RESUMO
Besides interleukin (IL)-1ß and IL-18, the newly described cytokines of IL-1 family IL-33 and IL-37 can contribute to the differentiation and maintenance of different population of T cells. IL-33 acts as an allarmin and promotes a predominant Th2 inflammatory response, whereas IL-37 plays an important role as an antagonist of inflammation. In paracoccidioidomycosis (PCM), caused by the dimorphic fungi Paracoccidioides brasiliensis and P. lutzii, it has been shown that the acquired immune responses are associated with the diverse clinical manifestations. The severe and disseminated forms (acute form [AF] and multifocal chronic form [CF-MF]) are characterized by high Th2 cytokines and antibody production, impaired cellular immune response, and eosinophilia. In contrast, in the localized form (unifocal chronic form [CF-UF]), the cellular immune response is preserved, with high production of Th1 and Th17 cytokines, and low antibody titers. This study aimed to quantify interleukin-1 family cytokines (IL-1ß, IL-18, IL-37, IL-33, and the soluble IL-33 receptor sST2) in sera of patients presenting different clinical forms of PCM before, during, and after antifungal treatment, as well as to analyze the expression of these cytokines in lesions of PCM patients. We found that AF patients presented high serum levels of IL-1ß, IL-18, IL-33, sST2, and IL-37, and that these cytokines are strongly expressed in lymph nodes lesions. Furthermore, antifungal therapy resulted in the diminution of circulating cytokines and sST2 levels in all groups of patients. These results indicate that, besides IL-1ß and IL-18, IL-33, IL-37, and sST2 can be associated with the disease activity and severity.
Assuntos
Antifúngicos/uso terapêutico , Interleucina-1/sangue , Paracoccidioidomicose/tratamento farmacológico , Paracoccidioidomicose/imunologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1/sangue , Interleucina-18/sangue , Interleucina-1beta/sangue , Interleucina-33/sangue , Masculino , Pessoa de Meia-Idade , Paracoccidioidomicose/sangue , Paracoccidioidomicose/microbiologia , Índice de Gravidade de Doença , Adulto JovemRESUMO
OBJECTIVES: Paracoccidioidomycosis (PCM) is a systemic mycosis caused by the dimorphic fungus Paracoccidioides brasiliensis that presents two main clinical forms: the adult form (AF) and the juvenile form (JF); and an asymptomatic form denominated PCM-infection (PI). These forms of PCM are related to the immune response developed after infection, which has been associated with Th1 and Th2 responses. However, some PCM characteristics cannot be explained by this balance. In this study we aimed to complement the characterization of the immune response in PCM, including the newly described T cells subpopulations (Th17, Th9 and Th22). METHODS: We analyzed the expression of cytokines and transcription factors characteristics of these different subpopulations of CD4(+) T cells in PBMCs from PCM patients and a PI group. RESULTS: The results showed that the PI group presented a predominant Th1 response; that JF patients were characterized by a mixed Th2/Th9 response; and AF patients were characterized by a predominant Th17/Th22 response, as well as substantial participation of Th1 cells. CONCLUSIONS: These results contribute to the existing knowledge on the immune responses associated with resistance or susceptibility to the P. brasiliensis infection, and thus could lead to the development of new strategies for patient management.
Assuntos
Paracoccidioidomicose/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Análise de Variância , Estudos de Casos e Controles , Estudos de Coortes , Citocinas/imunologia , Humanos , Paracoccidioidomicose/patologia , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologiaRESUMO
Patients with paracoccidioidomycosis (PCM) exhibit a suppression of the cellular immune response characterized by negative delayed-type hypersensitivity (DTH) to Paracoccidioides brasiliensis antigens, the apoptosis of lymphocytes, and high levels of expression of cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4), interleukin-10 (IL-10), and transforming growth factor ß (TGF-ß). The aim of this study was to investigate whether and how regulatory T cells (Treg cells) are involved in this immunosuppression by analyzing the number, phenotype, and activity of these cells in patients with active disease (AD group) and patients who had received treatment (TD group). Our results showed that the AD patients had more Treg cells than the TD patients or controls (C group) and also had elevated levels of expression of regulatory markers (glucocorticoid-induced tumor necrosis factor [TNF] receptor-related protein [GITR], CTLA-4, CD95L, LAP-1, and CD38). An analysis of regulatory activity showed that Treg cells from the AD group had greater activity than did cells from the other groups and that cell-cell contact is mandatory for this activity in the C group but was only partially involved in the regulatory activity of cells from AD patients. The addition of anti-IL-10 and anti-TGF-ß neutralizing antibodies to the cultures showed that the production of cytokines may be another mechanism used by Treg cells. In conclusion, the elevated numbers of these cells with an increased regulatory phenotype and strong suppressive activity suggest a potential role for them in the immunosuppression characteristic of paracoccidioidomycosis. In addition, our results indicate that while Treg cells act by cell-cell contact, cytokine production also plays an important role.