Modulation of the Immune Response in Dermatophytosis

While immunological mechanisms provide potential methods of defense, the persistence of infection in many apparently healthy individuals suggests that these are either ineffective or inoperative in some patients. It has been shown that some patients with persistent dermatophytosis have defective lymphocyte blastogenesis to T-cell mitogens and dermatophyte antigen and that this can be reversed either by substituting heterologous (foetal calf) for autologous serum or after successful antifungal treatment (Mayou et al., 1987). This suggests that an inhibitory factor(s) is present in serum. If this parallels the situation described in mice referred to previously then dermatophyte antigen is a potential candidate as a blocking agent (Calderon, 1989). Dermatophyte antigen has been identified in such infected serum employing an immunoradiometric assay using the mouse antidermatophyte IgM monoclonal TQ-1 (Calderon et al., 1987). Antigen derived from Trichophyton species, containing TQ-1 reactive epitopes, increases susceptibility of Balb/C mice to dermatophyte infection and interferes with T-cell-mediated immunity (Calderon, 1989). TQ-1 antibody reacts with phosphoryl-choline (PC) and immunoreactivity can be abrogated by pretreatment with PC. Phosphoryl-choline hapten is found in other parasites including filaria and this also affects expression of immune responses in these infections. Another, probably different, factor has also been identified. Oligosaccharides derived from glycoproteins present in the dermatophyte cell wall may interfere with both T- and B-lymphocyte activation. This is a reversible process in vitro, but pre-exposure of lymphocytes to dermatophyte inhibitory factor (DIF) will prevent proliferation of T cells in response to mitogens such as phytohaemagglutinin (PHA), as well as dermatophyte antigens (Dahl, 1994; McGregor et al., 1992).

It is clear that within the complex of antigen epitopes that make up the phenotype of a dermatophyte there are antigenic components that potentially stimulate as well as some that block effective immunity. There are also antigenic components that are more likely to trigger an 'allergic' or immediate-type hypersensitivity response, although these are usually the same as those that, under different circumstances, elicit effective immunity and delayed-type hypersensitivity (Woodfolk, 2005). The fungal components which are most closely identified with host resistance via T-cell activation are glycopeptides. However other emerging candidates are heat-shock proteins of the HSP60 family (Raska et al., 2004) and metalloproteinases or subtilases (Mignon, 2005). There is also evidence that these can induce protection against experimental infection in animals.

The possibility that there is interference with the process of immunological activation in the skin is supported by immunohistochemical studies of biopsies from chronically infected skin. In acute dermatophyte infections, immunophenotypic techniques can be used to demonstrate the presence of numbers of effector lymphocytes in the vicinity of the infection (Brasch & Sterry, 1992). Work has now shown that the dermal infiltrate mainly contains cells which are Leu2a positive (viz. T-helper cells) (Brasch & Sterry, 1992; Leibovici et al., 1995). Conversely few express CD-8 (T-suppressor markers). HLA-DR is strongly expressed and most biopsies show Langerhans cells using a variety of different cell markers. In other inflammatory processes cells of the epidermis produce certain cytokines. If fungi including the dermatophyte T. mentagrophytes are co-cultured with human keratinocytes produce IL8 and TNF but other cytokines were undetectable (Kano, 2004). It has been shown by co-incubation of dermatophytes such as T. tonsurans that cultured keratinocytes of the PHK16-0b cell line produce cytokines. With Arthoderma benhamiae (the perfect state of the T. mentagrophytes complex a wide range of cytokines, chemokines and immunostimulatory cytokines are secreted; this involved upregulation of genes encoding arrange of cytokines including IL-1, Il-2, IL-4, Il-6, IL-13, IL15, and IL-16 as well as interferon y. However T. tonsurans only triggered release of IL-8 and Il-16 with upregulation of IL-1 and IL-16. This suggests that there are very different responses to different dermatophytes (Shiraki et al., 2006). It is of further interest that an organism that normally causes a highly inflammatory reaction in man, A. benhamiae (T. mentagrophytes) triggers a wider range of inflammatory cytokines whereas T. tonsurans associated with chronic and less inflammatory disease stimulated a limited range. At present there is no evidence that this occurs in vivo.

Despite the presence of an infiltrate in chronically infected patients, adhesion molecules, such as ICAM-1, are poorly expressed in epidermis (Schectman et al., 1993). This may reflect suppression of the expression of these integrins in the epidermis despite intact cell-mediated immunity. Suppression of this aspect of immune activation by DIF produced by dermatophytes in situ is a possible explanation, which may account for the success of dermatophytes, such as T. rubrum, in causing persistent infections.

A recent study of the interaction between macrophages and T. rubrum conidia and hyphae showed that, in the presence of fungus, macrophages produce TNF and IL10 but not IL12 or nitric oxide. There was also evidence that the dermatophytes downregulated the production of co-stimulatory molecules CD80 and CD50. Phagocytosis is inhibited by addition of crude fungal exoantigen or mannan to the medium (Campos et al., 2006) and the viability of macrophages is reduced ingestion of dermatophyte spores

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