Theoretically, SIgA, serum IgG transu-dating through the mucosa, and cellular immunity might all play a role in protection of mucosal surfaces against Candida infections. Animal models have largely concentrated on systemic candidiasis possibly because of the difficulties in obtaining reproducible and relevant models of mucosal candidiasis.
Evidence suggests a role for CMI, even at mucosal surfaces. Infection with C. albicans is an almost universal finding in patients with severe immunodeficiency of the T cell type. It is, however, rarely seen in patients with B cell defects in the absence of concomitant T cell defects. Oral Candida infections are found in about 40% of HIV-infected individuals and in over 75% of patients who suffer from the acquired immunodeficiency syndrome (AIDS) (Palmer et al., 1996). Both erythematous and pseudomembranous candidiasis is found, particularly in association with low CD4 counts. However, in IgA-deficient individuals, a markedly increased prevalence of Candida infection is apparent, and in patients with CMCC, over 50% have reduced salivary IgA antibodies (Lehner et al., 1972).
In CMCC a wide spectrum of immune abnormalities have been reported, ranging from lowered serum IgM and IgG antibodies to defects in lymphocyte transformation and mitogen stimulation in the most severe types of CMCC (Lehner et al., 1972). It is not clear, however, whether these immune defects are primary to the disease or a consequence of it. Some studies have shown restoration of immune functions once Candida has been cleared by antifungal therapy (Valdimarsson et al., 1973).
The observation that only slight alterations in host physiological state can turn a normally harmless commensal yeast into an aggressive pathogen in the immunocompro-mised host points to the significance of the immune response in protection against Candida pathogenicity. At the mucosal level, CMI due to T cells represents the dominant protective response against C. albicans with Thl-type responses associated with resistance and Th2-type responses correlating with susceptibility (Romani et al., 1991a,b, 1993). Systemic CMI may play a more important role in oral candidiasis than vaginal candidiasis with local CMI responses, orchestrated by epithelial cells, chemokines, and cytokines being more relevant in the latter (Saavedra et al., 1999; Steele et al., 1999).
Using a germ-free mouse model of oral candidiasis, we have observed that adoptive transfer of mesenteric lymph node (MLN) cells after intragastric (i.g.) immunisation with whole cells of C. albicans or C. glabrata, and spleen cells after intraperitoneal (i.p.) immunisation, lead to significantly reduced colonisation of C. albicans cells in saliva after challenge (Rahman and Challacombe, 1995) though the protective antigens were not identified. CD8+ cells from MLNs, but not CD4+ cells, were responsible for this effect after i.g. immunisation, whereas after i.p. immunisation both CD8+ and CD4+ cells from the spleen were responsible for reduced colonisation of mice. These and other studies (Fidel et al., 1995a,b) indicate the importance of local and systemic CMI in the protection against mucosal candidiasis, though antibodies have also been shown to be protective in experimental vaginitis (De Bernardis et al., 1997).
In early animal studies using the rhesus monkey, the role of cellular immunity in chronic oral candidiasis was suggested since azathioprine-treated monkeys showed a depression of cellular immunity to Candida but a normal humoral antibody response. These animals had a prolonged and severe oral mucosal Candida infection, suggesting that cellular immunity to Candida is of primary importance in host resistance rather than serum antibody (Budtz-Jorgensen, 1973).
Most models since have been in mice and rats, but there appears to be strong evidence for the role of CD4 cells in protection against systemic candidiasis (Romani et al., 1997a-c), as well as an important immunoreg-ulatory role for neutrophils (Romani et al., 1996). The protective immunity seems to be associated with Th1 rather than Th2 responses. It is not clear, however, whether these findings are totally transferable to mucosal surfaces and to all types of oral candidiasis. Intragastric inoculation can lead to intestinal candidiasis and protective Th1 responses but defective IgA production from Peyer's patches (Bistoni et al., 1993). By contrast, oral immunisation and subsequent oral challenge in a murine model have shown the induction of salivary antibodies in the absence of detectable serum antibodies and inhibition of oral colonisation (Rahman and Challacombe, 1995).
A critical role for CMI in the host defence against oral candidiasis is suggested by the observations in a model of chronic oral C. albicans infection in immunodeficient mice that lack T lymphocytes (Farah et al., 2002a). Complete resolution of the infection in mice reconstituted with functional CD4+ T cells was found. There was evidence that the transferred CD4+ T cells infiltrated the oral tissues, and presumably exerted their activity there. Additionally, draining lymphocytes isolated from the submandibular and superficial cervical lymph nodes secreted high titres of IL-12, and moderate levels of IFN-y, suggesting a role for these cytokines in clearance (Farah et al., 2002b). These data also support the role for Th1-type cytokines and protective immunity in the resolution of oral candidiasis in infected mice. However, histology of hyperplastic candidiasis shows microabsecesses of polymorphs suggesting a non-specific role for innate immunity including polymorphonuclear neutrophils (PMNs), epithelial cells, and possibly toll-like receptors (TLRs).
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