Chapter Two
Inflammation
Inflammation is an essential defensive response that helps to destroy pathogens and maintain homeostasis in the body. However, when inflammation becomes long term, then this chronic inflammation can create negative health effects. As will become obvious after reading this book, chronic inflammation may be the primary cause of many health conditions.
Inflammation also impacts ASD individuals. Most ASD people have a higher number of inflammatory molecules. Many researchers have found immune system differences in ASD people (11, 12, 13, 14, 15, 16, 17). This is significant because chronic inflammation changes the immune system.
Reactive oxygen species, such as superoxide, hydrogen peroxide, and hydroxyl, are often the primary cause of inflammation. One way the body creates reactive oxygen species is in the metabolic process used to make energy.
Various other processes also lead to increased reactive oxygen species production. For example, the body creates reactive oxygen species on purpose to destroy dangerous pathogens and signal other cells.
However, if there are too many reactive oxygen species, then they steal electrons from cells and cause widespread damage, which leads to many different health conditions.
Antioxidant enzymes naturally created by the body help to reduce the number of reactive oxygen species, limiting the damage they cause. Importantly, research found lower antioxidant enzyme activity in ASD children (18). ASD people also had lower levels of the antioxidant proteins, ceruloplasmin and transferrin (19). Less antioxidant enzyme activity allows reactive oxygen species to cause more damage to ASD people.
As an important note, although excess reactive oxygen species are harmful, a regular amount is necessary for survival. Keeping some reactive oxygen species is critical because they destroy pathogens and function as signaling molecules. Maintaining the balance is the key to reactive oxygen species management because too little of them is just as much of a problem as too many. Therefore, taking too many antioxidants can have negative effects.
One of the essential functions of reactive oxygen species is that they can stimulate the release of inflammatory molecules known as cytokines. Inflammatory cytokines are helpful when they are not excessive. These cytokines function as signals to attract the immune system to assist in specific areas of damage (20). Cytokines provide an evolutionary benefit by reducing the expenditure of energy in outward activity, which is useful when someone has an illness and needs to rest. Cytokines cause “decreased food intake, decreased exploratory behavior, increased sleep, and impaired cognitive functioning (21).” The inflammatory process also assists in removing damaged cells and begin healing. Inflammation is critical for good health and may “efficiently minimize impending injury or infection (22).”
However, when inflammatory cytokine levels become excessive, then that can result “in a more severe and chronic neuroinflammatory cycle that actually promotes or propagates neurodegenerative disease,” such as Alzheimer’s and Parkinson’s disease (23). In addition, there are other associations between excess inflammatory cytokines and depression, anxiety, Alzheimer’s, Parkinson’s, as well as other health conditions (24). Furthermore, research on rats found infections caused higher levels of cytokines, which potentially lead to abnormal behaviors (25).
Interestingly, researchers also found that cytokines can alter synaptic plasticity (26). The synapse is the small space between neuron cells, in which neurotransmitters, such as dopamine and serotonin, pass between neurons. This passing of signals between neurons helps to form a well-connected neuron network. The impact of inflammation upon the network of neurons is critical for understanding ASD. Chapter 8 has a discussion of how inflammation affects neuron connections and how this causes many ASD symptoms.
The molecule interleukin-6 (IL-6) is one of the primary cytokines that affects inflammation. Research found an association between higher IL-6 levels and ASD (27). Other research found ASD patients had high levels of the pro-inflammatory cytokines IL-6, interleukin-1 beta (IL-1β), as well as tumor necrosis factor-alpha (TNFα) (28). IL-6 and TNFα are “implicated in the central control of responses to systemic disease and injury (29).”
Also, IL-6 receptors exist throughout the human fetus (30). Therefore, IL-6 levels in the mother can influence fetal development. Researchers found that an antibody stopping IL-6 may stop multiple behavior changes associated with oxidative stress (31).
IL-6 also affects stem cell differentiation, as high IL-6 levels caused more stem cells to become astroglia rather than neurons (32) (33). This is important because having more astroglia and glial cells can increase the inflammatory response in the brain. Chapter 8 has a further discussion about the importance of these cells and how they impact ASD.
One way that inflammation affects the brain is by increasing the permeability of the blood-brain-barrier (BBB). In normal conditions, the BBB helps to shield the brain from problems that occur in the body. However, IL-6 can create more vascular permeability in the BBB to allow the immune system to have increased access to the brain during more stressful times.
Many other pro-inflammatory cytokines may also create more permeability in the BBB (34). Others also note how the permeability can increase in response to inflammation (35). Importantly, general body inflammation outside of the brain can worsen “local brain inflammation and neuronal death (36).” Researchers have written that:
“the rationale for dismissing peripheral influences on the brain because of the belief that the brain is protected from events that impinge on the peripheral organs is being progressively undermined. We now know that “barrier is an over-statement regarding the blood-brain-barrier, because it does not mature until substantially after birth, and its permeability is significantly modulated even in adulthood by factors such as fever and circulating cytokines (37).”
Having elevated BBB permeability during inflammation improves the ability of the immune system to remove sources of inflammation in the brain. In human history, the primary sources of inflammation were pathogens, such as viruses and bacteria. Being able to increase the permeability of the BBB permitted the efficient destruction and removal of many pathogens.
The BBB may also become more permeable to allow the inflammation from outside of the brain to activate microglia to release additional inflammatory cytokines and reactive oxygen species (38). Therefore, various inflammatory events taking place in different areas of the body, such as the gastrointestinal tract, has the potential to affect inflammation in the brain. Many ASD people have inflammation throughout their bodies, which affects their brain development and function.
