Eosinophils Outside The Lung

Peritoneal invasion with a variety of fungal organisms can occur in patients receiving continuous ambulatory peritoneal dialysis (CAPD) and in some cases is associated with an eosinophilic infiltrate (Ampel et al. 1988; Lee et al. 1997; Nankivell et al. 1991). The cell wall fraction from H. capsulatum induced peritoneal eosinophilia through an IL-5 dependent mechanism. In a murine model of infection with H. capsulatum or inoculation with H. capsulatum derived beta-glucan, leukotrienes were demonstrated to play and important role in the recruitment of eosinophils and other inflammatory cells (Medeiros et al. 2004, 2004; Sa-Nunes et al. 2004).

Fungal infection of the central nervous system (CNS) has been reported to cause eosinophilic meningitis and blood eosinophilia. Patients infected with Coccid-iodes immitis that has disseminated to the CNS may demonstrate an eosinophilic pleocytosis, or eosinophilic meningitis (Ismail and Arsura 1993; Ragland et al. 1993). In cryptococcal invasion of the CNS, blood and CSF eosinophilia have been reported, and histological examination of cerebral granuloma revealed the presence of eosinophils (Anderson et al. 1985; Kamezawa et al. 2000; Gross et al. 2003). Other reports of CSF eosinophilia include a case of chronic eosinophilic meningitis associated with positive culture for Candida guillermondii, and cases of eosinophilic meningitis associated with Aspergillus sinusitis or disseminated histoplasmosis (Chan et al. 2004; Livramento et al. 1993; Paz-Sendin et al. 1999). The purpose of eosinophils in the CNS is not well understood, nor has it been extensively examined, but is felt to be associated with adverse clinical outcome.


Fungal allergy and infection are often associated with increased numbers of eosinophils in the serum and at the sites of disease. In most cases, eosinophils and secreted granule constituents, contribute adversely to the pathophysiology of fungal diseases; however, the eosinophil may also contribute to host defense, as it has been reported to phagocytose fungi at the site of infection and produce products toxic to fungi. It remains to be determined what distinguishes protective versus adverse eosinophilic responses to fungal infection.


Innate cytotoxic lymphocytes include the semi-invariable TCR-bearing natural killer T-lymphocytes (NKT) and natural killer (NK) cells. Both these cell types are important regulators and effectors in the immune response to fungal infection. They are able to participate in the absence of adaptive responses through their cytotoxic ability or the secretion of cytokines to help create a resistant environment and clear fungal pathogens.


NKT cells are innate cytotoxic lymphocytes with a semi-invariable T-cell receptor (TCR). The TCR consists of a conserved Va chain and semi-conserved P chains that recognize lipid antigen in the context of the CD1 family of surface antigen on APC, and more recently have been reported to recognize microbial antigen exogenously (Kinjo et al. 2005; Mattner et al. 2005). Literature regarding the role of these cells in fungal infection is incomplete; though there is evidence they exhibit anti-microbial activity, and participate in host response to pulmonary infection with C. neoformans (Gansert et al. 2003; Kawakami, 2002).

NKT cells contribute to the host response against cryptococcal infection primarily through the secretion of cytokines and subsequent regulation of Th1/Th2 response to fungal infection. Originally, cytokine production by NKT cells was analyzed in response to stimulation with alpha-galactosylcerimide (a-gal-cer) in murine models of cryptococcosis. a-gal-cer is a marine-sponge-derived lipid that is recognized specifically by NKT cells when presented by CD1, and stimulates the production of both Th2 and Th1 type cytokines (Kawano et al., 1997). In a murine model of crypto-coccal infection, serum IFN-7 production was stimulated using a-gal-cer, and levels of IFN-7 were attributable to NKT cells, as NKT-knockout mice did not display the observed increases (Kawakami et al. 2001B). Upon restimulation with live C. neoformans, spleen cells of a-gal-cer-treated mice produced a large amount of IFN-7 not seen in NKT-knockout mice. Furthermore, the fungal burden was significantly reduced in the lung and spleen of a-gal-cer-treated mice compared to treated or untreated NKT-KO mice, establishing the contribution of IFN-7-producing NKT cells in the host response against C. neoformans (Kawakami et al. 2001B).

The IFN-7 response of a-gal-cer stimulated mice was further characterized in IL-18 knockout mice. IFN-7 production and cryptococcal clearance were augmented in an IL-12 and IL-4-dependent fashion (Kawakami et al. 2001C). The role of NKT cells in cryptococcal infection under naïve conditions was subsequently analyzed (Kawakami et al. 2001A). It was determined that Va 14+ NKT cells accumulated in the lung of mice infected with C. neoformans in an MCP-1-dependent fashion, and contributed to the development of fungal-specific acquired cellular responses (Kawakami et al. 2001A). It has since been reported that in the C57BL/6 mouse, conflicting data regarding the ability of this mouse to clear C. neoformans is at least partially attributable to the development of NKT cells (Blackstock and Murphy, 2004). Elegant experiments involving the adoptive transfer of thymocytes from mice at early and later stages of development have demonstrated the importance of mature NKT cells (Blackstone and Murphy, 2004). It is becoming increasingly clear that the recruitment of mature NKT cells capable of producing large quantities of IFN-7 is an important feature of host defense against pulmonary infection with C. neoformans (Blackstone and Murphy, 2004). In addition to a defined role for cytokine production, NKT cell cytotoxic activity against C. neoformans may also contribute to host defense.

Despite an understanding of the contribution of NKT cell-derived cytokine regulation of the host immune response to fungal pathogens, there is little known regarding other potentially important effector functions of these cells. NKT cells are known to express granulysin, to be cytolytic, and important in the defense against intracellular pathogens such as Mycobacteria (Krensky, 2000; Sugawara et al. 2002). Furthermore, NKT cells have been demonstrated to exhibit direct anti-microbial activity against mycobacterium and express the cytolytic molecule ganulysin; known to mediate the direct anti-cryptococcal activity of CD8+ T-lymphocytes (Gansert et al. 2003; Ma et al. 2002). Together, this information suggests that NKT cells may participate in direct anti-fungal activity.

Thus, NKT cells appear to regulate the response to infection with C. neoformans through the production of the Th1 inflammatory cytokine IFN-7, an important feature of protective host responses against fungal pathogens, and exhibit, at least the potential, to mediate direct anti-fungal activity.

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