Aristo Vojdani

Antibodies to neuron-specific antigens in children with autism: possible cross-reaction with encephalitogenic proteins from milk, Chlamydia pneumoniae and Streptococcus group A

We measured autoantibodies against nine different neuron-specific antigens and three cross-reactive peptides in the sera of autistic subjects and healthy controls by means of enzyme-linked immunosorbent assay (ELISA) testing. The antigens were myelin basic protein (MBP), myelin-associated glycoprotein (MAG), ganglioside (GM1), sulfatide (SULF), chondroitin sulfate (CONSO4), myelin oligodendrocyte glycoprotein (MOG), α,β-crystallin (α,β-CRYS), neurofilament proteins (NAFP), tubulin and three cross-reactive peptides, Chlamydia pneumoniae (CPP), streptococcal M protein (STM6P) and milk butyrophilin (BTN). Autistic children showed the highest levels of IgG, IgM and IgA antibodies against all neurologic antigens as well as the three cross-reactive peptides. These antibodies are specific because immune absorption demonstrated that only neuron-specific antigens or their cross-reactive epitopes could significantly reduce antibody levels. These antibodies may have been synthesized as a result of an alteration in the blood–brain barrier. This barrier promotes access of preexisting T-cells and central nervous system antigens to immunocompetent cells, which may start a vicious cycle. These results suggest a mechanism by which bacterial infections and milk antigens may modulate autoimmune responses in autism.

Infections, Toxic Chemicals and Dietary Peptides Binding to Lymphocyte Receptors and Tissue Enzymes are Major Instigators of Autoimmunity in Autism

Similar to many complex autoimmune diseases, genetic and environmental factors including diet, infection and xenobiotics play a critical role in the development of autism. In this study, we postulated that infectious agent antigens such as streptokinase, dietary peptides (gliadin and casein) and ethyl mercury (xenobiotic) bind to different lymphocyte receptors and tissue enzyme (DPP IV or CD26). We assessed this hypothesis first by measuring IgG, IgM and IgA antibodies against CD26, CD69, streptokinase (SK), gliadin and casein peptides and against ethyl mercury bound to human serum albumin in patients with autism. A significant percentage of children with autism developed anti-SK, anti-gliadin and casein peptides and anti-ethyl mercury antibodies, concomitant with the appearance of anti-CD26 and anti-CD69 autoantibodies. These antibodies are synthesized as a result of SK, gliadin, casein and ethyl mercury binding to CD26 and CD69, indicating that they are specific. Immune absorption demonstrated that only specific antigens, like CD26, were capable of significantly reducing serum anti-CD26 levels. However, for direct demonstration of SK, gliadin, casein and ethyl mercury to CD26 or CD69, microtiter wells were coated with CD26 or CD69 alone or in combination with SK, gliadin, casein or ethyl mercury and then reacted with enzyme labeled rabbit anti-CD26 or anti-CD69. Adding these molecules to CD26 or CD69 resulted in 28–86 % inhibition of CD26 or CD69 binding to anti-CD26 or anti-CD69 antibodies. The highest % binding of these antigens or peptides to CD26 or CD69 was attributed to SK and the lowest to casein peptides. We, therefore, propose that bacterial antigens (SK), dietary peptides (gliadin, casein) and Thimerosal (ethyl mercury) in individuals with pre-disposing HLA molecules, bind to CD26 or CD69 and induce antibodies against these molecules. In conclusion, this study is apparently the first to demonstrate that dietary peptides, bacterial toxins and xenobiotics bind to lymphocyte receptors and/or tissue enzymes, resulting in autoimmune reaction in children with autism.

Low natural killer cell cytotoxic activity in autism: the role of glutathione, IL-2 and IL-15.

Although many articles have reported immune abnormalities in autism, NK cell activity has only been examined in one study of 31 patients, of whom 12 were found to have reduced NK activity. The mechanism behind this low NK cell activity was not explored. For this reason, we explored the measurement of NK cell activity in 1027 blood samples from autistic children obtained from ten clinics and compared the results to 113 healthy controls. This counting of NK cells and the measurement of their lytic activity enabled us to express the NK cell activity/100 cells. At the cutoff of 15-50 LU we found that NK cell activity was low in 41-81% of the patients from the different clinics. This NK cell activity below 15 LU was found in only 8% of healthy subjects (p<0.001). Low NK cell activity in both groups did not correlate with percentage and absolute number of CD16(+)/CD56(+) cells. When the NK cytotoxic activity was expressed based on activity/100 CD16(+)/CD56(+) cells, several patients who had displayed NK cell activity below 15 LU exhibited normal NK cell activity. Overall, after this correction factor, 45% of the children with autism still exhibited low NK cell activity, correlating with the intracellular level of glutathione. Finally, we cultured lymphocytes of patients with low or high NK cell activity/cell with or without glutathione, IL-2 and IL-15. The induction of NK cell activity by IL-2, IL-15 and glutathione was more pronounced in a subgroup with very low NK cell activity. We conclude that that 45% of a subgroup of children with autism suffers from low NK cell activity, and that low intracellular levels of glutathione, IL-2 and IL-15 may be responsible.

