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Mycotoxin Detoxifier: QUIMITŌX®
Mycotoxin-induced immunotoxicity refers to the adverse effects that these toxins can exert on the immune system, both at the local and systemic levels. These compounds are known to suppress or stimulate the immune response; however, their specific mechanisms of action are not yet fully elucidated.
Mycotoxins can suppress or stimulate immune function depending on several factors, including toxin dose, duration of exposure, route of administration, and the presence or absence of immunological stimulants (Sun et al., 2022). In general, exposure to mycotoxins at low doses may induce an inflammatory response, whereas higher doses tend to trigger immunosuppression (Abbès et al., 2006). With respect to exposure duration, prolonged exposure to certain mycotoxins has been associated with immunosuppressive effects, in contrast to shorter exposure periods. Furthermore, the presence or absence of immunological stimulants (such as lipopolysaccharides, phytohemagglutinin, concanavalin A, among others) can influence the interaction between mycotoxins and the immune system. Under these conditions, mycotoxins may act as immunosuppressive agents when stimulatory signals are present, and as immunostimulatory agents when such signals are absent (Sun et al., 2022).
Other important determinants of mycotoxin-induced immunotoxicity include species, sex, and age. Susceptibility to mycotoxins varies considerably among species. Pigs are generally regarded as the most sensitive animals, followed by humans, poultry, rodents, and marine organisms, whereas ruminants are considered the least susceptible. Sex-related differences have also been reported, with females showing greater sensitivity to certain mycotoxins. Age represents another relevant factor, since young animals typically exhibit higher susceptibility than adults. All these variables are closely linked to individual host characteristics; therefore, mycotoxin-induced immunotoxicity depends on a combination of interacting factors (Sun et al., 2022).
Mycotoxin-induced immunotoxicity involves several mechanisms, including oxidative stress, apoptosis, autophagy of immune cells (macrophages, lymphocytes, neutrophils, and T cells), immune signalling pathways, and other cellular communication routes (Sun et al., 2022). The main mechanisms of immunosuppression associated with major mycotoxins are outlined below.
Aflatoxin B1 (AFB1) exerts its immunosuppressive effects through mechanisms involving oxidative stress, apoptosis, and interference with immune-related signalling pathways. AFB1 induces oxidative stress by increasing the production of reactive oxygen species (ROS) and promoting the oxidation of biomolecules (Mary et al., 2012). Oxidative stress is closely associated with apoptosis, or programmed cell death. Apoptosis involves a complex molecular machinery, and AFB1 has been shown to stimulate ROS-dependent caspase activation, thereby mediating cellular apoptosis (Liu et al., 2020). At the level of cell signalling, AFB1 can inhibit lymphocytic proliferation and reduce IL-2 production. In addition, it promotes IL-10 secretion, which favours the phenotypic shift of alveolar macrophages from the M1 (immunostimulatory) to the M2 (immunosuppressive) profile. Although the immunosuppressive mechanisms of AFB1 are relatively well characterised, additional pathways of immune suppression remain to be elucidated (Sun et al., 2022).
Deoxynivalenol (DON) is an immunosuppressive mycotoxin that exerts its effects through multiple mechanisms. It has been shown to impair immune function via the ROS-mediated mitochondrial pathway and can induce apoptosis in T lymphocytes, thereby compromising their activity. DON also activates autophagy-related processes and may directly inhibit inflammatory mediators, further disrupting the immune response (Sun et al., 2022).
The immunosuppressive effects of other mycotoxins are of comparable relevance. For instance, ochratoxin A (OTA) is closely associated with autophagy, as it inhibits regulatory pathways involved in this cellular process. The mechanism of T-2 toxin is similar to that of DON. T-2 toxin can induce apoptosis in splenic cells and reduce the populations of CD4+ and CD8+ T lymphocytes. Additionally, T-2 toxin alters cytokine levels (IL-6, IL-10, and IL-1β) by inducing endoplasmic reticulum stress, leading to reduced production of inflammatory mediators such as IL-1β, tumor necrosis factor-α (TNF-α), and nitric oxide (NO) (Sun et al., 2022). The immunotoxic mechanism of fumonisin B1 (FB1) is primarily associated with oxidative stress. Finally, the mechanisms of action of zearalenone (ZEN) remain poorly characterised; nevertheless, this mycotoxin is thought to stimulate apoptotic pathways in T lymphocytes (Marin et al., 2011).
