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Ppt, immune cns network lt may 2015
- 1. Question... WHY WOULD ANIMMUNE CHALLENGE SUCH AS VACCINATION, AFFECT BRAIN DEVELOPMENT AND/OR FUNCTION ?
- 2. o “Until recently,the brain was studied almost exclusively by neuroscientists and the immune system by immunologists, fuelling the notion that these systems represented two isolated entities. o ....the crosstalk between these systems can no longer be ignored and a new interdisciplinary approach is necessary.”
- 3. o Many proteinsfirst identified in the immune system are also expressed in the developing and adult nervous system. Unexpectedly, recent studies reveal that a number of these proteins, in addition to their immunological roles, are essential for the establishment, function, and modification of synaptic connections.
- 4. o “Recent studiesdemonstrate that immune molecules are present at the right place and time to modulate the development and function of the healthy and diseased central nervous system (CNS). o “...functions for immune molecules during neural development suggest that they could also mediate pathological responses to chronic elevations of cytokines in neurodevelopmental disorders, including autism spectrum disorders and schizophrenia.”
- 5. o “Despite thedogma that peripheral immune responses could not affect CNS function under normal circumstances, substantial evidence over the past 10 years suggests that immune-CNS cross-talk may be the norm rather than the exception.”
- 6. In: Handbook ofNeurochemistry and Molecular Neurobiology: A Lajtha, HO Besedovsky, A Galoyan (Eds), Springer, 2008. o Because the communication between the immune system and the brain occurs at multiple levels, this communication is now defined as a “immune–neuroendocrine network.” o The immune–neuroendocrine network plays a key role in: ‒ immune regulation ‒ brain function ‒ maintenance of general homeostasis (circadian rhythms, endocrine and metabolic functions)
- 8. Disruption of the immune-neuroendocrinenetwork leads to a wide range of diseases: − neurological − immuno-inflammatory − metabolic disorders
- 10. What kind ofdisorder is autism?
- 11. “Increased oxidative stressand immune dysregulation are present in autism spectrum disorders.” “We recently demonstrated the presence of neuroglial and innate neuroimmune system activation in brain tissue and cerebrospinal fluid of patients with autism, findings that support the view that neuroimmune abnormalities occur in the brain of autistic patients and may contribute to the diversity of the autistic phenotypes.”
- 12. o The evidencethat changes in brain activity occur during the immune response implies that signals released by immune cells mediate these effects. o peripheral immune insults can directly stimulate the synthesis of pro-inflammatory cytokines (i.e., IL-1β, IL-6, TNF)-α within the brain → brain inflammation o It is clearly established that products derived from the immune system, particularly cytokines, affect neuroendocrine functions. − Laye et al. Mol Brain Res 1994; 27:157-162 − Besedovsky & Rey, Handbook of Neurochemistry and Molecular Neurobiology, in: A. Lajtha, H.O. Besedovsky, A. Galoyan (Eds.), Springer, 2008 IMMUNE STIMULATION, IMMUNE CYTOKINES AND THEIR EFFECTS ON BRAIN ACTIVITY
- 13. − Endocrine functions −Autonomic functions − Growth, differentiation and repair − Neurotransmitter & neuropeptide synthesis & release − Neuronal activity and plasticity − Learning & memory − Behavior − Sleep − Pain − Food intake − Thermoregulation Cytokines NEUROENDOCRINE EFFECTS OF IMMUNE CYTOKINES
- 14. + Endocrine functions +Autonomic functions + Growth, differentiation and repair + Neurotransmitter & neuropeptide synthesis & release + Neuronal activity and plasticity NEUROENDOCRINE DEFFECTS IN AUTISM
- 15. + Learning & memory +Behavior + