, including host-derived lipids. Although fatty acids and phospholipids accumulate in the lesions of individuals with the lepromatous (also known as disseminated) form of human leprosy (L-lep), the origin and significance of these lipids remains unclear.

Conserved mycobacterial lipoglycoproteins activate TLR2 but also require glycosylation for MHC class II-restricted T cell activation.

CD4(+) T cell clones derived from a leprosy lesion and patient blood were used to monitor the isolation and identification of an Ag associated with the self-limited form of the disease. Biochemical purification and genetic analysis identified the T cell Ag as a conserved mycobacterial lipoglycoprotein LprG. LprG-mediated activation of CD4(+) T cells required specific MHC class II restriction molecules and intracellular processing.

Angiogenesis in cutaneous lesions of leprosy: implications for treatment.

Objective: To examine the potential role of angiogenesis in leprosy.

Design: Immunohistochemical analysis of leprosy lesions.

Setting: Department of Dermatology, Venereology, and Leprology, Kasturba Medical College; Division of Dermatology, University of California at Los Angeles; and Departments of Dermatology and Pathology, Emory University.

LILRA2 activation inhibits dendritic cell differentiation and antigen presentation to T cells.

The differentiation of monocytes into dendritic cells (DC) is a key mechanism by which the innate immune system instructs the adaptive T cell response. In this study, we investigated whether leukocyte Ig-like receptor A2 (LILRA2) regulates DC differentiation by using leprosy as a model. LILRA2 protein expression was increased in the lesions of the progressive, lepromatous form vs the self-limited, tuberculoid form of leprosy.

Activation of human CD4+ T cells by targeting MHC class II epitopes to endosomal compartments using human CD1 tail sequences.

Distinct CD4(+) T-cell epitopes within the same protein can be optimally processed and loaded into major histocompatibility complex (MHC) class II molecules in disparate endosomal compartments. The CD1 protein isoforms traffic to these same endosomal compartments as directed by unique cytoplasmic tail sequences, therefore we reasoned that antigen/CD1 chimeras containing the different CD1 cytoplasmic tail sequences could optimally target antigens to the MHC class II antigen presentation pathway. Evaluation of trafficking patterns revealed that all four human CD1-derived targeting sequences delivered antigen to the MHC class II antigen presentation pathway, to early/recycling, early/sorting and late endosomes/lysosomes.

Regulation of human T-cell homing receptor expression in cutaneous bacterial infection.

We investigated the regulation of T-cell homing receptors in infectious disease by evaluating the cutaneous lymphocyte antigen (CLA) in human leprosy. We found that CLA-positive cells were enriched in the infectious lesions associated with restricting the growth of the pathogen Mycobacterium leprae, as assessed by the clinical course of infection. Moreover, CLA expression on T cells isolated from the peripheral blood of antigen-responsive tuberculoid leprosy patients increased in the presence of M.

Functional characterization of a T-cell receptor BV6+ T-cell clone derived from a leprosy lesion.

Human infection with Mycobacterium leprae, an intracellular bacterium, presents as a clinical and immunological spectrum; thus leprosy provides an opportunity to investigate mechanisms of T-cell responsiveness to a microbial pathogen. Analysis of the T-cell receptor (TCR) repertoire in leprosy lesions revealed that TCR BV6(+) T cells containing a conserved CDR3 motif are over-represented in lesions from patients with the localized form of the disease. Here, we derived a T-cell clone from a leprosy lesion that expressed TCR BV6 and the conserved CDR3 sequence L-S-G.

Clinical and histologic variations among thirty patients with Lucio's phenomenon and pure and primitive diffuse lepromatosis (Latapi's lepromatosis).

The clinical and histologic experience with 30 patients who had Lucio's phenomenon, and pure and primitive diffuse lepromatosis (Latapi's lepromatosis) has been reviewed. The unanticipated clinical findings were a male to female ratio of nearly 1:1, a 21 month median time of onset of erythema nodosum leprosum (Type 2 reaction) after starting antibacterial treatment, and an absence of a stocking-glove pattern of anesthesia in 7 patients. The only unanticipated histologic finding was a lepromatous-granulomatous vasculitis, occurring in comparatively large vessels, or in vessels made large by pathologic changes, located near the dermal-subcutaneous interface.

TLR activation triggers the rapid differentiation of monocytes into macrophages and dendritic cells.

Leprosy enables investigation of mechanisms by which the innate immune system contributes to host defense against infection, because in one form, the disease progresses, and in the other, the infection is limited. We report that Toll-like receptor (TLR) activation of human monocytes induces rapid differentiation into two distinct subsets: DC-SIGN+ CD16+ macrophages and CD1b+ DC-SIGN- dendritic cells. DC-SIGN+ phagocytic macrophages were expanded by TLR-mediated upregulation of interleukin (IL)-15 and IL-15 receptor.