Download The Role of Environmental Triggers in Autoimmunity

Presentation Title: The Role of Environmental Triggers in Autoimmunity
Speaker: Aristo Vojdani, PhD, MSc, CLS
Contact: Immunosciences Lab., Inc. 822 S. Robertson Blvd., Ste. 312, Los Angeles, CA 90035
(310) 657-1077
[email protected]
Human autoimmune diseases affect roughly 5-10% of the world’s population and impose a significant
burden on the quality of life and health care resources through morbidity and mortality. The development
of an autoimmune disease is a very complex process. Autoimmunity arises when the host’s immune
system is directed against self-tissue antigens. Accumulating evidence has suggested a close interplay
between genetic factors and environmental triggers such as infections, toxicants and some dietary
components in the pathogenesis of autoimmune diseases. In relation to the role of heritability in
autoimmunity, genome-wide association studies have reported that genetics accounts for only a minority
of autoimmune disorders. Consequently, since 1997 research and publications devoted to environmental
triggers in autoimmunity has grown by an average of 7% every year.
The mechanisms by which environmental factors induce autoimmunity have been described variously as
involving cross-reactivity, over-stimulated or dysregulated activation of innate and adaptive immune
response, aberrant cell death, or the binding of toxicants to tissue proteins with the subsequent formation
of neoantigens. These environmental insults open the tight junctions of essential body barriers allowing
for the invasion of external immunogens. Once the invasion has begun, environmental antigens can
induce alterations in self-tissue proteins to which the immune system is normally self-tolerant,
consequently eliciting cellular or IgG, IgM or IgA antibody response, resulting first in autoimmune
reactivity and subsequently in autoimmune disease.
Understanding the mechanisms of environmentally-induced autoimmunity allows the practitioner to
better recognize the early stages of pathogenesis, before clinical manifestations appear. With advanced
clinical testing environmental triggers can be identified and removed, broken barriers can be healed and
targets of autoimmunity can be protected. If these steps are taken, autoimmune reactivity can be
arrested and the onset of disease avoided.
Learning Objectives
At the end of this presentation attendees should be able to:










Apply the ‘Triad of Autoimmunity’ concept to the clinical practice
Identify triggers of environmentally-induced autoimmune disorders
Expertly assess common pathogenic triggers such as gluten and lipopolysaccharides
Expertly assess intestinal integrity
Interpret next generation assessment tools
Map gut to brain cascades of inflammation
Use predictive antibodies in the clinical setting
Connect specific autoantibodies to certain autoimmune conditions
Use assessment tools for the ‘triad of autoimmunity’
Interpret test results with confidence
Outline for 4 hour presentation:
0:00-0:30
Overview – understanding the triad of autoimmunity and the cascade from health to
disease
The American Autoimmune Related Disease Association reports that 53 million Americans
have autoimmune disease. Autoimmunity is thought to result from interaction between
genetics and environmental triggers. However, since <10% of individuals with genetic
susceptibility to various autoimmune disorders actually develop the disease during their
lifetime, accumulated evidence indicates that initiation of autoimmune diseases is
impacted by environmental factors. The triad of autoimmunity comes from multiple
studies documenting the inflammatory cascades of environmentally-induced
autoimmune disorders. An environmentally-induced autoimmune disease requires, first,
a genetic susceptibility for the disease, second, increased intestinal permeability, and
third, an environmental trigger to switch on the pathogenesis, which leads to an
autoimmune condition. Dr Vojdani will present research supporting this concept.
0:30-0:40
Essential body barriers
The human body is an incredibly complex system, and since time immemorial man has
struggled to work out what exactly his gut and his brain have to do with his health, and
whether perhaps the two are connected somehow. While there is still a minority that
believes there is no connection at all, the majority accurately perceives that the parallels
between the gut and brain immune systems are too self-evident to deny. Bidirectional
signaling between the brain and gut, and many points in between, has been confirmed by
numerous studies. The gut’s influence on the brain cannot be overestimated, so much so
that it can be called a second brain. Studies have linked gastrointestinal diseases to brainlinked disorders such as depression, anxiety, multiple sclerosis and autism. Uncontrolled,
chronic inflammation, disturbances in the gut microbiota, and other gastrointestinalrelated dysfunctions, have been linked to neurodegenerative disorders. A spotlight has
been focused on the role of intestinal barrier function in the pathogenesis not just of
gastrointestinal diseases but of neurodegenerative ones as well. This opens the
possibility of prevention, amelioration and even reversal of autoimmune disorders, both
gastrointestinal and neurodegenerative, through treatment modalities involving the
repair of the gut and brain barriers, thus restoring the functionality and the stability of
their environments.