In animal production, the immunosuppressive mechanisms described above may weaken the host immune response to pathogens, thereby increasing susceptibility to disease. In many cases, these effects are not manifested as overt clinical signs but rather as reduced production performance.
Immunostimulation induced by mycotoxins involves the activation of immune signalling and cellular communication pathways. AFB1, OTA, DON, and T-2 toxin are among the principal mycotoxins reported to exert immunostimulatory effects (Sun et al., 2022).
AFB1 promotes inflammatory responses and liver damage through activation of the NF-κB signalling pathway. This toxin can increase the production of pro-inflammatory cytokines, including IL-6 and TNF-α, mediated by NF-κB activation. Additionally, AFB1-induced oxidative stress contributes to an exacerbated inflammatory response (Sun et al., 2022).
Similarly, OTA increases the production of pro-inflammatory cytokines through activation of the NF-κB signalling pathway (Hou et al., 2018). In addition, OTA induces intestinal inflammation and activates T-cell responses.
DON, in turn, exerts more pronounced effects on immune cells than on other cell types. Its immunological actions include activation of T-cell responses (associated with increased intracellular calcium), upregulation of pro-inflammatory genes (including IL-6, IL-1β, and TNF-α), and enhanced expression of cyclooxygenase-2 (COX-2) and other inflammatory pathways (Sun et al., 2022).
Finally, the immunostimulatory effects of T-2 toxin involve activation of pathways associated with apoptosis and amplification of inflammatory signalling. As observed with several other mycotoxins, T-2 may induce inflammation and cellular damage through oxidative stress, leading to increased production of pro-inflammatory cytokines and intensification of the inflammatory process (Yin et al., 2020).
Having outlined the immunostimulatory effects of mycotoxins, it is important to emphasise that this is a highly complex process involving numerous inflammatory mediators and molecular signalling pathways that regulate immune-cell activation and proliferation. Nevertheless, multiple factors influence this process, leading to variability in immune responses among animals.
Below, the effects of mycotoxins on the animal immune system are described.
In pigs, susceptibility to mycotoxins is reflected in pathological findings and reduced productive performance. The effects of mycotoxins on the porcine immune system vary depending on the specific toxin and the conditions at the time of exposure.
In pigs, aflatoxins have been shown to dysregulate dendritic cell-mediated antigen presentation at low concentrations. Moreover, these toxins may impair the synthesis of pro-inflammatory cytokines.
Developing piglets are particularly susceptible to AFB1, as this mycotoxin reduces the overall lymphoproliferative response. In addition, studies indicate that when sows are exposed to these mycotoxins, macrophages and neutrophils in piglets may also exhibit reduced functional capacity (Pierron et al., 2016).
Trichothecenes, such as DON and T-2 toxin, may regulate, increase or decrease immune function in pigs (Pierron et al., 2016). The literature indicates that DON suppresses the immune system at high concentrations, whereas it may stimulate immune responses at lower concentrations (Holanda et al., 2020). Consistent with this, a study in pigs demonstrated that chronic dietary exposure to DON increased the expression of inflammatory cytokines and elevated IgA and IgG antibody levels (Pestka et al., 2004). T-2 toxin in pigs may induce leukopenia and a reduction in the cellularity of lymphoid organs. Moreover, prolonged exposure to low doses of T-2 toxin may affect memory T lymphocytes, exerting adverse effects on B-cell-mediated humoral immunity and leading to an impaired secondary immune response (Adhikari et al., 2017).
Other mycotoxins with significant impact on the swine immune system include fumonisins and, to a lesser extent, OTA. In pigs, FB1 alters the balance between Th1 and Th2 cytokines, thereby affecting the humoral immune response. Exposure to FB1 also significantly reduces cell viability through the induction of apoptosis (Zhu et al., 2022). Several studies indicate that FB1 interferes with the maturation of antigen-presenting cells by reducing intestinal IL-12 p40 levels and decreasing major histocompatibility complex class II (MHC II) expression, which in turn limits T-cell activation (Pierron et al., 2016). OTA in pigs primarily affects cytokine expression, with less impact on the concentrations of total or specific immunoglobulins (Pierron et al., 2016).
ZEN is more widely recognised for its reproductive toxicity than for its effects on immunity, and evidence regarding the latter remains limited. Nevertheless, one study demonstrated that the swine immune response is compromised following exposure to ZEN and its derivatives, reporting reductions in immune cell viability, antibody production, and cytokine synthesis (Marin et al., 2011).
