The Unseen Epidemic of Autoimmunity AAFN Part T H E P H A N T O M M E N A C E

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1 The Unseen Epidemic of Autoimmunity AAFN Part T H E P H A N T O M M E N A C E II

2 There is a difference between autoimmune reactivity and autoimmune disease. Predictive antibodies can detect autoimmune reactivity sometimes years before the onset of active autoimmune disease, and can therefore be used as early diagnostic biomarkers. The gut and the brain are immunologically linked, so that uncontrolled inflammation in the gut can lead to inflammation in the brain, resulting in neuroinflammation and neuroautoimmunity. The pathogenicity of antibodies is demonstrated by the fact that transfer from one host to another has resulted in the transfer of diseases. AAFN Part

3 The innate immune system, in particular cytokines and antibodies, plays a significant role in traumatic brain injury (TBI) Inflamed cytokines and antibodies cross barriers to cause neuroautoimmune damage. Neuroautoimmunity and neurodegeneration can be prevented through various strategies hinging upon balanced gut microflora, intact gut barrier, intact BBB, and the prevention of autoreactive T H 1 and T H 17 cells from crossing the barriers. Detecting the biomarkers of autoimmunity, removing the triggers, and repairing the barriers can stop and even reverse the course of autoimmune disorders. AAFN Part

4 Autoimmunity means immunity against self. It is the third most common disorder in the US and the world. 53 million people in the US have autoimmune disease. Autoimmune disease can mean many years of suffering. To facilitate timely intervention and prevent years of suffering, the next generation of assessment tools are needed for the very early detection of autoimmune disease. AAFN Part

5 The very early stage of autoimmune disease where an individual s immune system produces antibodies against self tissue antigens. AAFN Part

6 A clinical syndrome What caused is Autoimmune by the activation of T cells or B cells, or both,...[resulting in tissue destruction and/or dysfunction.] Disease? J Autoimmune Dis, 2005; 2:9 AAFN Part

7 When the Body s Homeland Security is sleeping on the job, that s when the terror of Autoimmunity strikes. AAFN Part

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9 Different mechanisms involved in the increased autoimmunities in aging Thymus dysfunction Breakdown in immunological tolerance - Change in good microbiota - Increased gut permeability - Binding of haptenic chemicals to human tissue - Aberrant DNA methylation Dysregulation of immune homeostasis Pathological activation of the innate immune system and autoinflammation AAFN Part

10 copyright Aristo Vojdani, PhD, MSc, CLS X X X AAFN Part

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13 NEW PREDICTORS of DISEASE Molecules called predictive autoantibodies appear in the blood years before people show symptoms of various disorders. Tests that detected these molecules could warn of the need to take preventive action. Abner Louis Notkins, Scientific American, 296(3):72-79, 2007 Leslie D, Lipsky P, Notkins AL. Autoantibodies as predictors of disease. J Clin Invest 2001 ; 108 : AAFN Part

14 Aristo Vojdani, 2(6): , 2008 International Journal of Immunopathology and Pharmacology Antibodies as predictors of complex autoimmune diseases. Vojdani, A., 2008, 21(2): International Journal of Immunopathology and Pharmacology Antibodies as predictors of complex autoimmune diseases and cancer. Vojdani, A., 2008, 21(3): AAFN Part

15 The interval between first detection of autoimmune phenomena (auto-antibodies) and first symptoms can last 10 years. Rantapaa-Dahlqvist et al. Arthritis Rheum, 2003; 48: AAFN Part

16 The risk of diabetes increases with the number of diabetes-related autoantibodies in the blood. Tyrosine Phosphatase IA-2 GAD-65 Insulin AAFN Part

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18 Potential of Biomarkers: Predictive Antibodies for Autoimmune Reactivity Enable diagnosis before the onset of symptoms Predict specific organ involvement Predict disease flares Identify clinically meaningful disease subsets Predict and monitor response to therapy Describe organ or tissue damage AAFN Part

