IgM and IgG Antibodies to Phenolic Glycolipid I from Mycobacterium leprae in Leprosy: Insight into Patient Monitoring, Erythema Nodosum Leprosum, and Bacillary Persistence

Leprosy is a chronic granulomatous disease with a long incubation period caused by Mycobacterium leprae that mainly affects the skin, mucous membranes and the peripheral nervous system. It carries the risk of per-manent sequels with a significant impact on the patient’s quality of life. It has a considerable clinically diver-sity and possible atypical presentations. We present a case of a 31-year-old, skin phototype V woman with multibacillary leprosy characterized by multiple outbreaks of erythema nodosum leprosum, as an inaugural manifestation of the disease. The disease was acquired within a group of children and adolescents from an endemic region of Africa, evolved untreated for 3 years, and presented with unusual features and remarkable lymphatic involvement. We highlight the importance of building and maintaining collaboration between expert centers and institutional partnerships in order to provide the adequate diagnostic resources and appropriate care to the affected populations.

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Pediatric Leprosy Profile in the Postelimination Era: A Study from Surabaya, Indonesia

American Journal of Tropical Medicine and Hygiene ◽

10.4269/ajtmh.21-0458 ◽

2022 ◽

Author(s):

Cita Prakoeswa ◽

Novianti Reza ◽

Medhi Alinda ◽

M. Listiawan ◽

Hok Bing Thio ◽

...

Keyword(s):

Retrospective Study ◽

Erythema Nodosum ◽

Elimination Rate ◽

Mycobacterium Leprae ◽

Tertiary Hospital ◽

Disease Prevalence ◽

Erythema Nodosum Leprosum ◽

Common Problems ◽

Endemic Areas ◽

Frequent Exposure

Children who live in leprosy-endemic areas are susceptible to infection due to early and frequent exposure to Mycobacterium leprae. Indonesia is on the verge of eliminating this disease (prevalence rate < 1/10,000 population), but pediatric leprosy continues to occur in low-endemic areas. This study aimed to evaluate pediatric leprosy over a decade in a tertiary hospital in Surabaya, Indonesia. A retrospective study of leprosy in children under 15 years old between 2010 and 2019 was conducted in the Morbus Hansen Division, Outpatient Clinic at Dr. Soetomo Hospital in Surabaya, Indonesia. Seventy pediatric leprosy cases were identified between 2010 and 2019, consisting of 58 multibacillary (MB)-type cases and 12 paucibacillary (PB)-type cases. Slit skin smear (SSS) was positive in 26 cases. There were two cases of grade-2 disability and 15 cases of leprosy reaction (erythema nodosum leprosum) in children at the time of diagnosis. There was an insignificant decline in the number of pediatric leprosy cases in the last 10 years. Cases and disabilities in children were found in some leprosy pocket areas even though the national elimination rate has been achieved. MB infections, disability, and treatment defaults were common problems in pediatric leprosy.

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The miR-125a-3p is Associated With Leprosy Phenotypes and Correlated With Bacillary Index

10.21203/rs.3.rs-763395/v1 ◽

2021 ◽

Author(s):

Nadja de Lima Santana ◽

Tainã Souza do Lago ◽

Thaillamar Silva Vieira ◽

Thyago Leal-Calvo ◽

Paulo Roberto Lima Machado ◽

...

Keyword(s):

Peripheral Nerves ◽

Target Genes ◽

Erythema Nodosum ◽

Mycobacterium Leprae ◽

Local Context ◽

Functional Study ◽

Quantitative Real Time Pcr ◽

Potential Therapeutic Target ◽

Clinical Forms ◽

Erythema Nodosum Leprosum

Abstract Background. Mycobacterium leprae infects skin and peripheral nerves causing a broad of clinical forms. Data have shown that the miR-125a-3p can influence immune mechanisms such as autophagy as well as to target genes leading to abnormal proliferation, metastasis, and invasion of cells. Methods. Here we used quantitative real time PCR (qPCR) to evaluate the miR-125a-3p expression pattern as a marker for leprosy phenotypes in biopsies obtained from patients with and without reactions. Data were analysed according to clinical forms and bacillary index (BI). Results. Our results show a significant increase in the miR-125a-3p expression in paucibacillary (PB) vs multibacillary (MB) (p = 0.007) and vs RR (reversal reactions) (p = 0.005), respectively; and also a higher expression in patients with erythema nodosum leprosum (ENL) vs MB without reactions (p = 0.002). In addition, there was a positive correlation between the miR-125a-3p expression and BI in patients with reactions (r=0,81; p=0,002). Conclusions. All together we underpin a role for miR-125-3p in leprosy pathogenesis, raising the hypothesis that this miR might have a distinct role in PB and ENL forms, influencing mechanisms such as apoptosis and autophagy according to the local context. A functional study should help to validate the miR-125a-3p as a potential therapeutic target for leprosy treatment.