0:40-:0:60
Role of essential body barriers in health and disease – Intestinal Barrier
Increased intestinal permeability has been shown to play a significant role in the
pathogenesis of environmentally-induced autoimmune disorders by providing an opening
for trigger antigens to invade the body. Hippocrates stated, “All disease begins in the
gut.” The father of modern medicine understood the importance of intestinal barrier
integrity, yet somewhere along the line, this vital concept became lost. As a result,
gastrointestinal tract issues go unaddressed. Patients are told they have IBS and are sent
away. Indeed their bowels are irritable and it is up to us to identify the cause, remove
the trigger and heal the gut. Dr Vojdani will present how to expertly assess intestinal
barrier integrity. This presentation will include case studies and test interpretation
guidance.
0:60-1:15
Role of essential body barriers in health and disease – the Blood-Brain Barrier
The blood brain barrier (BBB) is a physical barrier between the brain and the circulating
blood, formed by the arrangement of endothelial cells and tight junctions that line the
capillaries, which supply blood to the brain. It is a highly selective barrier that restricts the
movement of all soluble proteins greater than 400 Da from the blood across to the brain.
Acting like a filter, the BBB protects the brain from infections, the products of infections
such as lipopolysaccharides (LPS), and toxic chemicals, etc., that circulate in the blood.
The BBB naturally permits the passage of essential metabolites, small hydrophobic (lipid
soluble) molecules like oxygen, carbon-dioxide, hormones, etc. The presence of BBB
autoantigens may indicate a breakdown of the BBB. BBB protein autoantigens that have
persisted for an extended period following repetitive BBB disruptions may cause neuronal
cell death, the release of neural antigens, and an early cognitive decline. Traumatic brain
injury (TBI) is a multifaceted pathology involving excitotoxicity, free radical formation,
brain swelling, and the entry of locally produced molecules such as cytokines,
chemokines, and other molecules When the BBB is damaged it provides a gateway for
environmental triggers to infiltrate the brain and nervous system. Due to the similarity
between some of these triggers and neurological tissues, neuro-reactive antibodies can
be formed. Neuronal autoantibodies contribute to the onset of neurological diseases.
1:15-1:20
Environmental triggers
Triggers of autoimmunity vary greatly and include chemical toxins to bacterial toxins.
These triggers are known to induce inflammatory cascades that can switch on an
autoimmune gene, or contribute to disharmony within the body, which result in the onset
of an autoimmune condition. The contributions of selected chemicals such as drugs,
heavy metals, pesticides, solvents, cosmetics, smoking, and biologicals, including
bacteria, viruses, parasites, and dietary proteins such as gluten and casein in
autoimmunity will be discussed. Dr Vojdani will emphasize the pathogenic roles of
lipopolysaccharides, and food proteins, which healthcare professionals encounter in their
daily clinical practice.
1:20-1:45
Environmental triggers – Dietary Proteins
While immunologic reactivity to wheat and milk proteomes has been extensively
researched, the immune response against many other food antigens and peptides has not
been characterized. Despite this lack of standardization, thousands of food IgG and IgA
antibody assays are still reported by many laboratories to health care practitioners. In
many cases, false-positive test results and the removal of the indicated foods from the
diet can have a very negative impact. The root of these testing problems stems from
improper preparation of the food extracts; the use of only raw food antigens and not also
processed foods; the lack of a proper validation process on an individual antigen basis;
and the cross-reactivity of food antigens with antibodies against infectious agents. In our
study we investigated immune reactivity against various raw and/or modified food
antigens after taking all the biochemical steps necessary to ensure reproducible test
results. These antibodies were further analyzed for reactivity to infectious agents as well
as to different tissue antigens such as thyroid, islet cell antigens, adrenal gland, joints,
heart, skin, gut, brain, etc. While cross-reaction between food proteins and the
production of antibodies against them may have some protective value against the
infections, their immune reaction against tissue antigens may play a role in autoimmune
reactivity. Therefore, if food immune reactivities are detected reliably, the removal of the
responsible immunological food triggers can then be the basis of the development of
proper treatment and the prevention of autoimmune diseases, which affect about 10%
of the world population.
