This chapter provides a brief review of the literature on immunomodulation by aflatoxin and other mycotoxins, examines immunomodulation by mycotoxins that co-occur in food, reviews possible mechanisms through which mycotoxins exert their effects, and considers future research in the field. Studies conducted in several species of animals and in animal and human cell cultures have shown that aflatoxins act as immunomodulators, primarily as immunosuppressors, of various aspects of cell-mediated immunity and phagocytic cell function. The effect of aflatoxin on humoral immunity in animals is less consistent. Recently, two studies have been published that show association between aflatoxin Bi albumin adduct levels in blood and antibody and cellular immune status of humans chronically exposed to aflatoxin in their diet. Several other immunotoxic mycotoxins co-occur with afla-toxin in foods, and are likely to have an additive, if not synergistic, effect on the immune system. Aflatoxin seems to exert its immunomodulatory effects by modulating cytokine production either at the mRNA or protein level, but, the mechanisms of immune modulation by aflatoxin and other mycotoxins remain to be clearly determined.
Aflatoxins are a group of secondary metabolites produced by strains of some Aspergillus species, mainly A. flavus and A. parasiticus (Gourama and Bullerman, 1995). These compounds are potent carcinogens found in crops such as maize, groundnuts, legumes and other grains that form the staple diet in many developing countries (Cardwell, 2001). Among the aflatoxin chemotypes (B1, B2, G1 and G2), B1 is the most common and toxic form (Park et al., 2002). Aflatoxin M1 is a hydroxylated metabolite of aflatoxin B1 found in the milk and urine of humans or other mammals that consume a diet contaminated with aflatoxin B1
© CAB International 2008. Mycotoxins: Detection Methods, Management, Public Health - 41 -and Agricultural Trade (eds. J. F. Leslie et al.).
(Neal et al., 1998). Chronic exposure of humans to low levels of aflatoxins occurs more commonly than acute toxic exposure. Chronic aflatoxin exposure is associated with the development of hepatocellular carcinoma in humans (Bosch and Munoz, 1988; Ozturk, 1991; IARC, 1996), especially in those infected with hepatitis B virus (Ross et al., 1992; Qian et al., 1994; Wang et al., 1996, 2001). Thus, chronic aflatoxin exposure is a major and significant public health problem.
Aflatoxins are less well known for their role in immune suppression, although numerous studies have been published since the late 1960s (Gallikeev et al., 1968; Pier and Hed-dleston, 1970; Savel et al., 1970) on the effects of aflatoxin on the immune system of animals (in vivo studies) and on animal and human immune cells in vitro. These studies have been reviewed extensively (Pier, 1986; Richard, 1991; Bondy and Pestka, 2000; Oswald et al., 2005). However, data on the immunotoxic effects of aflatoxins in humans are limited and only two reports have been made in recent years on the effects of aflatoxins on humans who are chronically exposed to it in the diet (Turner et al., 2003; Jiang et al., 2005).
Immunomodulation by aflatoxin in animals and animal & human cell cultures
The cells of the immune system are continually proliferating and differentiating and are vulnerable to the immunomodulatory, primarily immunosuppressive, effects of mycotox-ins. Previous studies on the effect of aflatoxin on the immune system in animals and in cell cultures examined cell mediated and antibody responses, NK cell activity, macrophage phagocytic function, and infectivity and host-resistance challenges. In most of these studies, cellular immunity was examined with methods such as delayed type hypersensitivity (Reddy and Sharma, 1989), expression of regulatory cytokines such as interleukin 2 (IL-2) production by spleenocytes (Hatori et al., 1991; Dugyala and Sharma, 1996), graft versus host response, leukocyte migration and lymphoblastogenesis using [3H]-thymidine (Ghosh et al., 1991; Kadian et al., 1988). The effect of aflatoxin on the humoral immune system was usually investigated by examining antibody responses to sheep red blood cells and the results have been inconsistent (van Heugten et al., 1994). Studies conducted on the immunotoxic effect of aflatoxin up to the year 2001 have shown that exposure to aflatoxin decreased T or B lymphocyte activity (Reddy et al., 1987; Richard et al., 1978), impaired macrophage/neutrophil effector functions (Neldon-Ortiz, 1991; Cusumano et al., 1996; Silvot-ti et al., 1997; Moon et al., 1999), modified synthesis of inflammatory cytokines (Jakab et al., 1994; Moon, 1999), suppressed NK cell-mediated cytolysis (Reddy and Sharma, 1989), decreased resistance to infectious diseases (Hamilton and Harris, 1971; Edds et al., 1973; Boonchuvit and Hamilton, 1975; Wyatt et al., 1975; Cysewki et al., 1978; Joens et al., 1981; Pier, 1986), induced reactivation of chronic infection (Venturini et al., 1996; Kubena et al., 2001), decreased immunity to vaccination (Gabal and Azzam, 1998; Gabal and Di-mitri, 1998) and impaired immune function in developing animals (Pier et al., 1984; Silvot-ti et al., 1997). Studies of interleukin-1 (IL-1) production by peritoneal macrophages of rats given a single injection of 1 ^g/g aflatoxin B1 showed increase in IL-1 (Cukrova et al., 1992). However, aflatoxin Bi did not have an effect on IL-1 production by bovine macrophages (Walsh et al., 1991) suggesting that aflatoxin may have an immunomodulatory rather than simply an immunosuppressive role.
One study in animals published after 2001 that merits special review is that by Marin et al. (2002) on the effect of aflatoxin on cellular and humoral immunity in weanling piglets. In this study, several parameters of immune function were examined in relation to levels of aflatoxin that are normally allowed in animal feed (low-dose = 140 ppb and highdose = 280 ppb). There was a biphasic change in the total number of white blood cells depending on whether aflatoxin was fed at the low or high dose. Low-dose aflatoxin decreased the total number of white blood cells while high-dose aflatoxin increased the number of white blood cells. Marin et al. (2002) found an increase in y-globulin concentration in serum and a non-significant reduction in antibody levels in piglets fed 280 ppb aflatoxin and immunized with Mycoplasma agalacticae. Other investigators have found significant changes in y-globulin levels in swine fed high levels of aflatoxin (Annau et al., 1964; Cy-sewki et al., 1978; Miller et al., 1981) and in other species [discussed in Marin et al. (2002)]. Marin et al. (2002) also reported a significant decrease in mRNA expression of interleukin-1p (IL-10) and a slight non-significant decrease in mRNA of tumor necrosis factor-a (TNF-a). There was an increase in cytokine mRNA expression of the antiinflammatory cytokine interleukin-10 (IL-10), which might account for down regulation of the inflammatory cytokines IL-10 and TNF-a. The authors found no effect on the total number of leukocytes or on expression of either Th1 (IL-2) or Th2 (interleukin 4; IL-4) cytokines.
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