Our patient group was composed of seven males and three females, whose mean age was 38 years-old (range 21–57) and presenting either involvement of two (70% of the cases) or one body segment (30%). The anatomical sites affected were abdomen, buttocks and thighs. The lesions were in general typical, circular or oval, and erythematous, often with scaling, with more intense signals of inflammation within the limits. Time of onset ranged from 8 months to 2 years. In the control group, eight were male and four were female, their mean age was 34 years (range 28–52). All patients’ samples were culture positive for T. rubrum. Histopathology analysis showed perivascular lymphohistiocytic infiltration in the upper dermis and absence of neutrophils in the lesions (Supplementary data).
Keratinocytes are the most abundant cells in the epidermis, comprising approximately 95% of all cells. Keratinocytes are able to secrete multiple cytokines, such as TNF-α, IL-10, IL-6 and IL-8 in presence of dermatophyte cells or their metabolites. TNF-α is a cytokine that mediates inflammatory reactions against injurious events caused by microbial agents or UV irradiation, while IL-10 inhibits cytokine production in activated T lymphocytes and antigen-presenting cells [5, 6]. Depending on the balance between these cytokines, a protective or disease-promoting environment may be induced [7].
Campos et al showed that murine macrophages secreted TNF-α and IL-10 after stimulation with T. rubrum conidia [8]. In addition, our group showed previously that macrophages and neutrophils derived from chronic dermatophytosis patients displayed defective phagocytic activity, diminished secretion of pro-inflammatory cytokines such as TNF-α, IL1-β but increased IL-10 secretion. Thus, the cytokine balance can vary depend on the type of cells challenged by dermatophytes cells or their metabolites [9].
Considering the importance of the balance between pro- and anti-inflammatory cytokines in determining the course of some infectious diseases, we evaluated the expression of TNF-α and IL-10 in skin samples from patients with dermatophytosis. Our results show that IL-10 expression was significantly increased in the affected epidermis (ODI: 86,0 ± 35,1 mean ± s.d.) compare to unaffected skin (ODI: 48,3 ± 21,3 mean ± s.d.) and control group (ODI: 35,75 ± 23,03). TNF-α expression was also significantly increased in the epidermis of affected skin (ODI: 75,60 ± 22,20, mean ± s.d.) when compared to control group (ODI: 53,17 ± 14,02, mean ± s.d.) but not to the unaffected skin (ODI:57,50 ± 16,46, mean ± s.d.) (Fig. 1). Moreover, the magnitude of the expression of these cytokines was comparable.
Because T. rubrum is known to cause mild inflammation in humans [1], we can hypothesize that this infection would be responsible for the balance of pro-and anti-inflammatory signals which would control and limit this fungal infection. Consistent with this, our group demonstrated that dermatophyte lesions exhibit reduced expression of TLR-4, a receptor related to the production of inflammatory cytokines, and preserved expression of TLR-2, which is in turn related to an anti-inflammatory response profile in the disease [10].
Our previous publication, showed that patients with dermatophytosis have a lower density of CD1a+ (Langerhans cells) in the epidermis [11]. This lower density could be explained by down regulation of this cell population in the presence of the cytokine IL-10, which reduces the recruitment of these cells to the infectious site. Another hypothesis is that this low density would be the result of the T. rubrum-activated Langerhans cells having migrated to regional lymph nodes where they would induce ineffective adaptive immune responses, leading to chronicity of the disease. On the other hand, macrophages and dermal dendrocytes showed no altered cellular density in the dermis; this may be explained by the fact that the inflammatory response in dermatophytosis patients spares the dermis.
In conclusion, we suggest that the balanced expression of TNF-α and IL-10 in dermatophytosis lesions shown here, together with our previous observations of decreased TLR-4 expression and density of CD1a+ cells, delineate a potential mechanism limiting the host’s inflammatory damage that, by one side, would favor the development of a mild pathology but, by the other side, would contribute to the chronicity of the infection (Fig. 2). Understanding the immune environment in the lesions may be an interesting starting point for identifying specific therapeutic targets.