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The human brain contains more than ten billion capillaries, which translates to one vessel for each neuron. These capillaries form a circulatory network with over 400 miles (644 km) of blood vessels that nourish the brain, transporting as much as 20% of cardiac output. The entire length of this network is protected from toxins by the blood-brain barrier (BBB), a complex structure lining the capillaries throughout the brain.
When the BBB is damaged, circulating antibodies that cross-react with neurological tissues can infiltrate the brain and nervous system, with the potential destruction of neurologic tissues. The cycle of neuroautoimmunity begins with a breach of the gut and/or blood-brain barriers. BBB permeability and the effects of "leaky brain" contribute to many devastating neurological and autoimmune conditions, including traumatic brain injury (TBI).
New breakthroughs in laboratory testing make it possible to identify BBB permeability in trauma ranging from suspected concussions to TBI. The testing is also relevant to neurological disorders as advanced as Alzheimer's dementia and as subtle as chronic headaches or memory loss. Testing for key antibodies makes it possible to diagnose many of these conditions at a preclinical stage, before frank symptoms of injury or disease are present. Increased permeability can manifest as CNS symptoms of neurotoxicity, autoimmunity, or even cancer.
Breaching or damage to this vast network is an underappreciated factor in a wide range of neurologic and autoimmune conditions, including:
- ADD, ADHD, autism spectrum disorder, developmental disorders
- Autoimmune conditions – celiac disease, type 1 diabetes, Hashimoto's encephalitis, lupus with CNS involvement, rheumatoid arthritis, and sarcoidosis, as well as neuroimmune conditions such as CFS and FMS
- Concussions and traumatic brain injury
- Mental illness – obsessive-compulsive disorder, schizophrenia, and others
- Neurodegenerative disorders and diseases of aging – AIDS dementia, ALS, Alzheimer's disease, epilepsy, multiple sclerosis, Parkinson's disease, peripheral neuropathy, senile dementia, stroke
- Neurologic symptomology – cognitive impairment or decline, memory problems, chronic headaches, sleep disturbances, fatigue, dizziness, tremors, poor coordination, anxiety, depression
Barrier Dysfunction and Disease
Composed of highly specialized brain and endothelial cells, the BBB is fully differentiated to the neurovascular system, and present in all brain regions, except in those regulating the autonomic nervous system and the endocrine glands. Capillaries permit diffusion of blood-borne molecules, screening out molecules larger than 400 Daltons (Da), approximately the size of blood glucose. Larger molecules such as proteins, which can occur in the range of 50,000 to 100,000 Da, are denied access to the nervous system when the BBB is intact. Specific carriers, or transporters, in apical and basolateral membranes, control the influx of small polar solutes needed by the brain (nutrients such as glucose and amino acids) and the efflux of many waste products. Transporters also exclude many potentially toxic compounds, such as xenobiotics, food antigens, and peptides present in the circulation.
Absence of Immune Tolerance
Innumerable endothelial tight junctions in the BBB function to prevent the passage of large soluble molecules into the CNS. Consequently, the barrier also prevents developing B-cells from contact with brain antigens. During immune maturation, B cells are not exposed to the variety of unique brain antigens expressed on neurons, oligodendrocytes, microglia, and astrocytes. The immune system apparently has no innate mechanisms for establishing tolerance to brain antigens or for preventing the production of antibodies against them. When exposure to an environmental trigger occurs that opens the BBB, the immune system, by producing antibodies against the CNS, attacks the CNS tissues.
Numerous exposures can trigger BBB permeability:
- Inflammatory responses associated with chronic or acute traumatic brain injury and concussions
- Environmental exposures – viral (CMV, Guillain-Barre, hepatitis B, herpes 6); bacterial (streptococcus, Chlamydia pneumoniae); molds and mycotoxins; EMF from power lines, computers, cell-phones, microwaves; and radiation
- Inhalation or touch contact – chemicals including formaldehyde, insecticides, pesticides; solvents such as benzene; heavy cigarette smoke.
- Intestinal permeability and exposures via the gut –dysbiosis, endotoxins from bacterial overgrowth; PCBs and other toxins ingested in food or water
- Other internal exposures and dysfunction – toxic metals such aluminum and heavy metals such as mercury; certain medications; silicone implants; shock, stress, and inflammation; hypertension; ischemia
Breaches of the BBB can result in the damaging effects of TH 1 and TH 17 lymphocytes, as well as antibodies that can target and damage neurons and tissues such as myelin basic protein. Autoantibodies can become pathogenic on penetration into the CNS through either BBBD (blood-brain barrier dysfunction) or extravasation into cerebrospinal fluid from the sub-arachnoid space.
Testing for Barrier Dysfunction
Advanced antibody testing now allows accurate evaluation of BBB competence. Patients with neuroautoimmunity frequently have high levels of antibodies against various components of the nervous system, particularly antibodies to S100-B and to occludin and zonulin.
