This page addresses how environmental factors can affect the immune system, focusing on autoimmunity. In an autoimmune response, the immune system attacks the body's own cells. In type 1 diabetes, it is the insulin-producing beta cells that are attacked and destroyed by an autoimmune attack.
People with type 1 (and some with type 2! See the types of diabetes page) have certain autoantibodies that may appear years before the disease develops, even in utero. These autoantibodies are used as markers of the disease, but do not necessarily lead to or cause beta cell destruction. Some people, in fact, have these autoantibodies but never develop diabetes. The autoantibodies associated with type 1 diabetes include:
Antibodies to insulin are generally the first to appear (Narendran et al. 2005). There are difficulties testing for islet cell antibodies, generally present at diagnosis in early-onset type 1 diabetes, but not often present in people with later-onset type 1 diabetes. These antibodies come and go over time. GAD antibodies, meanwhile, are present in everyone, with or without diabetes, and a "positive" test means they are higher or lower, depending on an arbitrary cutoff point that is not consistent among studies (Gale 2005a). Interestingly, a surprisingly high percentage (16%) of children newly diagnosed with type 1 diabetes test negative for the antibodies associated with the disease. The younger the diagnosis, the higher the chance of autoantibodies being positive. Those who tested negative for antibodies had a higher body mass index, and may have a non-immune form of diabetes (perhaps different from either type 1 or type 2) (Wang et al. 2010).
Atkinson and Gale (2003) point out that the autoimmune processes that leads to type 1 diabetes can begin very early in life, and that to explore causation, we should consider the developing immune system, genetics, and the timing, duration, and combination of various environmental exposures.
The immune system A number of environmental factors can affect the body's immune system. Some are thought to be supportive to the development and proper functioning of the immune system, such as vitamin D, breastmilk, and omega-3 fatty acids. These factors have sometimes been shown to be protective against type 1 diabetes development as well, perhaps due to their immune system effects.
Other factors can have detrimental effects on the immune system. Viruses, for example, fall into this category (although they may sometimes show protective effects as well). A number of contaminants can have toxic effects on the immune system. Some of these contaminants may influence the progression of autoimmune disease. The ability for contaminant exposures to affect autoimmunity appears to depend on genetic susceptibility, the duration of exposure, and the timing of the exposure (Inadera 2006), which appears to be the case for viruses as well (van der Werf et al. 2007).
There is some evidence that environmental exposures to adults may result in other autoimmune diseases (besides type 1 diabetes). Studies of occupational exposures have associated various autoimmune diseases to silica, solvents, pesticides, and ultraviolet radiation, although data are limited (Cooper et al. 2002). Developmental exposuresDevelopmental immunotoxicology is a subfield of immunotoxicology that looks at the effects of exposure to various environmental factors (including toxins, drugs, viruses, etc.) on the developing immune system (beginning in the womb through childhood). These effects may occur during childhood or in adulthood, and include autoimmunity, immunosuppression, allergic responses, and inflammation (Dietert 2009). A disturbance in the early development of the immune system may allow an autoimmune reaction that would have been suppressed to flourish instead, and contribute to the accelerated progression of type 1 diabetes (Gale 2005b). In a fetus, the immune system develops in particular stages during particular times. An environmental exposure during one of those critical times can disrupt the development of the immune system, and lead to lifelong effects. Dietert and Piepenbrink (2006) point out a number of important factors to consider with regard to exposures during gestation or in childhood:
The timing makes the poisonFor centuries, toxicology has been based on the idea that "the dose makes the poison." In other words, something might not be toxic at low levels of exposure even if it is toxic at high levels. But for exposures during early development, another paradigm has emerged, that the "the timing makes the poison." A number of animal studies show that events that occur during immune system development may be responsible for disease later in life. Some of these events are seen with environmental contaminants at levels similar to those humans are exposed to in the environment (Grandjean et al. 2008).
Timing may be critical for the effects of immunosuppressive substances. Immunosuppression is often considered to be the opposite of autoimmunity, which involves a hyperactive immune system. Yet both might be the result of a disruption in the balance of the immune system. Some environmental exposures, in fact, have been associated with both increased autoimmunity and decreased immune competence (Hertz-Picciotto et al. 2008). For example, exposure to mercury was found to first lead to immunosuppression, and then to autoimmunity in mice (Havarinasab and Hultman 2005).
