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Environmentally Acquired Illness, part I
- 1. EAI Environmentally Acquired Illness Sonia Rapaport MD Haven Medical Chapel Hill, NC USA
- 2. Systems Biology Institute for Systems Biology. Systemsbiology.org “It is a holistic approach to deciphering the complexity of biological systems that starts from the understanding that the networks that form the whole of living organisms are more than the sum of their parts.”
- 3. Systems Biology “It is not enough to understand only one part of a system when studying the complexity of biology.” Institute for Systems Biology. Systemsbiology.org Network of Networks “It is collaborative, integrating many scientific disciplines … to develop solutions to the world’s most pressing health and environmental issues.”
- 5. Genetic Template • “Home-biome”: a built environment: • Nature’s contribution to the development of an individual (Nature-vs-Nuture) • Epigenetics: • Environmental effects • Transcriptomics
- 6. Genetic Template • Genetics • DNA: nuclear and mitochondrial • Transcriptomics • RNA • Proteomics • Proteins • Metabolomics • Metabolites
- 7. External Triggers: Sites of Entry • Skin • Gastrointestinal Tract • Respiratory Tract • Genital Urinary Tract
- 8. External Triggers: Skin • Infective organisms • Bacterial • Fungal • Topical • Personal care products • Airborne • Trauma • Physical • Skin breakdown • EMF
- 9. External Triggers: GI Tract • Foods • Allergens • Infections (viral, bacterial, parasitic) • Biotoxins (ciguatoxin, etc) • Non-food • Toxic Chemicals (glyphosate, phthalates, styrenes, etc) • Reabsorption of toxins
- 10. External Triggers: Respiratory • Routes of absorption: • Oropharynx • Alveoli • Olfactory nerve • Water-Damaged Buildings (WDB) • inflammagens • aka mold • Pollutants • VOCs
- 11. External Triggers: Psychosocial • Trauma • Personal vs witnessed • Post-Traumatic Stress Syndrome (PTSD) • Abuse • Emotional • Physical • Adverse Childhood Events (ACE)
- 12. Somatobiome The collection of living organisms present across all the ecological niches of the body. Gut Microbiome Sinu-rhinobiome Vasculo-biome Dermo-biome Vagino-biome Pulmo-biome
- 13. Somatobiome • Categories of organisms • Beneficial • Commensal • Infectious • Types of organisms • Viral • Bacterial • Parasitic • Fungal
- 14. Danger Responses • Pathogen Associated Molecular Patterns (PAMPs) • Danger Associated Molecular Patterns (DAMPs) • Cell Danger Response
- 15. Danger Responses • Immune • Autonomic Nervous System • Hypothalamic-Pituitary-Adrenal (HPA) Axis • Mitochondria
- 16. Danger Responses: Immunity • T Helper Response • TH1/TH2 balance • TH17: autoimmunity • Innate Immune Response • Cytokine production • Acquired Immune Response • Antibody response (depends on antigen presentation) • Mast cells • Connective tissue, mediator release • Microglial cells • Neurological tissue
- 17. Danger Responses: ANS • Autonomic (Vegetative) Nervous System • Sympathetic: Fight or Flight • Parasympathetic: Restore and Repair • Enteric: Gastrointestinal • Other areas of importance: • Vagal tone: Polyvagal Theory • Limbic system: Cyclical Amplification
- 18. Danger Responses: HPA • CNS hormonal regulation • Hypothalamus: CRF • Pituitary: ACTH • Adrenals: • Adrenaline • Noradrenaline • Cortisol
- 19. Danger Responses: Mitochondria • ATP Demand • Free radical production and damage • Defective mitochondrial biogenesis • Affected organs: • Brain: memory, brain fog • Muscle: weakness, trigger points • Autonomic nervous system: dysautonomia. POTS
- 22. Cyclical amplification: Mitochondria Mitochondrial dysfunction Dysautonomia Decreased cardiac output and blood flow
- 23. Cyclical amplification: Limbic system activation Emotional trauma Limbic system dsyfunction Sympathetic overactivation
- 24. How Do We Unravel This?