19 Array 5 Multiple Autoimmune Reactivity Screen Parietal Cell + ATPase Intrinsic Factor ASCA + ANCA Tropomyosin Thyroglobulin Thyroid Peroxidase 21 Hydroxylase (Adrenal Cortex) Myocardial peptide a-myosin Phospholipid Platelet Glycoprotein Ovary + Testis Fibulin Collagen complex Arthritic peptide Osteocyte Cytochrome P450 Hepatocyte Insulin + Islet Cell Antigen Glutamic- Acid Decarboxylase Myelin Basic Protein Asialoanglioside GM1 a + b Tubulin Cerebellar Synapsin AAFN Part

20 For a patient with any idiopathic conditions caused by environmental triggers Infections Chemicals Dietary Proteins Follow up with a patient who has chronic increased intestinal permeability, which is the gateway for environmentally-induced disorders Follow up with an autoimmune patient to monitor treatment and to screen for additional autoimmune disease AAFN Part

21 y.o. Male Medical History Diagnosed with Neuropathy Diagnosed with Pulmonary Fibrosis Hypothyroidism Irritable Bowel Syndrome Three Stents in his Heart AAFN Part

22 Clinical Complaints Decrease in his physical exertion tolerance Gas and bloating Alternating constipation/diarrhea Experiencing faintness Constant burning and discomfort in stomach Cold hands and feet Tinnitis AAFN Part

23 Parietal + ATPase Intrinsic Factor ASCA+ANCA Tropomyosin Thyroglobulin TPO 21 Hydroxylase Myocardial Myosin Phospholipid Platelet Glyco Ovary/Testis Fibulin Collagen Arthritic Peptide Osteocyte Cyto P450 Insulin+Islet Cell GAD65 MBP Ganglioside Tubulin Cerebellar Synapsin 9 # AAFN Part

24 # Range 1.6 Result AAFN Part

25 Wheat IgG Wheat IgA WGA IgG WGA IgA Gli-33 IgG Gli-33 IgA Gli-17 IgG Gli-17 IgA Gli-15 IgG Gli-15 IgA Gli-17 IgG Gli-17 IgA Glutenin-21 IgG Glutenin-21 IgA Glute+Pro IgG Glute+Pro IgA Gliadin-tTG IgG Gliadin-tTG IgA ttg-2 IgG ttg-2 IgA ttg-3 IgG ttg-3 IgA ttg-6 IgG ttg-6 IgA 8 # AAFN Part

26 Had this patient s gluten reactivity been discovered when he was still in his 30 s, a gluten-free diet may have prevented Neuropathy Diabetes Cardiovascular disease Many years of suffering 26

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29 The neuroimmune connection. 29

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31 TRENDS Immunol, 2008, 29(8): We hypothesize that in the diseased CNS, interactions between damaged neurons and dysregulated, overactivated microglia create a vicious self-propagating cycle causing uncontrolled, prolonged inflammation that drives the chronic progression of neurodegenerative diseases. AAFN Part

32 Diamond B, et al. In recent years, numerous brain-reactive antibodies have been identified in human sera and have been proposed to associate with neurological or neuropsychiatric symptoms. These antibodies can be divided into three categories: antibodies that have a causal relationship with the development of symptoms; antibodies that are generated as a secondary symptom during brain disease, perhaps as a result of brain injury; and antibodies that will turn out to not be associated with disease as more careful studies are carried out (false-positive cases). AAFN Part

33 Moreover, in the presence of MBP, MOG peptides or a-bcrystallin, a significant percentage of lymphocytes from MS patients underwent blast transformation, which resulted in high levels of IFN-g, TNF-a and TNF-b production. Detection of antibodies against MBP, MOG peptides, a-bcrystallin, lymphocyte stimulation and production of proinflammatory cytokines in response to these antigens could be used as surrogate markers for the confirmation of MS diagnosis. AAFN Part

34 N Engl J Med 2003;349: Patients with anti-mog and anti-mbp antibodies had relapses more often and earlier than patients without these antibodies. Analysis of antibodies against MOG and MBP in patients with a clinically isolated syndrome is a rapid, inexpensive, and precise method for the prediction of early conversion to clinically definite MS. AAFN Part

35 AAFN Part Additionally, there were increased titers to dopamine and S100B (96% and 89%) in the 5-year patient group. All of these values subsided in 10-year sufferers. Furthermore, CD3+, CD4+, CD8+ T-lymphocyte and B-lymphocyte subsets declined in the patient cohort during Parkinsonism indicating disease associated reductions in these lymphocyte subsets.