As discussed above, the swine immune response to mycotoxin exposure varies depending on the specific mycotoxin involved, the dose, and other contributing factors. Consequently, the observed effects may differ, ranging from immunostimulatory to immunosuppressive outcomes. Despite this variability, certain components appear to be consistently affected, including immune cells, cellular signalling pathways, and inflammatory mediators (Cimbalo et al., 2020).
Although aflatoxicosis has been investigated for more than 50 years, the mechanisms underlying its immunosuppressive effects have not yet been fully elucidated. During the initial stages of exposure, birds may exhibit a marked increase in the humoral immune response. However, humoral immunity tends to decrease with increasing duration of exposure.
DON is characterised by its ability to inhibit the biosynthesis of proteins, RNA, and DNA, in addition to its effects on cellular membranes. Tissues with high protein turnover are particularly susceptible to DON exposure, including immune tissues. Information regarding DON-induced immunotoxicity in poultry remains limited. In chickens, DON, together with other trichothecenes, may either stimulate or impair humoral immunity (Awad et al., 2013). Assessment of DON effects on humoral immunity often relies on measuring serum antibody titres against common viral vaccines. In this context, DON has been shown to suppress post-vaccination responses to viruses such as infectious bronchitis virus (IBV) and Newcastle disease virus (NDV) (Yunus et al., 2012). Recent studies indicate that DON may reduce IgA levels and spleen weight. However, other investigations in chickens have reported increased antibody responses following DON exposure, suggesting that immune effects vary depending on mycotoxin concentration and other influencing factors. Additionally, DON exposure has been associated with reduced white blood cell and lymphocyte counts in laying hens (Awad et al., 2013).
In poultry, T-2 toxin reduces immune response by decreasing the number of lymphoid cells in the bone marrow, thymus, and spleen. Such reductions may compromise immune competence and may increase susceptibility to infectious agents. As lymphoid cell populations decline, several immune organs undergo size reduction, including the bursa of Fabricius (Filazi et al., 2017).
Other mycotoxins also affect the avian immune system, although typically to a lesser extent. For instance, OTA reduces the size of immune organs such as the thymus and the bursa of Fabricius. FB1, in contrast, alters macrophage morphology and function, thereby increasing susceptibility to bacterial infections and contributing to impaired antibody responses in chickens.
In ruminants, mycotoxins interfere with immune function through multiple mechanisms. They may impair cell-mediated immunity, for example by reducing phagocytic activity, as well as compromise humoral immunity. Such immune dysfunction increases disease susceptibility, particularly during physiologically stressful periods such as calving or weaning. Notably, transition cows and calves are more vulnerable to the immunosuppressive effects of mycotoxins than mature cows (Gott et al., 2021).
Owing to the rumen’s detoxifying capacity, many mycotoxins do not exert the same effects observed in monogastric animals. However, aflatoxins are partially metabolised to aflatoxicol.
This compound exerts immunotoxic effects through several mechanisms, including inhibition of lymphocyte blastogenesis and suppression of lymphocyte proliferation (primarily mediated by AFB1).
Importantly, chronic exposure to mycotoxins in ruminants has been shown to interfere with vaccine-induced immunity.
Among companion animals, both dogs and cats are susceptible to the immunosuppressive effects of mycotoxins. Data on pet food contamination remain limited, and the impact of mycotoxins in these species is still an area requiring further investigation. Nevertheless, prolonged ingestion of contaminated diets is known to negatively affect the health of dogs and cats, with documented impairment of immune function (Grandi et al., 2019).
In dogs, aflatoxins are the most extensively studied mycotoxins, as these animals, similar to pigs, are highly susceptible to their effects (Wouters et al., 2013). Another relevant mycotoxin is OTA, which has been associated with reduced resistance to infections in companion animals exposed to contaminated diets (Koerich et al., 2012).
Conclusion
The immune system is a complex network of signals and specialized cells responsible for protecting the organism against infectious threats, through either rapid, non-specific responses (innate immunity) or long-term, highly specific responses (adaptive immunity). Owing to the wide variety of components involved, immune responses may differ considerably among individuals, making this system inherently complex to study. Mycotoxins, as immunotoxic agents, can disrupt immune function and may exert either immunosuppressive or immunostimulatory effects. Consequently, exposure to these toxins can seriously compromise animal health, and, therefore, negatively impact productive performance.
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