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Autoimmunity

Autoimmunity
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This page addresses how environmental factors can affect the immune system, focusing on autoimmunity. Studies of twins show that environmental factors are a strong determinant of the immune system throughout life (Brodin et al. 2015).

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.

Type 1 Diabetes Autoantibodies

People with type 1 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:
  • islet cell antigen (ICA) antibodies (present in 90% of people with type 1 at diagnosis);
  • antibodies to insulin and pro-insulin (present in 23 and 34% of patients at diagnosis, respectively);
  • glutamic acid decarboxylase (GAD) antibodies (present in 73% of patients at diagnosis);
  • protein tyrosine phosphatase (IA-2) antibodies (present in 75% of patients at diagnosis); and
  • Zinc transporter 8 (ZnT8A) antibodies (more newly discovered).
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). 

According to a large, international, longitudinal study, children who develop type 1 diabetes generally test positive to two or more autoantibodies. Higher IAA and IA-2 levels, as opposed to GAD antibody levels, appear to especially increase risk of the disease (Steck et al. 2015). The same study shows that autoantibodies at 3-6 months were rare, but did occur. Of the 6.5% of children in the study who did develop autoantibodies by age 6, 44% developed IAA only, 38% developed GAD only, 14% developed both IAA and GAD, and smaller percentages had others. IAA peaked in the first year of life and then declined, and GAD peaked in the second year of life and then remained stable. Genetic background also influences the development of these antibodies (Krischer et al. 2015). A German study showed somewhat similar numbers, and that over 50% of the children who developed multiple antibodies developed type 1 diabetes within 10 years (Giannopoulou et al. 2015). A Finnish study found that IAA antibodies generally appear first, but sometime disappear by the time of diagnosis, whereas IA-2 antibodies are most prevalent at diagnosis (Ilonen et al. 2017). A Colorado study showed that children who had lower IAA levels and older ages had a slower progression to type 1 diabetes (Steck et al. 2016). These researchers also found that later-onset autoimmunity is more common in African-American or Hispanic children than in Caucasians (Frohnert et al. 2017). Ethnic differences are also seen in populations with type 1 diabetes from Asia vs Europe; one study found higher GAD antibody frequencies in Europeans, and higher IA antibody frequencies in Asians (Ong et al. 2017). Islet antibodies are linked to type 1 diabetes risk in everyone-- not just those genetically susceptible (Ling et al. 2017).

The ZnT8A antibodies are associated with a more aggressive disease process (Juusola et al. 2015). In contrast, the loss of insulin (IAA) antibodies over time is associated with a delayed development of type 1 diabetes (Endesfelder et al. 2016). In general though, once someone has developed multiple autoantibodies, the risk of type 1 remains high even if individual antibodies revert (Vehik et al. 2016). Another study found that people who progressed most rapidly to type 1 diabetes had higher antibody levels, more antibodies, and were younger in age -- or in early puberty (Pöllänen et al. 2017). (see the puberty page for more on type 1 diabetes and puberty). Higher antibody levels have been associated with abnormal glucose levels even before the diagnosis of diabetes (Sanda et al. 2017). In fact, some authors propose calling the time between antibody positivity and type 1 diagnosis as "autoimmune beta cell disorder (ABCD)" (Bonifacio et al. 2017).

Depending on the type 1 antibody, the risk of diagnosis can vary. For example, the risk of developing type 1 was higher in the six months after testing positive for IAA and GAD antibodies (as compared to 3 years after), while for I2A2, the risk did not change over time (Köhler et al. 2017). Over a long period of time, 20 years, the risk of testing positive to single to multiple antibodies increases over time, however (Gorus et al. 2017).

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. 2011).

Meanwhile, a group of adults without diabetes or autoimmune disease found a percentage (21%) of people tested positive for GAD antibodies. GAD levels were associated with lower beta cell secretion, but not with insulin resistance (Mendivil et al. 2017).

The levels and types of antibodies varies by population; a study of people with diabetes from Ethiopia, for example, did not find any IA-2A antibodies, but did find the others (Siraj et al. 2016).

Other markers are also being investigated to see if they can help predict the development of type 1 diabetes and/or autoimmunity. For example, electrochemiluminescence assays can help predict the risk of both. Those who test positive on this assay are at increased risk of developing multiple autoantibodies, and progressing to type 1 diabetes (Sosenko et al. 2017). Another new biomarker is "IA-2ec autoantibodies," which are "autoantibodies directed to the extracellular domain of the neuroendocrine autoantigen IA-2." (I do not know what any of these markers really mean...). Anyhow, they have been detected in people with type 1 diabetes (and even a small percentage of people with type 2) (Acevedo-Calado et al. 2017). Other researchers have found a type of T cell that shows up before autoantibodies as well (Heninger et al. 2017). Levels of unmethylated DNA, an epigenetic marker, are another potential marker of beta cell death (Zhang et al. 2017). And, other markers (intermediate monocytes) are also linked to the level of residual beta cell function after type 1 diagnosis (Ren et al. 2017). Another biomarker, 12-hydroxyeicosatetraenoic acid (12-HETE), has been found in people newly diagnosed with type 1, but not in people with established type 1 (Hennessy et al. 2017). Antibodies to "post-translationally modified insulin" is another one (Strollo et al. 2017). Now that we can predict it so well, we just need to figure out how to prevent it! (See preventT1D.org for more on that!)

