Game Changer: Brain Immunity

Ten years ago, science assumed that immunity was in the body, not the brain, which was thought to have "immune privilege." What does it mean to learn that the brain has an immune system? Does this change our understanding of mental illness? Neurology? Cancer? What about risks of side effects to pharmaceutical interventions that target the immune system such as vaccines?

A seminal paper entitled, Novel roles for immune molecules in neural development: implications for neurodevelopmental disorders, helps to elucidate the history of this paradigm shift.  Scientific dogma had it that the immune system might infiltrate a brain in acute trauma or pathology. The earliest observations of the role of the immune system in even healthy brains arose from observations of cognitive impairment in severe combined immunodeficient mice who had peripheral T-cell depletion (but no specific blood-brain-barrier breach).

With the activity of agents called cytokines, complement, and complexes that help to identify invasive pathogens such as MHC, the presence alone, of these agents represents a new way of thinking about brain function. Then there is the consideration that patterns of immune functioning change over the course of neurodevelopment with immune agents participating in learning and brain growth. Sprinkle in the daunting complexity of genetic individuality as demonstrated in this quote:

"One of the defining features of MHC molecules and their receptors is their complexity. They are both polygenic-containing multiple genes and polymorphic-containing multiple variants of each gene. The MHC genes are the most polymorphic genes known."

...and we end up with more questions than we have answers.

Suffice it to say:

"The link between environmental factors, the immune response, and neurological dysfunction is not completely clear at present, but it is receiving increasing attention and support...the sheer number of immune molecules that could be important for nervous system develop­ment and function is staggering. Although much progress has been made in the past 10 years in our appreciation that immune molecules play critical roles in the healthy brain, the large major­ity of immune molecules have not yet been studied for their presence and function in the brain. For the immune molecules that we know are important, almost nothing is understood about their mechanisms of action."

The complexity of this review serves to highlight just how much we have left to discover about immune activity in the brain relative to the rest of the body. That said, the notion of immune-brain cross-talk has become the underpinning of modern theories of cytokine models of mental illness.

When the Brain's Immunity Goes Awry - Depression

One of the most predictable side effects of interferon therapy for Hepatitis C is depression. In fact, 45% of patients develop depression with interferon treatment, which appears to be related to elevated levels of inflammatory cytokines IL-6 and TNF.  Cytokines can also be induced by lipopolysaccharide (LPS), an endotoxin produced by gram-negative bacteria that can be administered orally and is employed in animal models to induce depression-like syndromes.Mice that lack IL1-B (a cytokine that mediates inflammatory response), however, are protected against these LPS-mediated "depressive symptoms" (i.e., lost interest in sugar water), suggesting that these inflammatory messengers may be a key part of the depression equation.

Cytokines such as IL-1, IL-6, and TNF-alpha are the messengers of distress and have all been shown to be elevated in the setting of depression, and in a linear and predictive relationship. These cytokines can traverse the blood brain barrier and may also stimulate afferent neuronssuch as the vagus nerve.

Once in the brain, immune hubs called microglia are activated where an enzyme called IDO (indoleamine 2 3-dioxygenase) has been shown to direct tryptophan away from the production of serotonin and melatonin and towards the production of an NMDA agonist called quinolinic acid.

In the context of inflammation, however, cortisol, prolactin, and sex hormones are often dysregulated; in this model, depression is thought to represent a high cortisol state which may result from elevated levels of inflammatory cytokines.  This may, in part, explain the efficacy of exercise in the treatment of depression and yoga, and meditation in down regulation of inflammation.

How do we Modulate Immunity?

The most powerful and controllable access point to the immune system is the gut. With 70% of it housed in the Gut Associated Lymphoid Tissue (GALT) in the intestinal wall, the ecosystem of microbial residents are responsible for influencing the immune gatekeepers such as dendritic cells. These microbes include primarily around 100 trillion bacteria that outnumber our human cells 10:1, archaea, parasites, and viruses including bacteriophages. These microbes transfer genetic information between each other and to the human host, and also carry out a number of activities such as production of fatty acids, neurotransmitters, B vitamins, digesting gluten, and even detoxification of environmental chemicals. While the microbiome is readily influenced by diet, it is the maternal gift that keeps on giving – influenced by the mother's gut flora during pregnancy, birth mode, breastfeeding, and finallyweaning diet.

What's Wrong with This Picture?  

Given the vast interconnectedness we have just explored, perhaps breaching the blood brain barrier with fat-loving metals injected into the blood stream with a variety of pathogens and chemical additives may require reevaluation.  Vaccines may be the most egregious example of head-in-the-sand "science" that has failed to incorporate modern theories of intersystem immunology – gut, endocrine, adrenal – as well as the vast personalization required for such an intervention based on genetics and preexisting environmental exposures. Aluminum, used as a vaccine adjuvant, is administered to a child sixteen times before the age of two.  It activates microglia in the brain and is strongly linked to Alzheimers, Parkinson's disease and autoimmune disorders. This is a known neurotoxin and potent immune stimulant – added because the newborn immune system is actually built not to respond. This has been referred to as the anti-inflammatory phenotype and speaks to the powerful interplay between an infant, their mother's milk, and the priming of their immune system in the first 2 years of life. Several exploratory analysis have argued for a causative role for aluminum in autism incidence including one by Lucija Tomeljenovic and Shaw and by MIT researcher,Stephanie Seneff. For instance, one study found that children who received the Engerix B Hepatitis B vaccine were 74% more likely to develop "central nervous system inflammatory demyelination" than children who did not receive the vaccine, and 177% more likely to develop multiple sclerosis. The only primate study done with an unvaccinated control group, concerningly demonstrated delayed acquisition of neurodevelopmental reflexes in the thimerosol (ethylmercury-forming preservative) Hep B vaccinated group (particularly in those with low birth weight and gestational age) relative to the unexposed group. Studies such as this, along with those like this that determined a 9x greater risk for receipt of special educational services in boys receiving the pre-2001 Hep B vaccine series, and one that suggested a 3-fold greater risk of autismdiagnosis likely led to the removal of thimerosol from the product in 2001. The thimerosol-containing vaccine was on the market for 19 years before this change (and it is still an ingredient of the flu vaccine and tetanus), which may raise concerns for some about the delay in remediating dangers associated with these products. These dangers are learned of post-hoc, in the field, after many children have paid the price of inadequate placebo-controlled, long-term study. It seems that, by design, vaccines may be a means of sending the immune system, and therefore the brain, a signal of harm.

Real Medicine

Understanding these interrelationships in the beginning of a new form of medicine: one that regards the body and mind as a whole, that appreciates that myriad environmental and lifestyle influences upon genetic expression, and that seeks to promote optimal functioning rather than suppress symptoms, co-opt functioning, and kill pathogens. Millions of years of evolution have brought us to this place and we are just beginning to look through the keyhole.