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Intestinal hyperpermeability. Increased intestinal permeability (leaky gut) is a major gateway to environmentally induced autoimmune disorders. This malfunction occurs, for example, in gluten-sensitive individuals when gluten and other cross-reactive or immunoreactive foods are consumed. In the gut, inflammation opens the tight junctions, allowing unwanted antigens into the bloodstream, including food proteins, fragments of normal gut flora, intestinal pathogens, and toxic chemicals such as alcohol or bisphenol A from plastics. The passage of reactive food proteins and other substances through the gut lining can have an immediate effect on dendritic cells and other immune cells located just below the gut lining. At that point, inflammatory cytokine production increases. The continuous stimulation of this process due to ongoing consumption of reactive foods is a major factor in the development of autoimmunity.
To evaluate the presence and severity of leaky gut, we measure antibodies against components of the tight junctions (actomyosin and occludin/zonulin) and lipopolysaccharides (endotoxins released due to an imbalance in the gut flora, intestinal dysbiosis, which causes the tight junctions to open). These endotoxins are oversized proteins, so their presence is a clear indication of hyperpermeability in the gut.14 Evaluations for hyperpermeability are provided in Cyrex Array 2, which tests for actomyosin IgA; occluding/zonulin IgA, IgG, and IgM; and lipopolysaccharides IgA, IgG, and IgM.
Breaching the blood-brain barrier. If inflammation becomes chronic, inflammatory cytokines and other factors can also open the blood-brain barrier (BBB). As a result, unwanted molecules (including dietary proteins and peptides, toxic chemicals, and even infectious agents or their antigens) gain access to the nervous system, causing damage to neural tissue and the release of neural antigens. These substances can sensitize the immune system, triggering reactivity against both these foreign materials and brain tissue. Over time the effects of this chronic inflammation can produce autoimmune symptoms that resemble multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), or other neuroautoimmune disorders.
When the blood-brain barrier is intact, the only molecules that can penetrate are the size of glucose, exceptionally small molecules measuring approximately 160 daltons. In contrast, antigens are measured in kilodaltons, 10 to 10,000 times larger than glucose. The presence of gut-associated antigens in the blood is an indication of intestinal hyperpermeability. When the blood-brain barrier is opened under stress or neuroinflammatory conditions, these exceptionally large antigens can penetrate the nervous system along with immune cells. As a result, autoimmune reactivity to various triggers can occur within brain tissue or the nervous system in general, over a period of exposure from months to years.
Phases of Autoimmune Disorders
Autoimmunity is classified in three stages: stage 1, or silent autoimmunity, reflects the presence of antibodies; stage 2, or autoimmune reactivity, is characterized by the presence of antibodies with some associated symptomatology; and stage 3, or autoimmune disease, is differentiated by not only the presence of antibodies and symptoms, but also the loss of functionality.
Silent autoimmunity. Initially, autoimmune reactivity is classified as stage 1, characterized by elevated antibodies but no obvious symptoms or loss of function. Although this condition is referred to as silent, the ongoing production of antibodies targeted against tissues and organs can eventually induce some loss of function and the presentation of symptomatologies. It is therefore a predictor of future autoimmune disorders.
Autoimmune reactivity. As these conditions progress, elevated antibodies cause loss of function and discernible symptoms. Defined as stage 2, autoimmune reactivity has not yet resulted in the severe tissue destruction associated with the disease. Antigen-presenting cells and autoreactive T cells such as T-helper 1 and 17 attack and release various tissue antigens, stimulating B cells to produce antibodies. As tissue antigens are released, lymphocytes continue to react and B cells continue to produce antibodies. This process may continue over a period of three, five, or even ten years before tissue damage is detectable.
Autoimmune disease. When autoimmune reactivity persists, the disease becomes more advanced, with accompanying tissue damage and pathology. Damage occurs through the cumulative effects of autoreactive T-helpers 1 and 17, in tandem with antibodies and circulating immune complexes. This immune activity can cause significant damage, resulting in tissue dysfunction, which is detectable by imaging studies such as MRI. Once detectable damage occurs to various tissues such as brain, joints, thyroid, or pancreas, it is very difficult to reverse.