- 25. Identify the individual response • Anxiety, Depression, Panic Attacks • Insomnia, Hypersomnia, Circadian rhythm • Reflux, Leaky Gut Syndrome, SIBO • Candidiasis, Frequent Infections • Fatigue, Weakness, POTS • Headaches, Arthralgias, Pain • Rash, Histamine Intolerance, Allergies
- 26. Identify the individual pathology • Limbic system responses • Circadian rhythm dysregulation • Intestinal permeability and motility dysfunction • Immune dysregulation • Mitochondrial dysfunction • Inflammatory cytokines • Mast cell activation
- 27. Search history for exposures • Buildings: • Water-damaged buildings (home, work) • Environmental toxins • Foods: • allergens, toxins • Infection history; • Viral history • Bacterial exposures: Tick bites, fleas • Parasites, other infections • Traumas: • Traumatic Brain Injury (TBI) • Emotional, childhood • Dental history
- 28. Testing • Direct • Cultures • Toxin levels • Indirect • Inflammatory markers • Antibody responses • External • Buildings • Insects
- 29. Treatment Priorities A. Immune supportive • Inhaled biotoxins and inflammagens (water- damaged buildings) • Intestinal permeability • Autonomic balancing B. Infections • Lyme, co-infections • Activated viruses C. Cycle Resetting • Limbic system retraining
- 30. ENVIRONMENTALLY ACQUIRED INFLAMMATION: WATER DAMAGED BUILDINGS Chronic Inflammatory Response Syndrome (CIRS)
- 31. Environmentally Acquired Illness (EAI) Symptoms DIARRHEA Shortness of breath Anxiety insomnia JOINT PAIN Temperature Dysregulation Blurred Vision THIRST Night sweats vertigo Aches headaches FATIGUE
- 32. Environmentally Acquired Illness (EAI) Biomarkers Testosterone Anti-Diuretic Hormone DHEA progesterone Leptin OSMOLALITY VIP Melanocyte Stimulating Hormone ACTH thyroid Cortisol ACLA ESTROGEN
- 33. Suspecting EAI-WDB • Lyme disease resistant to treatment • Inability to lose weight • Low testosterone • Insufficient response to BHRT • Treatment failures • Chronic inflammation • High csCRP • Psychiatric symptoms • Memory problems • Sudden changes in vision • Thirst, frequent urination • Chronic Fatigue • Shortness of breath • Asthma
- 34. The EAI Detective • Suspect • Evidence of Biotoxin Exposure • Clinical picture: Symptoms and Signs • Diagnose • Abnormal labs and clinical tests • Physical exam • Treat • Improvement with treatment
- 35. Systems Biology Approach 1. Genetics 2. External Triggers 3. Somatobiome 4. Danger Responses
- 36. EAI-WDB Genetics • HLA: Shoemaker HLA susceptibility • Transcriptomics • Mitochondria • Sarcin-Ricin Loop • Ribosomal RNA • Risk Factors • EDS: Connective Tissue • Detoxification: Methylation, Sulfuration, etc
- 37. Human Leukocyte Antigen (HLA) • Major histocompatibility complex II • Cell-surface proteins • Capture extracellular antigens • Regulate acquired immune response • Chromosome 6p21 • Two genes • Disease associations
- 38. HLA Susceptibility • Multisuscpetible: 4.3.53, 11.3.52B, 12.3.52B, 14.5.52B, 13.3.52A • Mold susceptible: 7.2.53, 7.3.53, 13.6.52A, 13.6.52B, 13.6.52C, 17.2.52A, 18.4.52A • Borreliosis: 15.6.51, 16.5.51 • Low MSH: 1.5 • Dinoflagellates: 4.7.53, 4.8.53 -Ritchie Shoemaker, MD
- 39. HLA Controversies • Shoemaker HLA susceptibility (24%) • HLA allele frequency databases • Belgium: approximately 90% ‘susceptible’ • http://www.eupedia.com/genetics/HLA- DR_allele_frequencies_by_country.shtml • Cell surface expression: • CMV • HHV-6 • Trauma
- 40. EAI-WDB Genetics: Treatment • Support detoxification pathways • Improve HLA expression • Treat viruses • Plasmyc • Anti-viral herbals/medications • Treat and prevent trauma • Adverse childhood events • Meditative practices • Limbic system restructuring programs • Vasoactive Intestinal Peptide (VIP)
- 41. EAI-WDB: External Triggers • Fungi • Spores • Fragments • Mycotoxins • Bacteria • Mycobacteria • Actinomycetes • VOCs Factors contributing to toxicity of water- damaged buildings: a toxic stew
- 42. MOLDS
- 44. Mild Mold (?!?)
