Immunomodulation by aflatoxin in humans exposed to dietary aflatoxin

Only two studies (Turner et al., 2003; Jiang et al., 2005) are available on the association between aflatoxin levels and immune status/function in humans chronically exposed to aflatox-ins in their diets. In these studies, aflatoxin Bralbumin adducts in blood was used as a bio-marker of aflatoxin exposure. The aflatoxin Bi assay is a sensitive method that measures aflatoxin that is covalently bound to albumin in peripheral blood (Nyathi et al., 1987) and reflects aflatoxin exposure in the previous 2 to 3 months. Turner et al. (2003) investigated cell mediated and antibody responses in Gambian children exposed to aflatoxin in their diets. They found markedly reduced secretory immunoglobulin A (sIgA) levels in the saliva of children with detectable aflatoxin B1-albumin adducts compared to those without. Cell-mediated immunity was evaluated with the cell-mediated immunity multitest (Marcel Merieux, Lyon, France) in which test antigens (tetanus, diphtheria, streptococcus, tuberculin, candida, tricophy-ton, proteus, and glycerin as a control) were applied to the skin and a response (induration of 2 mm or greater) read 48 hours after application. The investigators found no association between cell-mediated immune responses to the test antigens and aflatoxin B1-albumin adducts.

Jiang et al. (2005) used three-color flow cytometric techniques to investigate the cellular immune status in relation to aflatoxin levels of adult Ghanaians chronically exposed to aflatoxin in their diets. They measured aflatoxin B1-albumin adduct levels in participants and examined the potential role of aflatoxin in modifying the distribution and function of peripheral blood leukocyte subsets (CD3, CD4, CD4CD69, CD8, CD 19, CD19CD69, CD 14, CD56), lymphocyte proliferation of CD4+ T cells; and cytokine production by CD4+ and CD8+ T cells and CD3-CD56+ (NK) cells. The proportion of, and cytokine secretion by, the different cellular subsets indicate the strength of specific immune responses carried out by each subset of cells and the overall strength of the immune response. All participants in the study had detectable aflatoxin B1-albumin adduct levels (mean ± standard deviation = 0.99 ± 0.40 pmol/mg albumin; range = 0.33-2.27 and median = 0.90 pmol/mg albumin); on average, participants consumed at least 10 ^g of aflatoxin Bi daily in their diet. For analysis, the median aflatoxin B1-albumin adduct level was used to separate participants into high aflatoxin B1 or low aflatoxin B1 groups.

The participants with high aflatoxin B1 levels had non-significantly lower percentages of CD3+, CD8+, CD19+, CD14+, mature cytotoxic T cells, CD3-CD56+CD16- NK cells, perforin+ NK cells and monocyte phagocytoses than those with low aflatoxin B1 levels. Although there were no significant differences in the percentages of CD3+ and CD19+ cells between the low and high aflatoxin B1 groups, participants in the low aflatoxin B1 group had significantly higher percentages of activated T and B cells (CD3+CD69+ and CD19+CD69+) than did participants in the high aflatoxin B1 group. This report is the first of the association of aflatoxin B1 albumin adducts with decreased level of activated T and B cells and is a significant finding since activation of T and B cells results in proliferation and amplification of immune responses that allow the immune system to fight infectious agents and produce effective antibody responses to vaccines. The decreased number of activated T and B cells in those with high aflatoxin B1 levels indicate that aflatoxin may decrease expression of the CD69 activation molecule and that the cells may not mount appropriate and effective immune responses. These results also indicate that aflatoxin may change the percentages of subsets of T lymphocytes and affect CMI without affecting the overall T-cell population.

No differences in the frequency of interferon-gamma (IFN-y) or IL-4 expressing CD4+ or CD8+ T cells were found in the study by Jiang et al. (2005), similar to findings from studies conducted in piglets, rats and mice exposed to aflatoxin in their diets (Dugyala and Sharma, 1996; Watzl et al., 1999; Marin et al., 2002). The investigators also found no difference in proliferation of CD4+ T cells in relation to aflatoxin B1 levels. Studies in animals have shown that aflatoxin decreased CD4+ T cell proliferation (Raisuddin et al., 1993; van Heugten et al., 1994; Harvey et al., 1995) but an in vitro study using human cells found that aflatoxin up to a concentration of 10 ^g/ml had no effect on CD4+ T cell proliferation (Meky et al., 2001). The concentration of aflatoxin used in the in vitro experiments with human cells or present in humans in the study by Jiang et al. (2005) may not be high enough to affect CD4+ T cell proliferation. The T cell responses observed in the animal studies could be induced by the type and amount of exposure to aflatoxin, the dosing schedule and the animal species used.

It is important to investigate cytokine expression by effector CD8+ T cells since these cells function in killing infected cells and preventing the spread of infectious pathogens in the body. Perforin and granzymes are two of the cytokines used by effector-type CD8+ cells in cell killing. Jiang et al. (2005) found significantly lower levels of perforin and granzyme-A expressing CD8+cells in participants with high aflatoxin B1 levels suggesting that CD8+T cell function (and consequently the cellular response to infectious agents) is impaired in those with high aflatoxin B1 levels. No other studies have been reported in the literature on cytokine expression by effector CD8+ cells in relation to aflatoxin or any other mycotoxin. Thus, this area warrants further investigation.

The study by Jiang et al. (2005) also found a non-significantly lower percentage of CD56bright NK cells (cells that express high levels of CD56 and CD16 negative) in people with high aflatoxin B1 levels. Since NK cells lyse target cells and provide early regulatory cytokines such as IFN-y to macrophages and other antigen presenting cells (Cooper et al.,

2001), further research needs to be conducted to determine whether aflatoxin affects NK cell subsets, and thereby, interferes with efficient control of infected and transformed cells.

Macrophages represent the first line of defense against infectious agents and through secretion of cytokines regulate T-lymphocyte activity. Jiang et al. (2005) found no difference in the percentage of monocytes in peripheral blood of study participants in relation to aflatoxin B1 levels. This finding is similar to that of Marin et al. (2002) who found no effect of aflatoxin on the number of monocytes in peripheral blood of weanling piglets. Jiang et al. (2005) also found a non-significant decrease in macrophage phagocytic rate in those with high aflatoxin B1 levels. Several animal studies have shown that aflatoxins suppressed macrophage phagocytic activity (Mohapatra and Roberts, 1985; Sorenson et al., 1986; Cu-samano et al., 1990; Neldon-Ortiz, 1991; Neldon-Ortiz et al., 1992; Moon et al., 1999). An in vitro study of the effect of aflatoxin on human monocytes showed impairment in phagocytic and microbiocidal activity by aflatoxin Bi at doses as low as 0.1 pg/ml (Cusamano et al., 1996). In contrast, a study by Silviotti et al. (1997) with monocyte-derived macrophages from sows fed aflatoxin in their diets found that the phagocytic ability of the macrophages was not compromised although the cells failed to efficiently produce superoxide anions after oxidative burst stimulation. Data from Moon et al. (1999) on murine macrophages suggest that aflatoxin B1 can inhibit the production of nitrous oxide, superoxide anion, hydrogen peroxide, TNF-a, IL-1 and IL-6, all of which are associated with macrophage dysfunction. Dugyala and Sharma (1996) also reported suppression of IL-1 and IL-6 secretion by murine macrophages treated with aflatoxin B1 and Kurtz and Czuprynski (1992) reported suppression of IL-1 by aflatoxin in bovine mononuclear phagocytes.

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