Antibodies to myelin basic protein, myelin oligodendrocytes peptides, alpha-beta-crystallin, lymphocyte activation and cytokine production in patients with multiple sclerosis.

Abstract Vojdani A, Vojdani E, Cooper E (Laboratory of Comparative Neuroimmunology, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles; Immunosciences Lab., Inc., Beverly Hills; and University of California Berkeley, Berkeley; CA, USA). Antibodies to myelin basic protein, myelin oligodendrocytes peptides, α‐β‐crystallin, lymphocyte activation and cytokine production in patients with multiple sclerosis. J Intern Med 2003; 254: 363–374.

A Potential Link between Environmental Triggers and Autoimmunity.

Autoimmune diseases have registered an alarming rise worldwide in recent years. Accumulated evidence indicates that the immune systems ability to distinguish self from nonself is negatively impacted by genetic factors and environmental triggers. Genetics is certainly a factor, but since it normally takes a very long time for the human genetic pattern to change enough to register on a worldwide scale, increasingly the attention of studies has been focused on the environmental factors of a rapidly changing and evolving civilization. New technology, new industries, new inventions, new chemicals and drugs, and new foods and diets are constantly and rapidly being introduced in this fast-paced ever-changing world. Toxicants, infections, epitope spreading, dysfunctions of immune homeostasis, and dietary components can all have an impact on the bodys delicate immune recognition system. Although the precise etiology and pathogenesis of many autoimmune diseases are still unknown, it would appear from the collated studies that there are common mechanisms in the immunopathogenesis of multiple autoimmune reactivities. Of particular interest is the citrullination of host proteins and their conversion to autoantigens by the aforementioned environmental triggers. The identification of these specific triggers of autoimmune reactivity is essential then for the development of new therapies for autoimmune diseases.

The Role of Th17 in Neuroimmune Disorders: A Target for CAM Therapy. Part III

Abundant research has mapped the inflammatory pathways leading to autoimmunity and neuroinflammatory disorders. The latest T helper to be identified, Th17, through its proinflammatory cytokine IL-17, plays a pathogenic role in many inflammatory conditions. Today, healthcare providers have a wealth of anti-inflammatory agents from which to choose. On one hand, pharmaceutical companies market brand-name drugs direct to the public and physicians. Medical botanical knowledge, on the other hand, has been passed down from generation to generation. The demands for natural healing therapies have brought corresponding clinical and laboratory research studies to elucidate the medicinal properties of alternative practices. With a variety of options, it can be difficult to pinpoint the proper anti-inflammatory agent for each case presented. In this review, the authors highlight a vast array of anti-inflammatory medicaments ranging from drugs to vitamins and from botanicals to innate molecules. This compilation may serve as a guide for complimentary and alternative healthcare providers who need to target neuroinflammation driven by Th17 and its inflammatory cytokine IL-17. By understanding the mechanisms of anti-inflammatory agents, CAM practitioners can tailor therapeutic interventions to fit the needs of the patient, thereby providing faster relief from inflammatory complaints.

Heat Shock Protein and Gliadin Peptide Promote Development of Peptidase Antibodies in Children with Autism and Patients with Autoimmune Disease

ABSTRACT Searching for a mechanism underlying autoimmunity in autism, we postulated that gliadin peptides, heat shock protein 60 (HSP-60), and streptokinase (SK) bind to different peptidases resulting in autoantibody production against these components. We assessed this hypothesis in patients with autism and in those with mixed connective tissue diseases. Associated with antigliadin and anti-HSP antibodies, children with autism and patients with autoimmune disease developed anti-dipeptidylpeptidase I (DPP I), anti-dipeptidylpeptidase IV (DPP IV [or CD26]) and anti-aminopeptidase N (CD13) autoantibodies. A significant percentage of autoimmune and autistic sera were associated with elevated immunoglobulin G (IgG), IgM, or IgA antibodies against three peptidases, gliadin, and HSP-60. These antibodies are specific, since immune absorption demonstrated that only specific antigens (e.g., DPP IV absorption of anti-DPP IV), significantly reduced IgG, IgM, and IgA antibody levels. For direct demonstration of SK, HSP-60, and gliadin peptide binding to DPP IV, microtiter wells coated with DPP IV were reacted with SK, HSP-60, and gliadin. They were then reacted with anti-DPP IV or anti-SK, anti-HSP, and antigliadin antibodies. Adding SK, HSP-60, and gliadin peptides to DPP IV resulted in 27 to 43% inhibition of the DPP IV-anti-DPP IV reaction, but DPP IV-positive peptides caused 18 to 20% enhancement of antigen-antibody reactions. We propose that (i) superantigens (e.g., SK and HSP-60) and dietary proteins (e.g., gliadin peptides) in individuals with predisposing HLA molecules bind to aminopeptidases and (ii) they induce autoantibodies to peptides and tissue antigens. Dysfunctional membrane peptidases and autoantibody production may result in neuroimmune dysregulation and autoimmunity.