1:45-2:15
Environmental triggers – Chemicals/Heavy Metals
The residues of industrial chemicals can now be detected in the air, soil, water and food
systems in the most remote regions of the world. It has come to the point that all humans
are now exposed to synthetic pollutants in their food, drinking water and in the air, as
well as in the ordinary things they use in everyday life. Thus, even individuals regarded as
nominally healthy have some measure, no matter how small, of exposure to
environmental chemicals. Some of these chemicals resist metabolism and excretion and
therefore accumulate in body tissues. Because many chemicals or their metabolites bind
to human cellular macromolecules and form neo-antigens, the measurement of chemical
levels by themselves in urine or blood is only an indication of exposure and excretion from
the body, and does not reflect the binding of chemicals to human tissue, and hence does
not show the actual body burden. Consequently, measuring levels of these
macromolecule adducts has been used as a risk assessment procedure in animal models.
However, it is obviously inconceivable to inject large doses of radiolabeled compounds
into human beings and then remove their tissues and organs to measure macromolecular
binding levels. Therefore, the best choice would be to measure antibodies against
macromolecule adducts in human blood, which is the subject of this presentation. We
examined the percentage of blood samples from healthy donors in which chemical agents
mounted immune challenges and produced antibodies against HSA-bound chemicals. The
levels of specific antibodies against 12 different chemicals bound to HSA were measured
by ELISA in serum from 400 blood donors. We found that 10% (IgG) and 17% (IgM) of
tested individuals showed significant antibody elevation against aflatoxin-HSA adduct.
The percentage of elevation against the other 11 chemicals ranged from 8% to 22% (IgG)
and 13% to 18% (IgM). Performance of serial dilution and inhibition of the chemicalantibody reaction by specific antigens but not by non-specific antigens were indicative of
the specificity of these antibodies. This protein adduct formation could be one of the
mechanisms by which environmental chemicals induce autoimmune reactivity in a
significant percentage of the population. The methodology described here for the
detection of antibodies against chemical adducts can be extended in the future to groups
at high risk for autoimmune diseases; these methods can be used to guide these
susceptible individuals toward lifestyles or protocols that involve avoiding exposure to
the chemicals, thus decreasing their risks of developing autoimmune diseases.
2:15-2:45
Environmental triggers – Infections
Viruses, bacteria and stealth organisms can infiltrate the human body and trigger acute
illnesses. Many of these acute illnesses resolve on their own or through medical
intervention. However, some of these infections manifest as low-grade fever, general
fatigue or slight achiness and therefore are not addressed. Patients can have underlying
chronic infections and not even know it. Furthermore, many of these organisms excrete
toxins such as lipopolysaccharides and cytolethal distending toxins, which can also
contribute to inflammation and downstream autoimmunity. When an infectious
organism reaches the blood stream, it can reside in tissues such as brain, joints and heart.
The inflammatory effect of these organisms can go undetected for years, if healthcare
practitioners do not think to look at infections as possible cause of general inflammation.
2:45-3:00
Biomarkers of autoimmunity
Molecules called predictive autoantibodies appear in the blood years before people show
symptoms of various disorders. Tests that detect these molecules can warn of the need
to take preventive action. Researchers and clinicians should ask the questions, why does
the human body react to its own antigens, which results in the production of potentially
harmful autoantibodies? The cause may be due to environmental factors such as
bacterial or viral infections, or haptenic toxic chemicals binding to human tissue, or
physical and mental stressors causing modifications of self-antigens and the subsequent
production of autoantibodies. Without the identification of factors such as infections,
dietary proteins and xenobiotics as major instigators of autoantibodies, clinicians will not
be able to take preventive action. Therefore, early detection of antibodies against various
tissue antigens can facilitate a proper and timely intervention. This would make a
significant difference in the management of autoimmune disease and prevent or
ameliorate the many years of suffering associated with multiple autoimmune disorders.
3:00-4:00
Putting it all together – Case Study Presentations
With so many pieces to the puzzle of autoimmunity and autoimmune disorders, their
detection, prevention and maintenance, it can be difficult to implement next generation
testing and treatment protocols into the clinical setting. Using the ‘Triad of
Autoimmunity’ concept, Dr Vojdani will walk attendees through step-by-step real world
case studies supplied by healthcare professionals in clinical practices across the United
States. These studies of autoimmunity will include patient case histories, test results,
interpretations, and protocols that were implemented by the healthcare professional.
