Potential plasma markers of type 1 and type 2 leprosy reactions: a preliminary report

Stefani, Mariane Martins de Araújo; Guerra, Jackeline Gomes; Sousa, Ana Lúcia Osório Maroccolo de; Costa, Maurício Barcelos; Oliveira, Maria Leide W. de; Martelli, Celina Maria Turchi; Scollard, David M.

doi:10.1186/1471-2334-9-75

Cited by 106 publications

(119 citation statements)

References 31 publications

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“…In line with this, IP-10 was recently described as a suitable biomarker for active TB (26,27) despite high IP-10 background levels compared to IFN-␥ in unstimulated control samples of latently infected TB cases. The latter finding could be due to a chronic state of inflammation as the immune system attempts to control infection, which may also explain the elevations of plasma IP-10 observed for leprosy patients with reversal reactions compared to controls without reaction (30). Still, the high levels of IP-10 in response to mycobacterial antigens make it an attractive cytokine that requires further investigation as a possible biomarker in leprosy diagnostics.…”

Section: Discussionmentioning

confidence: 91%

Enhancing Sensitivity of Detection of Immune Responses toMycobacterium lepraePeptides in Whole-Blood Assays

Geluk

Schip

Meijgaarden

et al. 2010

Clin Vaccine Immunol

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Although worldwide leprosy prevalence has been reduced considerably following multidrug therapy, new case detection rates remain relatively stable, suggesting that transmission of infection still continues. This calls for new efforts, among which is development of assays that can identify subclinical/early-stage Mycobacterium leprae-infected subjects, a likely source of transmission. Areas in which leprosy is endemic often lack sophisticated laboratories, necessitating development of field-friendly immunodiagnostic tests for leprosy, like short-term whole-blood assays (WBA). In classical, peripheral blood mononuclear cell (PBMC)-based gamma interferon (IFN-␥) release assays, M. leprae peptides have been shown to discriminate in a more specific fashion than M. leprae proteins between M. leprae-exposed contacts and patients as opposed to healthy controls from the same area of endemicity. However, peptides induced significantly lower levels of IFN-␥ than did proteins, particularly when whole blood was used. Therefore, possibilities of specifically enhancing IFN-␥ production in response to M. leprae peptides in 24-h WBA were sought by addition of various cytokines and antibodies or by mannosylation of peptides. In addition, other cytokines and chemokines were analyzed as potential biomarkers in WBA. We found that only interleukin 12 (IL-12), not other costimulants, increased IFN-␥ production in WBA while maintaining M. leprae peptide specificity, as evidenced by lack of increase of IFN-␥ in control samples stimulated with IL-12 alone. The IL-12-induced increase in IFN-␥ was mainly mediated by CD4؉ T cells that did not produce IL-2 or tumor necrosis factor (TNF). Mannosylation further allowed the use of 100-fold-less peptide. Although not statistically significantly, macrophage inflammatory protein 1␤ (MIP-1␤) and macrophage c protein 1 (MCP-1) levels specific for M. leprae peptide tended to be increased by IL-12. IP-10 production was also found to be a useful marker of M. leprae peptide responses, but its production was enhanced by IL-12 nonspecifically. We conclude that IFN-␥-based WBA combined with IL-12 represents a more sensitive and robust assay for measuring reactivity to M. leprae peptides.Leprosy is a disabling and stigmatizing disease caused by infection with Mycobacterium leprae. The characteristic immunological and clinical leprosy spectrum, classified by Ridley and Jopling in 1966 (25), ranges from tuberculoid (TT) or paucibacillary (PB) leprosy to lepromatous (LL) or multibacillary (MB) leprosy. In between these poles the borderline states borderline lepromatous (BL), borderline borderline (BB), and borderline tuberculoid (BT) leprosy are positioned. TT/BT patients in general show high cellular responses to M. leprae antigens injected in the skin as well as in in vitro T-cell assays; have low antibody titers to M. leprae antigens, including phenolic glycolipid I (PGL-I); and develop localized granulomatous disease with few, if any, detectable bacilli in their lesions. At the opposite end of the spectru...

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Section: Discussionmentioning

confidence: 91%

Enhancing Sensitivity of Detection of Immune Responses toMycobacterium lepraePeptides in Whole-Blood Assays

Geluk

Schip

Meijgaarden

et al. 2010

Clin Vaccine Immunol

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“…The low IL-6 expression was somewhat disappointing because there is evidence for: 1) elevated IL-6 levels in the serum of T2R patients and 2) an association between some IL-6 gene single-nucleotide polymorphisms and T2R. 26,27 However, elevated IL-6 serum levels have also been described in BL/LL patients without reaction as well as in T1R patients. [28][29][30] In addition, IL-6 messenger RNA and protein have been detected in T1R lesions.…”

Section: Resultsmentioning

confidence: 99%

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

Vieira¹,

Trindade²,

Pagliari³

et al. 2016

The American Society of Tropical Medicine and Hygiene

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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)-β-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-β 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.

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“…In relation to diagnosis, IP-10 is detected in pleural effusions and plasma of TB-infected humans, with potential as a biomarker for both treatment monitoring and disease progression (4,12). As with TB, IP-10 levels are elevated within tissues and sera of leprosy patients (25,26). Type 1 reactions, a systemic inflammatory syndrome of borderline leprosy patients, are associated with a significant increase in serum IP-10 but not IFN-␥ (25).…”

mentioning

confidence: 99%

Evaluation of Gamma Interferon (IFN-γ)-Induced Protein 10 Responses for Detection of Cattle Infected with Mycobacterium bovis: Comparisons to IFN-γ Responses

Waters

Thacker

Nonnecke

et al. 2012

Clin. Vaccine Immunol.

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Potential plasma markers of type 1 and type 2 leprosy reactions: a preliminary report

Cited by 106 publications

References 31 publications

Enhancing Sensitivity of Detection of Immune Responses toMycobacterium lepraePeptides in Whole-Blood Assays

Enhancing Sensitivity of Detection of Immune Responses toMycobacterium lepraePeptides in Whole-Blood Assays

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

Evaluation of Gamma Interferon (IFN-γ)-Induced Protein 10 Responses for Detection of Cattle Infected with Mycobacterium bovis: Comparisons to IFN-γ Responses

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