- 51. The Fab Five Toxic mold 1. Aspergillus penicilloides 2. Aspergillus versicolor 3. Chaetomium globosum 4. Stachybotrys chartarum 5. Wallemia sebi HERTSMI-2 testing Just a few of many toxic molds
- 52. Stachybotrys chartarum Toxic black mold Stachybotrys • Sticky spores being released into the atmosphere • High humidity required From EPA’s mold brochure Environ Health Perspect. 1999 Jun; 107(Suppl 3): 495–499. Overview of investigations into pulmonary hemorrhage among infants in Cleveland, Ohio. Dearborn, DG, et al.
- 53. Aspergillus Shoemaker, R. www.survivingmold.com • Common in damp homes • Low humidity required • HVACs
- 54. Mold growth requirements • Mold Spores • Temperature • Nutrient source • Dry wall • Framing • Furniture, personal effects • Moisture The ONE thing we can control is dampness
- 55. Water Damaged Buildings (WDB) • 50% of all American buildings have water damage (NIOSH, EPA) • Acceptable humidity levels: • < 55-60% < 30-45% Summer Winter
- 56. WDB: Get out • Find the source: • Building history: leaks, floods, fire, dust • Musty smells • Visible mold (take a photo) • Patterns of illness: timing • Don’t forget cars • At risk buildings: schools, rentals, dorms, hotels • Testing • Find a safe place
- 57. Safe Living • Air Purification: • Good quality air purifier • Air purifiers • Air cleaners/ozone • Check humidity • Humidity monitor (humidistat) • Get dehumidifier and use as needed
- 58. Remediation • Testing the environment: • Mold DNA: • HERTSMI-2: $155 • ERMI: $290 • Only tests that correlates with human health • Mold spore trapping (air flow testing) • Find the sources of moisture • Remediate and Retest • Removal of contaminated belongings
- 59. EAI: Somatobiome • MARCoNS: Multiple Antibiotic Resistant Coagulase Negative Staphlococcus bacteria • Borrelia • Viruses • Candida • Funneliformis mosseae? • Other commensal/infective/toxic organisms • Reduction in beneficial organisms
- 60. EAI: Somatobiome • MARCoNS: Multiple Antibiotic Resistant Coagulase Negative Staphlococcus bacteria • Thrive in water damaged buildings • Resistant to multiple antibiotics • Colonize deep nasal cavities • Biofilm producers • Staphylococcus Aureus competitor ? • Low Melanocyte Stimulating Hormone (MSH) ?