The development and progression of these disorders vary greatly from individual to individual. In fact, in some people this process may continue for years without major damage, while in others serious damage is detected within two to three years. In my opinion, autoimmunity should be detected at the earliest stage possible. If we wait five or ten years until full-blown autoimmune disease has developed, unfortunately, by that time the only choice clinicians have is to put the patient on immunosuppressive medication, corticosteroids, or monoclonal antibodies, which involve significant side effects. Conversely, the earlier we detect these conditions, the better we can help our patients. Currently the most effective intervention for these disorders is prevention through early detection of predictive antibodies.15
Triggers of Autoimmune Reactivity
For the clinician, it is not enough to simply detect and identify antibodies targeted against certain tissues or organs. It is also vital that we identify the mechanism of action triggering the development of tissue antibodies.
Gluten or cross-reactive foods. In conditions such as ataxia, for example, the immune system is reacting to the body's own cerebellar peptide because the patient is gluten sensitive and is producing antibodies against alpha-gliadin. Alpha-gliadin and cerebellar have a similar antigenic structure. If alpha-gliadin is cross-reacting with cerebellar, the solution is to remove gluten and cross-reactive foods from the diet, hence eliminating the source of autoimmune reactivity from the patient's environment.
Viral activation. Autoimmunity can also be triggered by reactivity to a dormant or sequestered virus. Epstein-Barr virus (EBV) provides a good example. Frequently, after viral infection, remnants of the virus remain in the body. When immune function is compromised due to injury, illness, or stress, the virus can be activated, and memory B cells reactive to EBV become activated to produce antibodies against EBV. Because the Epstein-Barr virus and neuronal cells have similar antigenic structures, if the antibodies cross the BBB, they will attack the nervous system, resulting in neurological symptoms such as multiple sclerosis. In these cases, by detecting and treating for EBV, it can be possible to prevent the progression of a condition such as MS.
Toxic chemicals. If toxins such as bisphenol A, heavy metals, or solvents bind to tissue, that tissue is then recognized as foreign material by the immune system. This is a common mechanism that triggers autoimmune reactivity against various tissue antigens. Chemicals that are lipophilic bind to fat tissue in the brain or to the myelin sheath, triggering autoimmune reactivity against neuronal tissue.
If this type of reactivity continues for more than five years, typically the result will be the loss of functionality in that tissue and the development of full-blown autoimmune disease.
Array 5: Multiple Autoimmune Reactivity Screen
The Multiple Autoimmune Reactivity Screen (MARS) measures 24 predictive antibodies, some of which can appear up to ten years before the clinical onset of disease. This panel includes antigens in the heart, liver, nervous system, gut, and joints, as well as endocrine tissue, thyroid, adrenal glands, and islet cells. The test can be used to detect not only full-blown autoimmune diseases but also the very early stages of autoimmunity. This is important because once a disease is fully developed, the efficacy of intervention is already extremely limited, but if reactive antibodies are detected early enough, then preemptive measures can be taken while organs and tissues are still functional.
Multiple Autoimmune Reactivity Screen (MARS)
Parietal Cell + ATPase IgG + IgA Fibulin IgG + IgA
Intrinsic Factor IgG + IgA Collagen Complex IgG + IgA
ASCA + ANCA IgG + IgA Arthritic Peptide IgG + IgA
Tropomyosin IgG + IgA Osteocyte IgG + IgA
Thyroglobulin IgG + IgA Cytochrome P450 (Hepatocyte) IgG + IgA
Thyroid Peroxidase (TPO) IgG + IgA Insulin + Islet Cell Antigen IgG + IgA
21 Hydroxylase (Adrenal Cortex) Glutamic Acid Decarboxylase 65
IgG + IgA (GAD 65) IgG + IgA
Myocardial Peptide IgG + IgA Myelin Basic Protein IgG + IgA
Alpha-Myosin IgG + IgA Asialoganglioside IgG + IgA
Phospholipid IgG + IgA Alpha + Beta Tubulin IgG + IgA
Platelet Glycoprotein IgG + IgA Cerebellar IgG + IgA
Ovary/Testis IgG + IgA Synapsin IgG + IgA
Individuals with one autoimmune disorder frequently develop additional autoimmune conditions; the genetic basis for this vulnerability has been described in the research literature.16,17 The detection of risk for additional autoimmune disorders in the future can be established by a simple blood test.
Multiple antigens indicating genetic risk. This screen economically and efficiently assesses the potential for possible tissue damage to multiple organs of the body. Autoimmune antibodies tend to be predictive; test results will indicate the involvement of various tissue antigens, and will correlate with risks for multiple potential autoimmune diseases in a given individual.