Silicone implants and systemic immunological disease: review of the literature and preliminary results.

Silicone has been utilized as an implant in reconstructive surgery. For years, silicone has been considered to be biologically inert and essentially harmless. Several studies and case reports show that female patients treated with silicone implants developed a systemic disease associated with immunological abnormalities. Removal of the silicone implants was associated with recovery and resolution of the immune abnormalities. Recently, specific antibodies to silicone have been isolated in children with silicone implants. Additionally, immunological abnormalities and high incidence of systemic progressive sclerosis in patients with silicone implants or injections further support the notion that silicone is not biologically inert, and can cause a syndrome of a systemic disease and immunological abnormalities. The specific mechanisms and duration of the latency period is not yet fully understood.

The Intestinal Barrier in Air Pollution-Associated Neural Invol vement in Mexico City Residents: Mind the Gut, the Evolution of a Chan ging Paradigm Relevant to Parkinson Disease Risk

Objective: Braak et al proposal in 2003 “a putative environmental pathogen capable of passing the gastric epithelial lining might induce α-synuclein misfolding and aggregation” could indeed be particulate matter gaining access through the most vulnerable section of the GI tract: the small bowel. This study is focused on the electron microscopy examination of tight junctions in duodenum of healthy dogs residing in one of the most polluted megacities in our continent, Mexico City Metropolitan Area (MCMA)with high concentrations of fine particulate matter (PM 2.5) and nanosize PM versus low-air pollution controls and to measure serum antibodies to tight junctions (TJ) and neural proteins in MCMA versus low air pollution exposed children.The small intestine would be a prime PM target: it has a single unattached mucus layer, particles have easy access to epithelial cells and Peyer’s patches, altering epithelial integrity and accessing the enteric nervous system.Autopsies in MCMA children v controls show extensive brainstem oxidative stress, microglial activation, and accumulation of α-synuclein, from the dorsal motor nucleus of the vagus to the substantianigrae.Air pollution targets the dorsal vagal complex in mice exposed to the polluted MCMA atmosphere. Methods: A pilot observational case-control dogs and children study of high versus low PM 2.5 exposures.We counted and evaluated the integrity of TJ’s in duodenal electron micrographs from 6 MCMA dogs (5.01 ± 1.36 years) and 4 control dogs (5.87 ± 1.50 years) and we measured by ELISA serum antibodies to tight junctions (TJ) and neural proteins in 95 MCMA versus controls (11.02 ± 3.6 years). Results: Disruption of epithelial integrity with TJ structural changes in MCMA v control dogs (p<0.0001), the major determinant of paracellular permeability characterized the MCMA dogs’ small bowel architecture. MCMA children had higher occludin-zonulin, actin, transglutaminase 3 and 6, and glutamic acid decarboxylase autoantibodies (p<0.01).Conclusion: The integrity of the gastrointestinal (GI) barrier is significantly compromised in MCMA dogs and could be altered in MCMA children as evidenced by the autoimmune response to TJ and neural proteins. The GI breakdown likely impacts neuronal enteric populations and PM could reach the vagus and the brainstem. In the setting of urban air pollution, the evolution of a changing paradigm favoring a pathogen penetrating an epithelial lining and via transsynaptic transmission reaching preganglionic parasympathetic motor neurons of the vagus nerve has to entertain particles as a potential culprit.Defining the linkage and the health consequences of the brain/ gut/ immune system interactions in urban children showing already the early hallmarks of Parkinson’s disease ought to be of pressing importance for public health, may provide a fresh insight into Parkinson disease pathogenesis and open opportunities for pediatric neuroprotection.

Novel Diagnosis of Lyme Disease: Potential for CAM Intervention

Lyme disease (LD) is the most common tick-borne disease in the northern hemisphere, producing a wide range of disabling effects on multiple human targets, including the skin, the nervous system, the joints and the heart. Insufficient clinical diagnostic methods, the necessity for prompt antibiotic treatment along with the pervasive nature of infection impel the development and establishment of new clinical diagnostic tools with increased accuracy, sensitivity and specificity. The goal of this article is 4-fold: (i) to detail LD infection and pathology, (ii) to review prevalent diagnostic methods, emphasizing inherent problems, (iii) to introduce the usage of in vivo induced antigen technology (IVIAT) in clinical diagnostics and (iv) to underscore the relevance of a novel comprehensive LD diagnostic approach to practitioners of Complementary and Alternative Medicine (CAM). Utilization of this analytical method will increase the accuracy of the diagnostic process and abridge the time to treatment, with antibiotics, herbal medicines and nutritional supplements, resulting in improved quality of care and disease prognosis.