No abstract

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 ␤ (TGF-␤). 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 (glucocorticoidinduced 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-␤ 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.

Besides interleukin (IL)-1β 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-1β, 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-1β, 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-1β and IL-18, IL-33, IL-37, and sST2 can be associated with the disease activity and severity.

Agradeço primeiramente a Deus por tudo, pela força nos momentos mais difíceis, nunca me deixou desistir de nada.Aos meus pais Jair e Sônia pelo amor, educação e por terem acreditado e me dado total apoio durante esses anos. Ao meu irmão Rodrigo, pela ajuda, preocupação e orgulho de ser meu irmão. À minha sobrinha Julia que, com toda a inocência de uma criança, me fez muitas vezes esquecer os problemas. Muito obrigada a minha cunha Cristiane, jamias vou me esquecer de você. À Dra. Heloisa, agradeço por ter me aceitado como aluna, pela confiança depositada e por tudo que me ensinou durante esses anos. À Dra. Cecilia, amiga e chefe, obrigada por toda ajuda, pelos inúmeros "sim" todas as vezes que precisei. Agradeço também pela análise de algumas lâminas.Ao Ronei, grande amigo, agradeço por tudo que aprendi, pelas dicas e pela ajuda na elaboração da tese.Aos meus amigos de laboratório, Larissa, Carol e Rômulo, pelos bons momentos vividos e por toda ajuda quando precisei; Eliane, Munir e Fernanda, pelos momentos de descontração; à Marcela, minha sucessora nas reações de IHQ e companheira na tão esperada disciplina de didática e a Lisandra, adoradora de gatos como eu.Ao Rômulo, companheiro estrada durante todos esses anos.