Page 441 - Clinical Immunology_ Principles and Practice ( PDFDrive )

ChaPTEr 29 Host Defenses to Fungal Pathogens 421

stimulating factor (GM-CSF), all of which play a critical role in These lymphocytes play a critical and nonredundant role in the
antifungal defense. Although IFN-γ has multiple effects on control of IFIs. Th17 cells are characterized by production of
different cell types, this cytokine induces several genes in mac- cytokines, IL-17A, IL-17F, and IL-22. Differentiation of this T-cell
rophages that potently modify the distribution of proteins on lineage requires stage-specific stimulation by cytokines and
the phagosome. The net result of these effects is enhanced activation of specific transcription factors. Transforming growth
intracellular killing. IFN-γ–treated macrophages have enhanced factor-β (TGF-β) and IL-6 prime the initial differentiation of
phagocytosis and are more efficient in antigen presentation. CD4 T cells to Th17 cells. IL-23 is required for both maintenance
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TNF-α has similar effects similar to those of IFN-γ and enhances and expansion of these cells. Activation of STAT3 by IL-6
the function of macrophages. Patients with mutations in the regulates transcription of retinoid orphan receptor-γt (ROR-γt),
TNF-α receptor or those who are treated with TNF-α are at the master transcription factor controlling Th17 lineage com-
heightened risk for fungal infections, including A. fumigatus. mitment. Several studies have confirmed the importance of Th17
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GM-CSF appears to increase ROS production in neutrophils cells and IL-17/IL-23 signaling for antifungal immunity. Mice
and macrophages. Two lines of evidence in humans suggest an deficient in IL-17 receptor fail to generate functional Th17 cells
important role for Th1 cells in antifungal defense. Patients with and are highly susceptible to both systemic and mucocutaneous
fever and neutropenia with documented IFIs, including candi- candidiasis. Additionally, IL-23–deficient animals develop progres-
demia, have improved resolution of infection independent of sively worse mucocutaneous disease. Likewise, in mouse models
the effect of GM-CSF on neutrophil mobilization. Patients with of vulvovaginal C. albicans infection, impairment of Th17 cell
protein alveolar proteinosis, which is a disease related to anti– function led to increased fungal burden. Interestingly, fungal
GM-CSF autoantibodies, have increased risk of IFIs. pathogens have devised mechanisms to subvert this component
of the immune system. Cell surface receptors found on Candida
CLINICaL rELEVaNCE and Aspergillus bind IL-17 and cause increased hyphal growth
Opportunistic Fungal Pathogens and transcriptional changes within these fungal organisms that
are thought to combat the immune response.
Cause Invasive Fungal Infections in
Immunocompromised Patients CD8 T Cells
• Advances in clinical medicine provide treatment modalities that bring Although CD8 T cells are critical for immune defense against
new promise to once-deadly diseases. During the course of these viral pathogens and tumors, their contribution to fungal immunity
treatments, many patients develop significant deficiencies in their is incompletely understood. They may provide functional
immune system that permit the development of opportunistic redundancy to confer protection in the absence of CD4 T cells.
infections. These cells will be important in the development of fungal
• Invasive fungal infections (IFIs) caused by Aspergillus fumigatus, vaccines, but further studies are required to delineate if they
Candida albicans, or Cryptococcus neoformans are considered the have any nonredundant role in antifungal immunity.
most serious infections that affect immunocompromised patients.
Despite effective fungicidal therapies, such as voriconazole and B Cells
amphotericin, mortality in these patients exceeds 25%.
• These data indicate that a robust immune response is required for Early data dismissed the role of humoral immunity during fungal
clinical efficacy. Patients with defects in innate immunity are at highest infection. However, clinical observations have suggested that
risk despite the fact that they typically have functional circulating antibodies contribute to fungal host defense. Patients with B-cell
lymphocytes. defects, including X-linked hyper-IgM syndrome and hypogam-
• There is a dire clinical need to develop novel therapeutics for IFIs to
address the significant public health burden caused by opportunistic maglobulinemia, demonstrate increased susceptibility to cryp-
fungal pathogens. tococcosis. Additionally, pediatric patients with selective IgG2
deficiency are at heightened risk for IFIs and other bacterial
infections that rely on antipolysaccharide antibody formation.
Th2 Cells Antibodies observed in normal individuals are typically
In contrast to Th1 cells, Th2 lymphocytes appear to be defense against fungal cell wall components and have the capacity to
against most fungal infections. Th2 lymphocytes secrete IL-4, inflict negative changes within the fungal cell. These include
IL-5, and IL-13. The effects of these cytokines on macrophages inducing transcriptional changes that are deleterious to the
diminish the antifungal response. IL-4 drives macrophage dif- microbe. Antibodies can work in conjunction with complement
ferentiation toward the alternatively activated phenotype. In mice and phagocytic cells to facilitate damage of the cell wall and
exposed to either Aspergillus or Cryptococcus in the respiratory trigger uptake by cells, respectively. Antibodies also have the
tract, Th2 skewing drives an allergic phenotype with airway capacity to trigger transcriptional changes that increase pathogen
hyperresponsiveness (AHR) and goblet hyperplasia. There is one virulence, thereby exacerbating disease. Pleiotropic effects have
notable exception to the deleterious effect of Th2 cells on invasive made it difficult to resolve the net value of humoral immunity
fungal disease—P. jiroveci. Th2 responses seem to be protective to IFIs.
in this infection. Mouse studies suggest that alternatively activated
macrophages are critical for clearance of this fungal pathogen. Natural Killer Cells
Recent studies have identified a nonredundant role for Th17 Natural killer (NK) cells exert an antifungal response, but
lymphocytes, suggesting that Th2 responses are necessary, but the rules that govern this response have only been elucidated
not sufficient, for clearance of P. jiroveci. recently. NK cell–mediated killing requires direct contact with the
fungus, which leads to release of perforin. The NK cell receptor
Th17 Cells p30 is required for NK cell-fungal conjugate formation, pI3K
Th17 cells are a subset of CD4 T cells that have emerged as signaling, and perforin release. p30 was previously identified
major contributors to host defense against fungal pathogens. as an activating receptor against tumor cells. In patients with