- 61. EAI: Somatobiome Treatment • MARCoNS: • Bactroban-EDTA-Gentamicin (BEG) • EDTA/colloidal (nano) silver • Mucolox additive (mucoadhesive polymer) • Sinu-rhinobiome repair (L. sakei) • Microbiome: Probiotics, prebiotics • Tickborne diseases: treatment protocols • Viral activation: antivirals herbals/medications • Biofilm producers: treatment protocols • Improve immunity: Transfer Factors
- 62. EAI: Danger Response Immune Dysregulation Symptoms • Flu-like symptoms such as headaches, chills, fatigue, brain fog, muscle and joint aches: cytokine storms • Food sensitivities including wheat: auto-immunity • Clotting: auto-immunity (anticardiolipin) • Allergy symptoms, rashes, GI symptoms, brain fog, interstitial cystitis, asthma: Mast cell activation
- 63. EAI: Danger Response Immunity • Cytokine Production: • Flu-like symptoms • Innate Immune Response: • T-regulatory cell dysfunction (TGFB1 elevation) • Complement cascade (C4a elevation) • Auto-Immunity • Anti-gliadin Ab • Anti-cardiolipin Ab • Mast cells • Histamine response, • MSH production
- 64. EAI: Danger Response Immune Treatment • Cytokine Production: • Cytoquel • Transfer Factor, Transfer Factor Enviro • Innate Immune Response: • Transfer Factor • Auto-Immunity • Transfer Factor • Avoidance • Mast cells • Quercetin • Ketotifen
- 65. Mitochondria and Cytokine Production • Targeting mitochondrial reactive oxygen species as novel therapy for inflammatory diseases and cancers. Li et al. Journal of Hematology & Oncology 2013, 6:19 • Cytokine production by mtROS: • Activation of RIG-1-like receptors • Inflammasome activation • MAPK
- 66. PAMPs, DAMPs, and Mitochondria • PAMPs: • Pathogen Associated Molecular Patterns • Exogenous: bacteria, viruses, fungi • DAMPs: • Danger Associated Molecular Patterns • Endogenous • “hidden-self”
- 67. Mitochondria: Source of DAMPS • Mitochondrial constituents as DAMPs: • Injection of mtDNA into joints induces inflammation and arthritis • Splenocytes exposed to mtDNA (not nDNA) increase cytokine secretion • mtDNA is released into circulation during trauma and shock • Mitochondrial extracts (with mtDNA) cause systemic lung and liver inflammation in vivo
- 68. Pattern Recognition Receptors • TLR: Toll-like Receptors • Transmembrane proteins, Interleukin-1 family • Recognize bacterial, viral and fungal PAMPs, and DAMPs • NLR: NOD-like Receptors • Cytosolic receptors • Recognize microbial PAMPs and DAMPs • CLR: C-type Lectin Receptors • Soluble and transmembrane proteins • Recognize carbohydrate structures on pathogens • RLR: RIG-1-like Receptors • Cytosolic receptors in immune and non-immune cells • Required for type I interferon and proinflammatory cytokine production through NFKB in viral infections Mitochondria in innate immune responses. West PA et al. Nat Rev Immunol. 2011 Jun: 11(6): 389-402.
- 69. Mycotoxin Stimulation of Mitochondrial DAMPS • NLRP3 Inflammasome • Member of NLR family • Activates caspase 1, leading to pro-IL-1B, IL-18 • Increased ROS production may be critical for activation • Trichothecene mycotoxins activate NLRP3 inflammasome through a P2X7 receptor and Src tyrosine kinase dependent pathway. Kankkunen P et al. Hum Immunol. 2014 Feb;75(2):134-40. • Roridin A (WDB-mycotoxin) acts as microbial danger signal • Triggers activation of NLRP3 inflammasome in human primary macrophages
- 70. Mitochondria and Innate Immunity • Centrally positioned for innate immune responses • Enhanced crosstalk between metabolic and immune pathways • Augment host ability to sense microbial virulence mechanism
- 71. TGF-β1 and Mitochondrial Defects • GSK3 inactivation is involved in mitochondrial complex IV defect in transforming growth factor (TGF) β1-induced senescence. Byun HO et al. Exp Cell Res. 2012 Sep 10;318(15):1808-19. • TGF-β1 stimulates mitochondrial oxidative phosphorylation and generation of reactive oxygen species in cultured mouse podocytes, mediated in part by the mTOR pathway. Abe Y et al. Am J Physiol Renal Physiol. 2013 Nov 15; 305(10): F1477–F1490. • Epithelial Cell Mitochondrial Dysfunction and PINK1 Are Induced by Transforming Growth Factor- Beta1 in Pulmonary Fibrosis. Patel A et al. PLoS One. 2015; 10(3): e0121246.
- 72. Strategies to Optimize Mitochondrial Structure • Lipid Replacement Therapy http://www.bbc.com/news/health-32434347