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New Insight into the Pathogenesis of Erythema Nodosum Leprosum: The Role of Activated Memory T-Cells

Frontiers in Immunology ◽

10.3389/fimmu.2017.01149 ◽

2017 ◽

Vol 8 ◽

Cited By ~ 3

Author(s):

Edessa Negera ◽

Kidist Bobosha ◽

Stephen L. Walker ◽

Birtukan Endale ◽

Rawleigh Howe ◽

...

Keyword(s):

T Cells ◽

Erythema Nodosum ◽

Memory T Cells ◽

Erythema Nodosum Leprosum ◽

Insight Into

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Critical residues of the Mycobacterium leprae LSR recombinant protein discriminate clinical activity in erythema nodosum leprosum reactions.

Infection and Immunity ◽

10.1128/iai.62.12.5702-5705.1994 ◽

1994 ◽

Vol 62 (12) ◽

pp. 5702-5705 ◽

Cited By ~ 13

Author(s):

S Singh ◽

P J Jenner ◽

N P Narayan ◽

G Ramu ◽

M J Colston ◽

...

Keyword(s):

Recombinant Protein ◽

Erythema Nodosum ◽

Mycobacterium Leprae ◽

Clinical Activity ◽

Erythema Nodosum Leprosum ◽

Critical Residues

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Higher Treg FoxP3 and TGF-β mRNA Expression in Type 2 Reaction ENL (Erythema Nodosum Leprosum) Patients in Mycobacterium leprae Infection

The Open Microbiology Journal ◽

10.2174/1874434602014010304 ◽

2020 ◽

Vol 14 (1) ◽

pp. 304-309

Author(s):

Luh Made Mas Rusyati ◽

Mochammad Hatta ◽

I Gede Raka Widiana ◽

Made Swastika Adiguna ◽

Made Wardana ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Mrna Expression ◽

Erythema Nodosum ◽

Mycobacterium Leprae ◽

Healthy Controls ◽

Erythema Nodosum Leprosum ◽

Leprosy Patients ◽

The Mean

Background and Aim: The pathology of leprosy is determined by the host immune response to Mycobacterium leprae. Almost 40% of patients with leprosy undergo immune-mediated inflammatory episodes such as type 1 reactions and Erythema Nodosum Leprosum (ENL or type 2 reactions). Regulatory T (Treg) is a subset of T cells that are involved in the immune response. Treg cells express Forkhead Box P3 (FoxP3), which plays a role in suppressing the immune response. FoxP3 may work alongside Transforming Growth Factor Beta (TGF-β) to down-regulate T cells responses, leading to the antigen-specific anergy associated with leprosy, whereas ENL occurrs mostly in multibacillary leprosy patients. Based on that, the aim of our study was to analyze Treg FoxP3 and TGF-β mRNA expression in type 2 reactions ENL with Mycobacterium leprae infection. Methods: Forty-nine newly diagnosed multibacillary (MB) leprosy patients attending the Dermatovenereology Clinic of Leprosy Subdivision, Sanglah General Hospital, Denpasar, Indonesia, were included in the study. The study group consists of 25 leprosy patients with ENL and 24 non-ENL leprosy patients. Twenty-five patients were included in the study as healthy controls. In this study, Treg FoxP3 and TGF-β mRNA expressions were identified with the Real-time PCR method. Analysis of Variant (ANOVA), Chi-square test and odds ratio (OR) calculation were used; p<0.05 was considered statistically significant. Results: The result of this study showed that the mean of Treg FoxP3 mRNA expression was 13.3 ± 2.9 on ENL leprosy patients, 11.6 ± 4.1 on non-ENL, and 9.3 ± 1.2 on healthy controls. The mean of TGF-β mRNA expression was 11.7 ± 2.7 on ENL leprosy patients, 9.5 ± 3.6 on non-ENL, and 9.3 ± 1.2 in healthy patients. Statistical analysis for Treg FoxP3 and TGF-β mRNA level between ENL, non-ENL patients and healthy control group showed significance at p<0.05. Conclusion: From this study, it was concluded that higher Treg FoxP3 and TGF-β mRNA expressions were found in type 2 reaction ENL patients with Mycobacterium leprae infection. The role played by Treg FoxP3 and TGF-β in type 2 reaction episodes can possibly provide a new target for the treatment of this still-challenging complication of leprosy. Further studies are required to determine the involvement of other cytokines in type 2 reaction ENL patients.

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Mycobacterium leprae Induces Neutrophilic Degranulation and Low-Density Neutrophil Generation During Erythema Nodosum Leprosum

Frontiers in Medicine ◽

10.3389/fmed.2021.711623 ◽

2021 ◽

Vol 8 ◽

Author(s):

Isabella Forasteiro Tavares ◽

Jessica Brandão dos Santos ◽

Fabiana dos Santos Pacheco ◽

Mariana Gandini ◽

Rafael M. Mariante ◽

...