One possible example of differing effects of exposures that depend on timing can be found with dioxin. When mice genetically prone to autoimmune disease were treated with dioxin prenatally, during immune system development, they had immune dysregulation. This dysregulation included autoantibody production and suggested an increased risk for later autoimmune disease (Mustafa et al. 2008). Yet a different study found that chronic exposure to dioxin prevents diabetes in non-obese diabetic (NOD) mice, an animal used to model autoimmune diabetes in the laboratory (Kerkvliet et al. 2009). While these differing results may result from the strain of animal (e.g., see Roep and Atkinson 2004 and the of mice and men page for more on NOD mice), it may also be that dioxin shows differing effects based on the timing of the exposure. Perhaps prenatal exposure to dioxin could increase the risk of autoimmunity, while later exposure could suppress it.
Regulatory T cells and the thymusHow might early exposure to environmental factors lead to autoimmune diseases such as type 1 diabetes later in life? There are a number of possible mechanisms, many of which are too complicated to describe here (e.g., see Dietert and Piepenbrink 2006). One possible mechanism might involve "regulatory T cells," or T regs. T regs are one type of immune system cell that are involved in destroying autoreactive cells (the cells that are attacking the beta cells, for example). During gestation, T regs are produced in the thymus, and learn how to function. Disruption of the biological processes that lead to the production and activation of T regs could be a significant factor in later autoimmune disease. The thymus is critical for the development of the immune system in utero, and plays a major role through childhood, although it plays a more minor role later in life (Dietert and Piepenbrink 2006). In fact, removing the thymus of newborn mice can lead to autoimmune disease (Sakaguchi 2004). A number of environmental contaminants can alter the fetal thymus, by shrinking it or by affecting the development of thymocytes. Affecting the maturation of thymocytes may have effects later in life, and possibly lead to autoimmunity (Holladay 1999). The article Peacekeepers of the Immune System, published in Scientific American (Fehervari and Sakaguchi 2006) is a good summary of T regs and their possible importance in autoimmune diseases, including type 1 diabetes. Researchers are beginning to study the potential role of T regs in the development of type 1 diabetes. One small study, for example, has found that some children with type 1 diabetes have lower percentages of T reg cells as compared to children without diabetes (Luczynski et al. 2009). Treatments that involve inducing T regs are now being tested for use in people with type 1 diabetes (Orban et al. 2009). Further research into how contaminants can affect T regs and immune system development and their potential relation to type 1 diabetes are clearly in order.
Developmental immunotoxicant contaminantsA number of environmental contaminants can be toxic to the developing immune system, including various persistent organic pollutants such as chlordane, PCBs and dioxin; heavy metals such as mercury and cadmium, benzo[a]pyrene, diazinon, bisphenol A, trichloroethylene, polycyclic aromatic hydrocarbons (PAHs), diesel exhaust, and some pesticides (e.g., atrazine) (Holladay 1999; Dietert and Dietert 2007). Some contaminants have been shown to increase the risk of autoimmunity in particular, including mercury, lead, gold, trichloroethylene, hexachlorobenzene (HCB), and dioxin (TCDD) (Dietert et al. 2010), as well as bisphenol A, and phthalates. Yet no contaminants have yet been shown to induce the antibodies associated with type 1 diabetes (indicating an absence of studies, not necessarily the absence of effects).
The immune system interacts extensively with the nervous system, including during the prenatal and early postnatal developmental periods (Hertz-Picciotto et al. 2008). Some research suggests that the events that control the development of type 1 diabetes involve neurological factors, not only the immune system (Tsui et al. 2007). Of the more than 80,000 known chemicals, Grandjean and Landrigan (2006) list over 200 chemicals that are known to be neurotoxic in humans, and identified over 1000 chemicals known to be neurotoxic in experiments. Whether these could be involved in type 1 diabetes development is not known.
Environmental factors in combinationWhile most studies focus on individual contaminants, humans are exposed to more than one contaminant at a time. Mixtures of chemicals, similar to those encountered in the environment, can have a greater effect on the immune system of animals than individual chemicals alone. One study looked at the effects of nine pesticides used on cornfields in the U.S. Midwest on amphibians. While some of the pesticides individually had effects on growth and development of the amphibians, the mixture of pesticides had much greater effects. The pesticide mixture also damaged the animals' thymus, resulting in immunosuppression and contraction of disease. Increased disease rates were associated with an increased frequency of animals with damage to the thymus (Hayes et al. 2006).Contaminants may also interact with other environmental factors, such as viruses, to affect the immune system (see the viruses page).
The bottom lineThe ability of environmental factors to induce autoimmunity is critically dependent on timing. Exposures in utero or early childhood are likely to be most important in type 1 diabetes development. It is possible that environmental contaminant exposures to the developing fetus or in early childhood may play a role in immune system development, and could potentially contribute to the development of type 1 diabetes later in life. |