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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

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  • Laboratory of Medical Investigation Unit 56, Division of Clinical Dermatology, Medical School, University of São Paulo, São Paulo, Brazil; Department of Pathology, Medical School, University of São Paulo, São Paulo, Brazil; São Paulo State Health Department, Health Institute, São Paulo, Brazil; Laboratory of Medical Investigation Unit 53, Tropical Medicine Institute, University of São Paulo, São Paulo, Brazil

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.

Author Notes

* Address correspondence to Gil Benard, Tropical Medicine Institute, University of São Paulo, Av. Dr. Enéas de Carvalho Aguiar 470, São Paulo, SP, 05403, Brazil. E-mail: mahong@usp.br

Financial support: This study was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo no. 2014/15286-0, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, and Fundação Paulista contra a Hanseníase. GB and AJSD are senior researchers of Conselho Nacional de Desenvolvimento Científico e Tecnològico.

Authors' addresses: Ana Paula Vieira, Laboratory of Medical Investigation Unit 56, Division of Clinical Dermatology, Medical School, University of São Paulo, São Paulo, Brazil, E-mail: anavieira@usp.br. Maria Ângela Bianconcini Trindade, São Paulo State Health Department, Health Institute, São Paulo, Brazil, and Division of Clinical Dermatology, Medical School, University of São Paulo, São Paulo, Brazil, E-mail: angelatrindade@uol.com.br. Carla Pagliari, Department of Pathology, Medical School, University of São Paulo, São Paulo, Brazil, E-mail: cpagliari@usp.br. João Avancini and Neusa Yurico Sakai-Valente, Division of Clinical Dermatology, Medical School, University of São Paulo, São Paulo, Brazil, E-mails: avancini.joao@gmail.com and neusavalente@gmail.com. Alberto José da Silva Duarte, Laboratory of Medical Investigation Unit 56, Division of Clinical Dermatology, Medical School, University of São Paulo, São Paulo, Brazil, and Department of Pathology, Medical School, University of São Paulo, São Paulo, Brazil, E-mail: adjsduar@usp.br. Gil Benard, Laboratory of Medical Investigation Unit 56, Division of Clinical Dermatology, Medical School, University of São Paulo, São Paulo, Brazil, and Laboratory of Medical Investigation Unit 53, Tropical Medicine Institute, University of São Paulo, São Paulo, Brazil, E-mail: mahong@usp.br.

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