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Development of Type 2, But Not Type 1, Leprosy Reactions is Associated with a Severe Reduction of Circulating and In situ Regulatory T-Cells.

ABSTRACT: Leprosy is frequently complicated by the appearance of reactions that are difficult to treat and are the main cause of sequelae. We speculated that disturbances in regulatory T-cells (Tregs) could play a role in leprosy reactions. We determined the frequency of circulating Tregs in patients with type 1 reaction (T1R) and type 2 reaction (T2R). The in situ frequency of Tregs and interleukin (IL)-17, IL-6, and transforming growth factor beta (TGF)-?-expressing cells was also determined. T2R patients showed markedly lower number of circulating and in situ Tregs than T1R patients and controls. This decrease was paralleled by increased in situ IL-17 expression but decreased TGF-? expression. Biopsies from T1R and T2R patients before the reaction episodes showed similar number of forkhead box protein P3+ (FoxP3+) and IL-17+ cells. However, in biopsies taken during the reaction, T2R patients showed a decrease in Tregs and increase in IL-17+ cells, whereas T1R patients showed the opposite: Tregs increased but IL-17+ cells decreased. We also found decreased expansion of Tregs upon in vitro stimulation with Mycobacterium leprae and a trend for lower expression of FoxP3 and the immunosuppressive molecule cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) in T2R Tregs. Our results provide some evidence to the hypothesis that, in T2R, downmodulation of Tregs may favor the development of T-helper-17 responses that characterize this reaction.

SUBMITTER: Vieira AP

PROVIDER: S-EPMC4824210 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Development of Type 2, But Not Type 1, Leprosy Reactions is Associated with a Severe Reduction of Circulating and In situ Regulatory T-Cells.

Vieira Ana Paula AP Trindade Maria Ângela Bianconcini MÂ Pagliari Carla C Avancini João J Sakai-Valente Neusa Yurico NY Duarte Alberto José da Silva AJ Benard Gil G

The American journal of tropical medicine and hygiene 20160222 4

Leprosy is frequently complicated by the appearance of reactions that are difficult to treat and are the main cause of sequelae. We speculated that disturbances in regulatory T-cells (Tregs) could play a role in leprosy reactions. We determined the frequency of circulating Tregs in patients with type 1 reaction (T1R) and type 2 reaction (T2R). The in situ frequency of Tregs and interleukin (IL)-17, IL-6, and transforming growth factor beta (TGF)-β-expressing cells was also determined. T2R patien ...[more]

PMID: 26903606

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Project description:Background: Reactions in Leprosy are immune exacerbations that cause debilitating consequences like nerve damage and permanent deformities. Prediction of these reactional states using appropriate biomarkers would enable early treatment interventions to prevent nerve function impairment. The current study investigated whole transcriptomic expression profiles of Mycobacterium leprae (M. leprae) that differentiate leprosy cases in type 2 (Erythema Nodosum Leprosum) reactions with those without reactions in host skin tissue derived RNA. Methods: Post clinical examination, excisional skin biopsy specimens were collected from skin lesions of subjects with and without type 2 reaction. Total RNA was extracted following the Trizol protocol and bacterial RNA was enriched in the samples. A 2 x 400K gene expression array (whole genome tiling array) was designed with the probes having 60-mer oligonucleotides tiling every 10bp of the genome sequence of M. leprae (NC_011896.1). The array comprised 420288 features which include probes and Agilent controls. The quality of RNA was estimated using BioAnalyzer (Agilent Technologies) followed by labelling, reverse transcription, amplification and hybridization to the arrays. The hybridized slides were scanned on a G2600D scanner (Agilent Technologies). The data thus acquired is analysed using GeneSpring GX Version 12.1 software. Data was normalized and fold difference in expression was noted from 359,922 probes which include sense and antisense orientations of 179,961 probes. The differentially expressing M. leprae genomic regions between type 2 reactions and non reactional cases were noted. Results: Considering a statistical cut-off value of 0.6 for fold difference in expression between the test and the control samples, a set of 107 genes indicated statistically significant up-regulation with volcano plot p-values less than 0.05. Functional characterization revealed higher-expression of genes encoding transmembrane proteins (12), regulatory proteins (9), fatty acid biosynthesis (6), amino acid metabolism (13), nucleic acid metabolism (7), DNA replication and repair (7), Secretory proteins (2) Krebs Cycle (1), Glycolysis (1), Drug Efflux Protein (1),Stress Response Protein (1), Energy Metabolism (2), Pantothenate biosynthesis (1), Metalloproteins (3), Hydrolases (1) and Hypothetical Proteins (40). Additionally there are 157 genes that are down regulated in cases with reaction. Conclusion: Differential expression of genes in the human skin biopsy specimens among leprosy cases with type 2 reaction in contrast to those without reaction suggests the role of pathogen associated gene expression triggers with the aetiology of these reactions. As most of the transmembrane and cell wall proteins possess epitope and surface exposed domains, higher expression levels of genes encoding these proteins may have a possible role in enhancing host immune responses characteristic of type 2 reactions in leprosy.

Project description:BackgroundThe ILEP Nerve Function Impairment in Reaction (INFIR) is a cohort study designed to identify predictors of reactions and nerve function impairment in leprosy. The aim was to study correlations between clinical and histological diagnosis of reactions.Methodology/principal findingsThree hundred and three newly diagnosed patients with World Health Organization multibacillary (MB) leprosy from two centres in India were enrolled in the study. Skin biopsies taken at enrolment were assessed using a standardised proforma to collect data on the histological diagnosis of leprosy, leprosy reactions and the certainty level of the diagnosis. The pathologist diagnosed definite or probable Type 1 Reactions (T1R) in 113 of 265 biopsies from patients at risk of developing reactions whereas clinicians diagnosed skin only reactions in 39 patients and 19 with skin and nerve involvement. Patients with Borderline Tuberculoid (BT) leprosy had a clinical diagnosis rate of reactions of 43% and a histological diagnosis rate of 61%; for patients with Borderline Lepromatous (BL) leprosy the clinical and histological diagnosis rates were 53.7% and 46.2% respectively. The sensitivity and specificity of clinical diagnosis for T1R was 53.1% and 61.9% for BT patients and 61.1% and 71.0% for BL patients. Erythema Nodosum Leprosum (ENL) was diagnosed clinically in two patients but histologically in 13 patients. The Ridley-Jopling classification of patients (n = 303) was 42.8% BT, 27.4% BL, 9.4% Lepromatous Leprosy (LL), 13.0% Indeterminate and 7.4% with non-specific inflammation. This data shows that MB classification is very heterogeneous and encompasses patients with no detectable bacteria and high immunological activity through to patients with high bacterial loads.Conclusions/significanceLeprosy reactions may be under-diagnosed by clinicians and increasing biopsy rates would help in the diagnosis of reactions. Future studies should look at sub-clinical T1R and ENL and whether they have impact on clinical outcomes.

Dataset Information

Development of Type 2, But Not Type 1, Leprosy Reactions is Associated with a Severe Reduction of Circulating and In situ Regulatory T-Cells.

Publications

Development of Type 2, But Not Type 1, Leprosy Reactions is Associated with a Severe Reduction of Circulating and In situ Regulatory T-Cells.

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