Multiple antigens due to leaky gut. When testing indicates significant levels of autoantibodies against five, six, or even ten different tissue antigens, it is vital to determine whether that patient is experiencing a problem with intestinal permeability. If leaky gut is present, we must first resolve this condition or we will not be able to reverse the course of autoimmune disease. We must evaluate the gut and blood-brain barriers, try to repair them, and explore potential environmental triggers. It is essential that we look deeper: is it the diet? Infectious agents? Toxic environmental chemicals? Unless we identify underlying exposures and triggers and remove them from the patient's environment, we will not be able to significantly help our patients.
Array 6: Diabetes Autoimmune Reactivity Screen
To date, two environmental triggers of type 1 diabetes have been identified. One is the coxsackievirus, which has almost 20% similarity with amino acid sequences in islet of Langerhans cells, as demonstrated in the research of J. Tian.18 When the coxsackievirus attacks islet cells, the immune system reacts against both the virus and islet cell antigens. This results in antibody production against GAD-65, islet cell antigens, or tyrosine phosphatase, and different chains of insulin. Subsequently, islet cells are gradually destroyed over a period of time, typically ranging from two to ten years, depending on the individual. The second environmental trigger that cross-reacts with islet cell antigens is milk and its associated antigens.3,19
Testing. Clinically these tests are intended for the early detection of autoimmune processes in type 1 diabetes, impaired blood sugar metabolism, and metabolic syndrome. It is noteworthy that some patients with type 2 diabetes also have type 1 diabetes. In these conditions, reactive T-helper 1 and T-helper 17 cells attack the islets of Langerhans, causing the release of insulin, glutamic acid decarboxylase (GAD-65), and protein tyrosine phosphatase (PTP). Therefore, in testing for autoimmune type 1 diabetes and for some cases of type 2 diabetes, the emphasis is on these three primary predictive antibodies: insulin, GAD-65, and PTP.
Tracking treatment effectiveness. This panel of testing can also be used to assess the effectiveness of treatment protocols in the management of autoimmune diabetes, and these tests are recommended for patients who have type 1 diabetes, a family history of type 1 diabetes, metabolic syndrome, or severe atypical manifestation of type 2 diabetes. GAD-65 antibodies are also found in many patients with other neuroautoimmune disorders, such as stiff-person syndrome or cerebellar ataxia. When there is the suspicion of gluten reactivity, dairy sensitivity, viral infection, and/or cerebellar ataxia, testing for insulin, GAD-65, and islet cell antigens can be beneficial for the patient. These tests are part of the Array 6 panel, Diabetes Autoimmune Reactivity Screen, offered by Cyrex Labs.
Conclusion
The prevalence of autoimmune disease is on the rise. Over the past four decades, many autoimmune disorders have increased three- and four-fold. These changes are not due to improved diagnostic criteria or increased recognition of autoimmunity. Rather, this crisis is due to factors in our environment, in particular, toxic chemicals. Due to exposure to these chemicals and the binding of chemicals or metabolites to human tissue, cellular defenses designed to protect the body attack the body's own tissues instead.
The empowering solution is to use predictive biomarkers to detect autoimmunity at the earliest stage possible, interrupting the progression of silent autoimmunity and autoimmune reactivity. "By making early intervention possible, predictive autoantibodies have the potential to alleviate much misery and to help provide extra years of healthy life."2 Then we can begin the process of cleaning up our bodies and our environment in order to reestablish immune homeostasis.
Researchers and clinicians should ask why the human body now reacts to its own antigens, which results in the production of potentially harmful autoantigens. The cause may be due to environmental factors such as bacterial or viral infections, or haptenic toxic chemicals binding to human tissue, causing modification of self-antigens and the subsequent production of autoantibodies. The final answer then for the prevention of autoimmune disease is to remove offending food antigens such as gluten from the diet of sensitive individuals; to pay attention to and maintain the balance of the gut microbiota; and to be wary of the viruses, pathogenic bacteria, and toxic chemicals that are responsible for the formation of neoantigens in our bodies.
"If we can detect autoimmune antibodies at an early stage, we can help millions of people reverse the course of autoimmune reactivity. By identifying disease triggers and removing them from the environment of the patient, I am confident that we can help millions of patients in America and worldwide stop or even reverse the course of their autoimmune reactivity."15
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