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Adaptive Immune Responses to Fungal InfectionsBY: Preethi Venkateswaran | Category: Biotech Research | Submitted: 2011-06-01 12:27:12
The adaptive immune responses to fungal infection involve the cell mediated and humoral responses. The cell mediated responses include effector cells and the humoral effector molecules include antibodies which play a role in combating fungal infections. 1. ANTIBODIES (EFFECTOR MOLECULES) Antibodies are produced in response to fungal infections. These antibodies are chiefly directed towards a variety of fungal polysaccharide and protein antigens (heat shock protein 90 (Hsp90) and mannoprotein 65 (MP65) in C. albicans. B cells mediate humoral responses to fungal infections by producing fungus-specific antibodies. The role of antibodies in host defence against fungi has been extensively studied in C. neoformans and C. albicans, and protective antibodies have been detected in the serum of experimentally infected (C. neoformans and C. albicans) animals. They function by inhibiting adherence of fungi (direct microbicidal or microbistatic action of antibodies on attachment to microbial surfaces), reducing formation of biofilm and are involved in fungal elimination by direct and indirect mechanisms. They can also function as opsonins, promoting fungal ingestion and killing by phagocytes. Antibodies are involved in activation of cellular responses; experimental findings state that during C. neoformans infection in mice, polysaccharide-binding antibodies co-operate with cellular immune mechanisms in the lung to produce enhanced granulomatous inflammation which helps in containment of infection. They influence cell mediated responses by modifying cytokine expression via Fc receptor activation. Studies with monoclonal antibodies have shown that antibodies can either be protective or disease-enhancing depending on the type of antibody. The existence of protective and harmful antibodies to fungal pathogens suggests that the efficacy of the protective antibody response depends on the composition of the antibodies with respect to their isotype and epitope specificity and titre. Research is being carried out in order to identify the antigens that elicit the protective antibody responses and these antigens can be considered as effective candidates for vaccine development. TH1 derived antibodies are usually of immunoglobulin IgG2 isotype, they act as excellent opsonins and promote fungal engulfment and killing. TH2 derived antibodies are of IgG1 isotype, these antibodies are associated with the induction of a non-protective immune response that causes suppression of the protective TH1 mediated immunity. 2. CELL MEDIATED IMMUNITY The clinical circumstances in which fungal infections occur are associated with impaired cell-mediated immunity. AIDS and severe haematological malignancies are examples of acquired defects in T-cell function that predispose individuals to fungal infections. T cells are the main effector cells which mediate cellular immune responses. In case of fungal infections T cell activation is crucial for the development of optimal protective immunity. Both CD4+ and CD8+ T cells are required for clearance of fungal pathogens. CD4+ T cells produce essential lymphokines that activate and recruit phagocytic cells to sites of fungal infection. CD8+ T cells lyse infected cells and limit tissue damage by reducing inflammatory responses. But, in case of several fungal pathogens the presence of CD4+ T cells are essential for host survival, during the primary stages of the disease, and CD8+ T cells are necessary to restrict infection. Therefore, host resistance to fungi depends on the induction of T cell mediated cellular immunity, cytokines and effector phagocytes. a. Th1/Th2 Cells CD4+ T cells (T helper cells) are classified as TH1 (producing IL 2, TNF, IFN gamma) these recruit and activate phagocytic cells for antimicrobial action. TH2 cells (producing IL-4, IL-5 and IL-10) trigger the differentiation of B cells and antibody production. The mechanism by which antigen-presenting cells prime CD4+ T cells and generate either TH1 or TH2-biased responses in response to fungal challenge remains unknown, but it is probably related to the induction of an inflammatory response upon initial exposure. A dominant TH1 response is necessary for the elimination of fungal pathogens. The absence of the TH1 signature cytokines like IFN and TNF leads to overwhelming occurrence of disease. Increased production of TH2 cytokines leads to the development of the disease. b. Th17 Cells Recent studies have shown that TH17 cells have an important role to play in immune responses to fungi. TH17 cells are a subset of CD4+ T helper cells and are distinct from TH1 and TH2 cells. CD4+ T cells in presence of TGF-β and IL-6 express the transcription factor RORγc (retinoid-related orphan receptor gamma c) and become TH17 cells. TH17 cells on activation secrete IL-17 and synthesize a plasma membrane receptor- IL-23R. The binding of IL-23 produced by DCs to the IL-23R leads to the proliferation of the TH17 cells. Studies have shown that TH17 cells are induced during fungal infections, through TLR- and non-TLR-dependent signalling. The antifungal effector activities of neutrophils are impaired due to the action of IL-23 and IL-17 even in the presence of IFN-γ. IL-12 and IL-23 cytokines cross-regulate each other and therefore, the relative levels of these cytokines may determine the outcome of infection. These cytokines lead to the activation of inflammatory program of neutrophils by opposing the IFN-γ-dependent activation of indoleamine 2, 3-dioxygenase (IDO) and also induce the release of metalloproteinases (MPs) and oxidants, causing tissue damage (inflammatory pathology) associated with TH17 cell activation. The role of IDO and kynurenines is to limit the inflammatory status of neutrophils against fungi by maintaining a balance, because though some degree of inflammation is required for protection, mostly in mucosal tissues, excessive inflammation worsens the disease and prevents pathogen clearance. TH17 cells, activated by several fungal components were found to play an inflammatory role previously attributed to uncontrolled TH1 responses. TH17 cell activation, and not failure to activate these cells, was associated with defective clearance of fungal in experimental settings of aspergillosis and mucosal candidiasis. Experimental observation state that IL-17 neutralization increased fungal clearance, prevented inflammatory pathology and restored protective TH1 antifungal resistance. The role of IL-17-producing T cells in protection versus pathology in fungal infections is still controversial. Studies have shown that TH17 are also involved in control of fungal infections, it is known that IL-17A and IL-17F are involved in neutrophil recruitment and granulopoiesis. It was observed that defective neutrophil recruitment was associated with the susceptibility to disseminated candidiasis in IL-17R-/- mice. Therefore, TH17 cells were considered to be protective against candidiasis. Also IL-23 which helps in differentiation of TH17 cells is known to be essential for IL-22 production. IL-22 which is expressed by TH17 cells is involved in the control of fungal growth at mucosal and non mucosal sites in both candidiasis and aspergillosis. c. T regulatory cells (Tregs) T regulatory cells (sometimes known as suppressor T cells) are a specialized subpopulation of T cells; they suppress activation of the immune system and maintain immune system homeostasis. CD4+ T cells activated in the presence of TGF-β and IL-2 upregulate expression of the transcription factor Foxp3 (forkhead box P3) and develop into inducible Tregs, natural Tregs exist in the thymus. Tregs suppress the immune responses. A reciprocal relationship exists between the development of Tregs and TH17 cells, so that naive T cell activation in the presence of innate stimuli divert iTreg generation to TH17 generation. They are thought to have a role in minimizing damage caused by immune activation, by functional antagonism of TH17. In mice with candidiasis, CD4+CD25+ Treg cells, producing IL-10 and TGF, prevent complete elimination of the fungus from the gastrointestinal tract; allow fungal persistence and development of memory immunity. 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