Altered distribution of peripheral blood dendritic cell subsets in patients with pulmonary paracoccidioidomycosis

Abstract

Paracoccidioidomycosis (PCM) is a systemic mycosis caused by fungi from the genus Paracoccidioides in Latin America. PCM-patients (PCM-p) are classified as having acute/subacute or chronic (CF) clinical forms. CF is responsible for 75%-90% of all cases, affects mainly adults over 30 years old and the clinical manifestation are associated mainly with lungs and mucosa of upper airdigestive tract. In addition, the CF patients exhibit fibrosis of the lungs, oral mucous membranes and adrenals, and pulmonary emphysema. Consequently, CF PCM-p with active disease, as well as those that have been apparently cured, seem to be an interesting model for studies aiming to understand the long-term host-fungi relationship and hypoxia. Dendritic cells (DCs) constitute a system that serve as a major link between innate and adaptive immunity composed of several subpopulations of cells including two main subsets: myeloid (mDCs) and plasmacytoid (pDCs). The present study aimed to access the distribution of PBDC subsets of CF PCM-p who were not treated (NT) or treated (apparently cured - AC). CF PCM-p were categorized into two groups, consisting of 9 NTs and 9 ACs. Twenty-one healthy individuals were used as the control group. The determination of the PBDC subsets was performed by FACS (fluorescence-activated cell sorting) and the dosage of serum TNF-α, IL1β, IL-18, CCL3, IL-10 and basic fibroblast growth factor (bFGF) by ELISA (enzyme-linked immunosorbent assay). A high count and percentage of mDCs was observed before treatment, along with a low count of pDCs in treated patients. Furthermore, the mDC:pDC ratio and serum levels of TNF-α was higher in both of the PCM-p groups than in the control group. In conclusion, our findings demonstrated that active PCM influences the distribution of mDCs and pDCs, and after treatment, PCM-p retained a lower count of pDCs associated with pro-inflammatory profile. Therefore, we identified new evidences of persistent immunological abnormalities in PCM-p after treatment. Even these patients showing fungal clearance after successful antifungal treatment; the hypoxia, triggered by the persistent pulmonary sequelae, possibly continues to interfere in the immune response.

The Syk-Coupled C-Type Lectin Receptors Dectin-2 and Dectin-3 Are Involved in Paracoccidioides brasiliensis Recognition by Human Plasmacytoid Dendritic Cells

“…The involvement of pDCs has been prominently described in viral infections ( 5 ). However, recent studies have opened new roles of pDCs to other types of pathogens, indicating an important role for these cells in bacterial ( 32 , 33 ) and fungal infections ( 8 – 12 , 34 ). However, to our knowledge, no data are available regarding the role of human pDCs in innate and adaptive immunity against P. brasiliensis .…”

“…Activated mature pDCs prime naive T cells for Th1 or Th17 differentiation ( 6 , 7 ). Outside of viral infections, important roles for pDCs have been described in the immune response against fungal infections ( 8 – 12 ). A pioneer study showed that human pDCs interact to and inhibit the growth of Aspergillus fumigatus -hyphae.…”

“…Importantly, in 24 of 46 PCM patients, the presence of pDCs was verified when their cutaneous lesions were immunostained with anti-pDC specific antibodies ( 11 ). In addition, peripheral blood pDCs appeared in lower numbers in PCM patients compared to the number of blood pDCs found in health donors, suggesting that pDCs migrate to the lymph nodes, spleen, and target organs during a P. brasiliensis infection ( 12 ). Taking in account these findings and the fact that human innate immunity against P. brasiliensis infection is poorly defined, we aimed to investigate the interaction of human pDCs with P. brasiliensi s yeast cells.…”

Increased peripheral blood TCD4+ counts and serum SP-D levels in patients with chronic paracoccidioidomycosis, during and after antifungal therapy

“…Our group has observed several peripheral immunological alterations in the PCM patients, after treatment, were observed. High counts of peripheral blood CD16 ++ monocyte subsets ( Venturini et al 2014 ), lower counts of peripheral blood plasmocytoid dendritic cells ( Venturini et al 2017 ), and an enhanced expression of the NRLP3 inflammasome gene (Unpublished observations) were observed. Considering the fact that the pulmonary sequelae observed in CF PCM patients typically worsen after antifungal therapy is initiated ( Costa et al 2013 ), it is possible that the observed alterations occur due to hypoxemia ( Tzouvelekis et al 2007 ).…”

Paracoccidioidomicosis con afectación mucocutánea. Reporte de un caso

“…gicamente se observará mayormente un epitelio plano estratificado, hiperplasia pseudoepiteliomatosa, muchas células gigantes donde los hongos muestran brotes hijos, conectados a sus células madre, en proceso de gemación, dando lugar a un aspecto clásico, ya bien descrito como de "rueda de timón" o de "orejas de Mickey Mouse" 15 . También se recurre a tinciones especiales con PAS o a la metenamina de plata de Grocott, con el propósito de mejorar la observación del hongo 1,16 .…”