BBB protein antibodies.The blood-brain barrier includes endothelial cells, tight junctions, the capillary basement membrane (BM), pericytes (PCs), and astrocyte end-feet that tightly ensheath the vessel walls. Astrocytes located beneath the endothelial cells prevent the entry of unwanted molecules and produce a protein identified as BBB protein, which is now used in laboratory testing as a marker to identify the presence of neuroautoimmune reactivity. Elevated antibody titers for BBB protein and other brain proteins have been described in Alzheimer's disease and epilepsy. In senile dementia, the presence of BBB protein antibodies is one of the early markers of cognitive decline. (Specific testing for BBB protein antibody is provided in Cyrex Laboratories' Array 20.)
Occludin and zonulin antibodies.Paracellular space between the endothelial cells of the BBB is protected by an extensive network of tight junctions, consisting of transmembrane proteins that include occludin, claudin, and junction adhesion molecule (JAM), as well as cytoplasmic proteins, specifically zonulin-1 (ZO1), zonulin-2 (ZO2), and zonulin-3 (ZO3). Many patients with autoimmune disorders produce antibodies against their own occludin and zonulin, which serve as useful laboratory markers in diagnostic testing. (This evaluation is provided in Cyrex Array 2.)
Lipophilic toxins.Tight junctions between the cells of the BBB endothelium form a physical barrier, significantly reducing passive diffusion through the paracellular pathway, and forcing any molecular traffic to occur mainly across the endothelial transcellular pathway. However, gases such as oxygen and carbon dioxide can easily diffuse across the barrier via the lipid membranes. This provides a security breach through which toxic lipophilic chemicals including petroleum-based products and other fat-soluble chemicals can cross the BBB, invading the CNS. (Antibodies targeting lipophilic toxins are among the 12 substances evaluated in Cyrex Array 11.)
A growing body of research has implicated the effects of BBB dysregulation in acceleration of chronic neurodegenerative disorders, including:
- Faulty BBB clearance of potential brain toxins in Alzheimer's and Parkinson's disease
- Inefficient clearance of excitotoxins across the BBB after an ischemic insult or TBI
- Increased transport of leukocytes across the activated BBB in AIDS dementia, Alzheimer's disease, multiple sclerosis, and during neuroinflammatory CNS responses
- BBB breakdown in Alzheimer's disease, amyotrophic lateral sclerosis, epilepsy, and multiple sclerosis.
The mechanisms by which toxic chemicals disrupt the endothelial tight junctions are shown in Figure 1, through processes that result in damage to astrocytes, microglia activation, the production of autoreactive antibodies, free radical generation, and immunoexcitotoxicity.
Figure 1. Proposed mechanism for excitotoxicity from leaky BBB. Environmental triggers, brain inflammation, and disruption of the BBB leads to the release of free radicals and immunoinflammatory factors, causing acute microglia activation, which contributes to immunoexcitotoxicity.
Chronic inflammation and deterioration.Chronic inflammation in the brain can be caused by environmental triggers such as infection or toxic chemicals that activate neurons, astrocytes, and microglia to produce cytokines. As is shown in Figure 1, environmental triggers and inflammation in the brain cause brain cells to produce TNFa, IL-1b,and IL-6, which contribute significantly to neuronal cell destruction and neuroautoimmunity.
Cancer. Polychlorinated biphenyls (PCBs) are a prime example of a toxin that can disrupt blood-brain barrier integrity and promote brain metastasis formation. When these exposures occur, the chemical opens the barrier, damaging the astrocytes, which then can no longer protect the barrier. The same process can occur with infections such as Borrelia burgdorferi, cytomegalovirus, Epstein-Barr virus, herpes type 6, and other environmental triggers which directly or indirectly damage the barriers, resulting in neuroautoimmunity and even cancer.
Traumatic brain injury (TBI).Injuries such as those occurring in accidents, military combat, or in many sports can lead to repeated disruption of the blood-brain barrier. It is estimated that in the United States alone, 4 million people experience sports and recreation-related concussions annually. In football, for example, approximately 40% of players experience concussions. The repeated head trauma and TBI associated with contact sports such as boxing, basketball, and soccer have also been shown to induce BBB permeability, followed by antibody production against BBB proteins through a number of processes:
- Autoantibodies targeting the BBB – indication of pathological alteration of the protective brain barrier.
- Neurotransmitter dysregulation – manifest in both pre- and post-synaptic dysregulation of neurotransmitters.
- Excitotoxicity – this pathology involves free radical formation, brain swelling, and the entry of locally produced molecules such as cytokines and chemokines, disrupting metabolism and contributing to neuroinflammation and oxidative stress.
These processes have been confirmed in clinical research such as a study of 57 football players, medically evaluated before and after games, measuring the level of S100-B proteins. Serum S100-B was detected in players who experienced the greatest number of sub-concussive hits. Since this is a large protein molecule (21 kDa), even trace amounts handled by cells involved in the immune system resulted in antibodies against S100-B. The presence of this protein in a blood sample means that the BBB has been breached or damaged, and antibodies produced against S100-B have invaded the CNS.
The high degree of sensitivity of this testing was confirmed in a French study involving 2,000 patients with minor head injuries, comparing CT scans with plasma S100-B levels. TBIs were identified by antibody testing with 99% sensitivity and 20% specificity, confirmed by CT scan with the conclusion that S100-B testing is a highly promising screening tool.
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