36 Schematic showing the differential generation of autoantibodies to α-synuclein monomers, oligomers, S100B and dopamine in 5- and 10-year Parkinson's disease sufferers in relation to their declining immune status and progressively increasing indicators of inflammation and oxidative stress. M.A. Gruden et al. / Journal of Neuroimmunology 233 (2011) AAFN Part

37 Association between Neural Antibodies and Different Neuroautoimmune Disorders Antigens Myelin Basic Protein (MBP) Myelin Oligodendrocyte Glycoprotein (MOG) a-b-crystallin Transaldolase Myelin Associated Glycoprotein (MAG GM 1, LM 1, GD 1b, GQ 1b ) Sulfatide Campylobacter Jejuni Sulfatide and Chondroitin Sulfate Glutamate Receptors Ion Channel Cerebellar Purkinje Cells MBP Neuron-Axon Filament Protein (NFP) Glial Fibrillary Acidic Protein (GFAP) Tubulin S-100 Ptotein, NFP, GFAP Muscarinic Acetylcholine Receptor Multiple Sclerosis Disease Occurences Demyelinating Sensorimotor Neuropathies Guillain-Barre Syndrome Chronic Sensory Neuropathy Amyotrophic Lateral Sclerosis Or Lou Gehrig s Disease Rassmussen s Encephalitis Paraneoplastic Cerebellar Degeneration Neurotoxicity, Autism Alzheimer s, Brain Aging & Vascular Dementia Schizophrenia Acetylcholine Receptor Myasthenia Gravis AAFN Part

38 Immunology, 2008; 125(2): Autoreactive T cells are thought to play an essential role in the pathogenesis of multiple sclerosis (MS). These data suggest that autoantigen-driven CD4+ T-cell proliferation and release of IL-17 and IL-5 may be associated with disease activity. AAFN Part

39 Immunology, 2008; 125(2): The attack of autoreactive T cells on the white matter of the central nervous system leads to multiple demyelinating lesions. The initiating event in the activation of autoreactive CD4+ T cells is the presentation of self-peptides by antigen-presenting cells. Naïve CD4+ T helper (Th) cells may develop into different committed helper cell subsets characterized by distinct cytokine profiles, 5 interferon-g (IFN-g) and interleukin-4 (IL-4) being the signature cytokines of Th1 and Th2 cells, respectively. A subset of memory CD4+ T cells (Th17 cells) producing IL-17 under the influence of IL-6, IL-23 and transforming growth factor-b (TGF-b) has been described in mice. AAFN Part

40 Polyreactive myelin oligodendrocyte glycoprotein antibodies: Implications for systemic autoimmunity in progressive experimental autoimmune encephalomyelitis Peterson LK et al., J Neuroimmunol, 2007; 183:69-80 Two myelin oligodendrocyte glycoprotein (MOG92 106) monoclonal antibodies (mabs) were produced from an A.SW mouse with progressive experimental autoimmune encephalomyelitis. Polyreactivity/specificity of the mabs was demonstrated by ELISA. Functionality and a potential role in pathogenesis of systemic autoimmunity were demonstrated in vitro in a lymphocytotoxicity assay and in vivo upon injection into naïve mice. Injection of MOG mab producing hybridomas into naïve mice resulted in immunoglobulin deposition in kidneys and liver. AAFN Part

41 Immunoglobulin (Ig) deposition in the kidney and lung of mice with progressive experimental autoimmune encephalomyelitis (EAE). Kidney and lung sections were immunostained for Ig deposition. (a) No Ig deposition was seen in glomeruli (G) or tubules (T) in the kidneys of MOG sensitized mice during the preclinical period. (b) Ig deposition was localized to the glomeruli of the kidney in mice with progressive EAE. AAFN Part