This section of the workshop is interactive and audience participation/discussion is
encouraged.
Partial list of References:
1.
Vojdani A. Antibodies as predictors of autoimmune diseases and cancer. Expert Opin Med Diagn;
2(6):593-605, 2008.
2.
Vojdani A. Antibodies as predictors of complex autoimmune diseases. Int J Immunopathol
Pharmacol; 21(2):267-278, 2008.
3.
Vojdani A. Antibodies as predictors of complex autoimmune diseases and cancer. Int J
Immunopathol Pharmacol; 21(3):553-566, 2008.
4.
Vojdani A., O’Bryan T., Green J.A., McCandless J., Woeller K.N., Vojdani E., Nourian A.A., Cooper E.L.
Immune response to dietary proteins, gliadin and cerebellar peptides in children with autism. Nutr
Neurosci; 7(3):151-161, 2004.
5.
Vojdani A. The characterization of the repertoire of wheat antigens and peptides involved in the
humoral immune responses in patients with gluten sensitivity and Crohn’s disease. ISRN Allergy;
2011, Article ID 950104, 1-12.
6.
Vojdani A, Lambert J. The onset of enhanced intestinal permeability and food sensitivity triggered
by medication used in dental procedures: A case report. Case Reports Gastro Med, 2012; doi:
1155/2012/265052. Epub 2012 Sep 12.
7.
Vojdani A, Tarash I. Cross-reaction between gliadin and different food and tissue antigens. Food
Nutri Sci, 44:20-32, 2013.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
Vojdani A, Perlmutter D. Differentiation between celiac disease, non-celiac gluten sensitivity, and
their overlapping with Crohn’s disease: a case series. Case Reports Immunol, 2013,
dx.doi.org/10.1155/2013/248482.
Selmi C, Lu Q, Humble MC. Heritability versus the role of the environment in autoimmunity. J
Autoimmun, 39:249-252, 2012.
Miller FW, Pollard KM, Parks CG, Germolec DR, Leung PSC, Selmi C, Humble MC, Rose NR. Criteria
for environmentally associated autoimmune diseases. J Autoimmun, 39:253-258, 2012.
Miller FW, Alfredsson L, Costenbader KH, Kamen DL, Nelson LM, Norris JM, De Roos AJ. Epidemiology
of environmental exposures and human autoimmune diseases: findings from a National Institute of
Environmental Health Sciences Expert Panel Workshop. J Autoimmun, 39:259-271, 2012.
Selmi C, Leung PSC, Sherr DH, Diaz M, Nyland JF, Monestier M, Rose NR, Gershwin ME. Mechanisms
of environmental influence on human autoimmunity: a National Institute of Environmental Health
Sciences Expert Panel Workshop. J Autoimmun, 39:272-284, 2012.
Germolec D, Kono DH, Pfau JC, Pollard KM. Animal m odels used to examine the role of the
environment in the development of autoimmune disease: findings from an NIEHS Expert Panel
Workshop. J Autoimmun, 39:285-293, 2012.
Wang J, Kay AB, Fletcher J, Formica MK, McAlindon TE. Is lipstick associated with the development
of systemic lupus erythematosus (SLE)? Clin Rheumatol, 27:1183-1187, 2008, doi:10.1007/s10067008-0937-6.
Banerjee BD, Chakraborti A, Suke SG, Ahmed RS, Tripathi AK. Xenobiotic-induced immune
alterations: implications in health and disease. Indian J Biochem Biophys, 45:7-75, 2008.
Barragan-Martinez C, Speck-Hernandez CA, Montoya-Ortiz G, Mantilla RD, Anaya JM, Rojas-Villaraga
A. Organic solvents as risk factor for autoimmune diseases: a systematic review and meta-analysis.
PLOS, 7(12):e51506, doi:10.1371/journal.pone.0051506.
Griem P, Wulferink M, Sachs B, Gonzalez JB, Gleichmann E. Allergic and autoimmune reactions to
xenobiotics: how do they arise? Immunol Today, 19(3):133-141, 1998.
Pollard KM, Hultman P, Kono DH. Toxicology of autoimmune diseases. Chem Res Toxicol, 23:455466, 2010.