Keyword(s):

Flow Cytometry ◽

Whole Blood ◽

Erythema Nodosum ◽

Mycobacterium Leprae ◽

Serum Levels ◽

Low Density ◽

Similar Frequency ◽

Erythema Nodosum Leprosum

Erythema Nodosum Leprosum (ENL) is a recurrent acute inflammatory complication of leprosy affecting up to 50% of all Borderline Lepromatous and Lepromatous Leprosy (BL/LL) patients. Although ENL is described as an immune reaction mediated by neutrophils, studies demonstrating the direct role of neutrophils in ENL are still rare. One subpopulation of low-density neutrophils (LDNs), present within the fraction of peripheral blood mononuclear cells (PBMC), has been associated with the pathogenesis and severity of diseases like sepsis, lupus, and tuberculosis. We herein analyzed LDNs and high-density neutrophils (HDNs) in terms of frequency, phenotype, and morphology. Serum levels of MMP-9 (a neutrophilic degranulation marker) were evaluated by ELISA; and LDNs were generated in vitro by stimulating healthy-donor, whole-blood cultures. PBMC layers of ENL patients presented segmented/hypersegmented cells that were morphologically compatible with neutrophils. Immunofluorescence analyses identified LDNs in ENL. Flow cytometry confirmed the elevated frequency of circulating LDNs (CD14−CD15+) in ENL patients compared to healthy donors and nonreactional Borderline Tuberculoid (BT) patients. Moreover, flow cytometry analyses revealed that ENL LDNs had a neutrophilic-activated phenotype. ENL patients under thalidomide treatment presented similar frequency of LDNs as observed before treatment but its activation status was lower. In addition, Mycobacterium leprae induced in vitro generation of LDNs in whole blood in a dose-dependent fashion; and TGF-β, an inhibitor of neutrophilic degranulation, prevented LDNs generation. MMP-9 serum levels of BL/LL patients with or without ENL correlated with LDNs frequency at the same time that ultrastructural observations of ENL LDNs showed suggestive signs of degranulation. Together, our data provide new insights into the knowledge and understanding of the pathogenesis of ENL while enriching the role of neutrophils in leprosy.

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Lsr2 of Mycobacterium leprae and Its Synthetic Peptides Elicit Restitution of T Cell Responses in Erythema Nodosum Leprosum and Reversal Reactions in Patients with Lepromatous Leprosy

Clinical and Vaccine Immunology ◽

10.1128/cvi.00762-12 ◽

2013 ◽

Vol 20 (5) ◽

pp. 673-682 ◽

Cited By ~ 6

Author(s):

Chaman Saini ◽

H. K. Prasad ◽

Rajni Rani ◽

A. Murtaza ◽

Namita Misra ◽

...

Keyword(s):

Synthetic Peptides ◽

Mononuclear Cells ◽

Erythema Nodosum ◽

Clinical Signs ◽

Mycobacterium Leprae ◽

Lepromatous Leprosy ◽

Rank Test ◽

Content Type ◽

Erythema Nodosum Leprosum ◽

Ifn Γ

ABSTRACTThe Lsr2 protein ofMycobacterium lepraeand its synthetic peptides have been shown to elicit lymphoproliferation and gamma interferon (IFN-γ) release by peripheral blood mononuclear cells (PBMCs) of patients with lepromatous leprosy (M. Chaduvula, A. Murtaza, N. Misra, N. P. Narayan, V. Ramesh, H. K. Prasad, R. Rani, R. K. Chinnadurai, I. Nath, Infect. Immun. 80:742–752, 2012). PBMCs from 16 patients with lepromatous leprosy who were undergoing erythema nodosum leprosum (ENL) (type 2) and 5 patients with reversal reactions (RR) (type 1) were stimulated withM. leprae, recombinant Lsr2, and six end-to-end synthetic peptides (A through F) spanning the Lsr2 sequence. During the reaction all patients with ENL showed lymphoproliferation (stimulation index, >2) in response to peptides A and F, with other peptides eliciting responses in 75 to 88% of the subjects. In PBMC cultures, both lymphoproliferation and IFN-γ release for peptide E were significantly higher than for peptides B and C and recombinant Lsr2 (P< 0.05, Wilcoxon signed-rank test). Five patients with RR also showed enhanced lymphoproliferative responses and IFN-γ release in response to Lsr2,M. leprae, and peptide E. Six months postreaction, 14 patients with ENL continued to exhibit responses to Lsr2 and its peptides, with the highest responses being elicited by peptide E. However, 5 subjects showed no lymphoproliferation and had reduced IFN-γ release in response to Lsr2 peptides (P< 0.001, Kruskal-Wallis test) but responded to recombinant Lsr2. Six patients with ENL had HLA-A*68.01, which the STFPEITHI program showed to have high peptide-binding scores of 20 to 21 for peptides E, B, and C. Eleven patients had HLA-DRB1*1501 and HLA-DRB1*1502, which had high binding scores for peptides C and E. Thus, Lsr2 and its peptides are recognized in leprosy reactions during and well after the subsidence of clinical signs.

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