Another connection between immune system issues and autism comes from studies on families with higher rates of autoimmune disease. An autoimmune disease is when the immune system attacks an individual’s own body. A research study states:
“The mean number of autoimmune disorders was greater in families with autism; 46% had two or more members with autoimmune disorders. As the number of family members with autoimmune disorders increased from one to three, the risk of autism was greater, with an odds ratio that increased from 1.9 to 5.5, respectively. In mother and first-degree relatives of autistic children, there were more autoimmune disorders (16% to 21%) as compared to controls (2% and 4%) (39).”
Other researchers found a connection between familial autoimmune disorders and pervasive developmental disorders, including autism (40). Also, ASD people have more autoantibodies, especially to mylein basic protein (41) (42).
Many health conditions besides just ASD have links with autoimmunity. Interestingly, there is possible “autoimmune involvement in essentially all psychiatric disorders, including schizophrenia, depression and obsessive compulsive disorder (43).”
Some types of autoimmunity feature an imbalanced ratio of attack T cells (Th1) to suppressor cells (Th2). Research notes how TH1 is much lower than Th2 in ASD people (44) (45) (46). Other research found ASD children have Th1 attack cells that lack power (47). These issues are often a sign of an imbalanced immune system.
The association between an altered immunity profile, autoimmune disease, and ASD is perhaps unsurprising if an excessive amount of inflammation influence all these conditions. As discussed in Chapter 8, inflammation has large effects on brain development and overall function, which both causes ASD and affects the symptoms.
Shift Perspective
The brief discussion about autoimmunity brings up an important idea. Perhaps many health conditions have a temporarily useful purpose, which is to prevent a more severe problem from happening. This idea is paradigm-shifting and significantly changes the current treatment strategies for many health conditions. There are discussions of this idea in multiple sections of this book.
Of course, this does not mean that all health conditions have a temporarily useful purpose. That is too simplistic and generalized to be true. Instead, as will be discussed later in this book, much more common health conditions, such as diabetes, cancer, and obesity, have a temporarily useful purpose.
Many autoimmune diseases may also occur for a reason. They may be part of the body’s effort to prevent a more severe problem from happening. Amazingly, researchers note how autoimmune disease might benefit self-maintenance (48). While other researchers report that controlled autoimmunity could help limit secondary damage (49).
For example, to slow down inflammation, the body could start an autoimmune attack on the thyroid gland, which influences the metabolic rate. Metabolism is a significant source of reactive oxygen species generation. Therefore, slowing down metabolism may lead to less inflammation.
In another example, the body may attack pancreatic cells to stop the release of the hormone insulin, which signals other cells to absorb glucose. Blocking this activity limits glucose metabolism. As Chapter 6 shows, the metabolism of glucose is a major source of inflammation in the body. Therefore, attacking the insulin-producing cells may be the body’s attempt to reduce inflammation. However, in a modern world of excess glucose, such an attempt does not work and causes serious health problems.
Autoimmune diseases often feature an imbalance in the Th1/Th2 ratio. An overactive Th1 response often leads to excessive inflammation. Whereas Th2 inhibits the development of the Th1 response (50). The Th2 response might strengthen to inhibit the continual inflammatory activity associated with Th1. If inflammation becomes excessive, then the balance between Th1 and Th2 will likely change. Chronic inflammation, combined with the altering of this balance, could cause the body to attack its own tissues. This attack might be a temporarily useful design to limit inflammation from becoming much worse.
Interestingly, different autoimmune conditions are often either Th1 or Th2 dominant. Organ-specific autoimmune diseases are characterized by Th1 dominance, whereas systemic autoimmune diseases are characterized by Th2 dominance (51). Perhaps the Th1 dominant organ-specific diseases is an earlier immune response to an organ that is a source of extra inflammatory damage.
In contrast, if the immune system is more overwhelmed and Th1 is low, then more Th2 autoimmune diseases will likely occur. Accordingly, the depletion of glutathione, an important antioxidant, “inhibits Th1-associated cytokine production and/or favors Th2-associated responses (52).”
Although many autoimmune diseases may have a useful purpose, healing from them still needs to occur. To heal, the original cause should first be identified and corrected. For many health conditions, this cause is excessive long-term inflammation. There is a discussion about potential treatments for inflammation later in this book.
On Fire
As mentioned, many health conditions have increased in the last few decades. Statistically, “western countries are being confronted with a disturbing increase in the incidence of most immune disorders, including autoimmune and allergic diseases, inflammatory bowel diseases, and some lymphocyte malignancies (53).” This is in addition to the multiple studies cited in the first chapter of this book.
Some researchers think improved hygiene is the causes of the rising disease rates. Their reasoning is there is less everyday exposure to bacteria and other pathogens in developed countries with clean, controlled environments. There is also the frequent use of antibacterial products. The hypothesis proposes that since the body is experiencing fewer germ-based challenges to the immune system, then the body may not be as familiar with future challenges. Due to this unfamiliarity, the immune system overreacts and creates excessive inflammation.
However, hygiene has not changed much over the last 60 years. In addition, the rise of many disorders, including ASD, mostly began in the early 1980s. The reason for this rise has to do with a combination of various factors, which are part of a later discussion in this book.
There are strong connections between inflammation and ASD. Excess reactive oxygen species can increase inflammation, which depletes the antioxidant defenses of the body. With a lack of defenses and continual exposure to sources of inflammation, the body is basically on fire with chronic inflammation.
Although the body does naturally reduce some of the pro-inflammatory molecules in response, the inflammation can continue to burn, damaging cells and weakening the immune system to attacks from pathogens and types of stress. This causes increased sensitivity to different foods and frequent illness. As will be discussed later, excessive inflammation affects ASD symptoms. Inflammation also influences many health conditions by slowing down the methylation cycle.