ABSTRACT
Paracoccidioidomycosis (PCM) is a systemic chronic mycosis, endemic in Latin America, especially Brazil, and is the eighth leading cause of death among chronic and recurrent infectious diseases. PCM infection is characterized by the presence of Th1 immune response; the acute form, by a mixed Th2/Th9, while the chronic form is characterized by Th17/Th22 profiles. The occurrence and severity of human PCM may also be associated with genetic factors such as single nucleotide polymorphisms (SNP) on cytokines encoding genes. We investigated the association between these polymorphisms and the different clinical forms of PCM. We included 156 patients with PCM (40 with the acute form, 99 with the chronic multifocal and 17 with the chronic unifocal form) and assayed their DNA samples for IFNG +874 T/A SNP by PCR-ARMS (Amplification Refractory Mutational System), IL12B +1188 A/C SNP on 3' UTR and IL12RB1 641 A/G SNP on exon 7 by PCR-RFLP (Restriction Fragment Length Polymorphism). We found similar genotypic and allelic frequencies of the investigated SNPs among the clinical forms of PCM. Considering male patients, the IL12RB1 641 AA genotype was more frequent in the chronic multifocal form while heterozygosis was in the chronic unifocal form of PCM (p=0.048). Although our data suggest that the AA genotype (IL12RB1) may be associated with the more disseminated chronic disease, more patients of the chronic unifocal PCM group need to be analyzed as well as the secretion patterns of IFN-γ combined with the IL-12Rß1 expression for a better comprehension of this association.
Subject(s)
Host-Pathogen Interactions , Interferon-gamma/genetics , Interleukin-12 Subunit p40/genetics , Paracoccidioidomycosis/genetics , Polymorphism, Single Nucleotide , Receptors, Interleukin-12/genetics , 3' Untranslated Regions , Acute Disease , Adolescent , Adult , Aged , Alleles , Brazil , Child , Chronic Disease , Female , Gene Expression , Gene Frequency , Genotype , Humans , Interferon-gamma/immunology , Interleukin-12 Subunit p40/immunology , Male , Middle Aged , Paracoccidioides/growth & development , Paracoccidioidomycosis/immunology , Paracoccidioidomycosis/microbiology , Paracoccidioidomycosis/pathology , Polymorphism, Restriction Fragment Length , Receptors, Interleukin-12/immunology , Sex FactorsABSTRACT
Cellular immune responses are a significant defence mechanism in human paracoccidioidomycosis (PCM), an endemic mycosis in Latin America; however, little is known about the role of dendritic cells (DCs) in human PCM. We investigated monocyte-derived DCs from patients with treated (TP) and active PCM (AP) compared with healthy non-PCM donors (CO). DCs from the TP group showed higher expression of HLA-DR, CD86 and DC-SIGN compared with CO, whereas AP showed similar expression to CO. Production of IL-10 was downregulated by TNF-α in all groups and lower levels were observed in untreated DCs from AP compared with CO. Conversely, IL-12p40 was significantly upregulated in the DCs of the TP group. TNF-α-activated DCs from the CO group produced significantly lower levels of IL-12p40 when differentiated from magnetic-sorted monocytes (MACS) compared with adhered monocyte-derived DCs. This comparison in the TP group revealed similar levels of IL-12p40, suggesting a T cell-independent increase in the production of IL-12p40. Higher expression of surface molecules with increased IL-12p40 may indicate a better activation of DCs after the treatment of PCM. Our findings suggest that DCs may be crucial in the protective response to Paracoccidioides brasiliensis and that in vitro-generated DCs might be useful in enhancing antifungal immunity, especially during active PCM.