People with type 1 diabetes are at an increased risk of other autoimmune diseases, thyroid disease, celiac disease, autoimmune gastritis, and Addison's disease (Krzewska and Ben-Skowronek, 2016). The risk of Addison's disease is about 10 times higher in people with type 1 diabetes (at least in some populations), and it develops at a younger age (Chantzichristos et al. 2017). People with type 1 diabetes may have a similar rate of allergies as people in the general population (Jasser-Nitsche et al. 2017), although others have found a decreased rate, and attribute that to a different type of immune response (Th1 vs Th2) (Tzeng et al. 2007). 
 
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.

Watch scientists describe the autoimmune attack in type 1 diabetes



Attack of the Beta Cells, Dr. Matthias von Herrath, La Jolla Institute for Allergy and Immunology.

The Immunologist's View, Dr. Jeffrey Bluestone, UCSF.

The Immune System

The immune system protects the body against pathogens. To accomplish this, immune cells must be able to recognize and fight these pathogens, but also be able to identify which molecules are pathogens, and which are harmless. The immune system is a complex system that controls the balance between defense and tolerance. If the system is altered, the result can be chronic inflammation, including autoimmunity (Lehmann 2017).

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 chemicals can have toxic effects on the immune system. Some of these schemicals may influence the progression of autoimmune disease. The ability for chemical 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).

Immunotoxic Chemicals

Environmental pollutants can alter the immune system by affecting the function of immune cells in such a way that they might react against the body's own tissues. These are a known effect of pesticides, heavy metals, wood preservatives, and volatile organic compounds (Lehmann 2017). In fact, many types of chemicals can enhance the immune system, depending on the levels, timing, and route of exposure. New research is focusing on the impacts of chemical exposure on the immune system during development in early life (Kreitinger et al. 2016).

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).

Scientists are now developing screening tools to help identify which environmental chemicals are toxic to the immune system. (Chemicals can affect the immune system in other ways, aside from autoimmunity, for example by suppressing the immune system) (Boverhof et al. 2014).

NIEHS Report on Autoimmunity

The National Institute of Environmental Health Sciences held a workshop to evaluate scientific evidence of environmental factors in autoimmune disease. Their report is available online: Epidemiology of environmental exposures and human autoimmune diseases: findings from a National Institute of Environmental Health Sciences Expert Panel Workshop (Miller et al. 2012).

The NIEHS found that: "There has been virtually no epidemiologic research on risks associated with relatively widespread synthetic chemical exposures, such as plasticizers (e.g., phthalates and bisphenol A). Some of these chemicals can act as endocrine or immune disruptors, and increased risks of some immune-mediated diseases, including asthma and eczema, in relation to exposure levels, have been reported in children. More research is needed to determine the role of plasticizers and other industrial chemicals in consumer products in the development of autoimmune disease."

My family

Because his mother and younger brother both have type 1 diabetes, my teenager is screened for autoantibodies through TrialNet. These antibodies are a sign of potential diabetes development. So far he has tested negative, thankfully. 

The NIEHS states that: "The growing number of genome-wide association studies and the largely incomplete concordance for autoimmune diseases in monozygotic twins support the role of the environment (including infectious agents and chemicals) in the breakdown of tolerance leading to autoimmunity via numerous mechanisms." These potential mechanisms are described in the report, Mechanisms of environmental influence on human autoimmunity: a National Institute of Environmental Health Sciences expert panel workshop (Selmi et al. 2012).

Exposures During Development

Developmental 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 doses required to produce an effect during development of the immune system are significantly lower than those required to affect an adult.
  • The effects of the exposures depend on timing of the dose, if given during a critical period of immune system development.
  • The effects of exposures on a fetus, or during early childhood, can be different from those seen in adults. The perinatal period (the months before and after the time of birth), is a sensitive time for the developing immune system. Adult exposure, therefore, does not necessarily predict the effects of exposure to a fetus, during the perinatal period, or in early childhood.
  • The effects of early life exposures often last long after the exposure, sometimes having lifelong effects. And, early exposures may be "latent" and invisible, until stressed later in life (for example, by a virus), causing abnormal immune responses.
  • Response can differ by gender; there are many cases where males and females have differing immune responses to early environmental exposures.
Factsheet on autoimmune diseases by the National Institute of Environmental Health Sciences (NIEHS)

The Timing Makes the Poison

For 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 chemicals 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 Thymus

How 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 chemicals 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 (Luczyński et al. 2009). Treatments that involve inducing T regs are now being tested for use in people with type 1 diabetes (Orban et al. 2010). Further research into how chemicals can affect T regs and immune system development and their potential relation to type 1 diabetes are clearly in order.

Developmental Immunotoxicants

A number of environmental chemicals 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 chemicals 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 PCBs, bisphenol A, and phthalates.

The Bottom Line

The 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 chemical 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.

Type 1 diabetes does involve a genetic risk, but also generally requires an environmental trigger. Determining the triggers is ongoing (e.g., see these reviews, published in The LancetPociot and Lernmark, 2016Rewers and Ludvigsson 2016).

References

To see articles on the role of autoimmunity in diabetes, as well as articles about various environmental factors that can initiate or influence the progression of autoimmunity, see my PubMed collection Autoimmunity.