42 Figure 13-2 part 1 of 2 Identification of autoantibodies that can transfer disease in patients with myasthenia gravis. Autoantibodies from the serum of patients with myasthenia gravis immunoprecipitate the acetylcholine receptor from lysates of skeletal muscle cells. Because they can bind to the murine as well as the human acetylcholine receptor, they can transfer disease when injected into mice. This demonstrates that the antibodies are pathogenic. AAFN Part

43 LPS induce inflammatory response, inducing production of cytokines and increase in the number of T H 17 positive cells in circulation. Expression of IL-17 and IL-22 receptors on BBB endothelial cells result in the binding of T H 17 cells to BBB tight junctions. This disrupts the tight junctions, leading to autoreactive CD4 cells and neurodegeneration. T H 17 cells then transmigrate across the BBB, setting the stage for the killing of neurons by the release of granzyme B. This release of neural cell antigen results in a vicious cycle of neuroautoimmunity and neurodegeneration. AAFN Part

44 Considering that gluten and casein cross-react with nervous system antigens, do you still want to give them mac and cheese? AAFN Part

45 Traumatic Brain Injury (TBI) is a multifaceted pathology including diverse mechanisms such as excitotoxicity, free radical formation, disrupted metabolism and brain swelling. A range of cytokines and chemokines have been implicated in these pathophysiological consequences of TBI. AAFN Part

46 The acknowledgement of risks for traumatic brain injury in American football players has prompted studies for sideline concussion diagnosis and testing for neurological deficits. While concussions are recognized etiological factors for a spectrum of neurological sequelae, the consequences of sub-concussive events are unclear. AAFN Part

47 In conclusion, we have shown that serum S100B elevations, which are indicators of BBBD, occur in football players even when concussions are not diagnosed. Our results suggest that these levels of S100B trigger production of auto-antibodies that may constitute a risk factor for premature neurodegeneration. AAFN Part

48 Proposed mechanism for excitotoxicity from leaky BBB AAFN Part

49 Autoreactive antibodies and intact BBB AAFN Part

50 Autoreactive antibodies and disrupted BBB AAFN Part

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52 BREACHING THE BARRIER How do autoreactive T cells invade and damage the brain? AAFN Part

53 Vojdani et al. The role of Th17 in neuroimmune disorders: target for CAM therapy III. ecam; advance access 2009, doi: /ecam/nep064. AAFN Part

54 Anti-inflammatory activity of plasma exchange in immune-mediated neuropathies: Plasma exchange (PE) removes autoantibodies, cytokines and complement as well as unknown (?) humoral factors that alter lymphocyte function (red arrow). Lehmann & Hartung, J Neuroimmunol 2011, 231(1), 61-9 AAFN Part

55 Anti-inflammatory activity of plasma exchange in immune-mediated neuropathies: IVIg (red IgG molecules) reduces interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF-α) and increases transforming growth factor beta (TGF-β) production. Lehmann & Hartung, J Neuroimmunol 2011, 231(1), 61-9 AAFN Part

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57 VOLUME 19 NUMBER 5 MAY 2013 pp nature medicine We demonstrate here that metabolism by intestinal microbiota of dietary L-carnitine, a trimethylamine abundant in red meat, also produces TMAO and accelerates atherosclerosis in mice Intestinal microbiota may thus contribute to the well-established link between high levels of red meat consumption and CVD risk. AAFN Part

58 Dietary-derived compounds Fiber Protein Fat Carbohydrates Change in microbiota Eubiosis Dysbiosis I n t e r a c t i o n w i t h t h e h o s t Immune homeostasis Healthy, stable state Systemic inflammation Asthma, atopic dermatitis, R. arthritis, multiple sclerosis, Guillain-Barré syndrome, obesity, metabolic syndrome Alteration of gut microbiota by dietary-derived factors AAFN Part

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60 EARLY DETECTION (Predictive Antibodies) AAFN Part

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62 FOXP3 + T REG cell Regulatory T Cells Pathogenic TH17 T H 17 AAFN Part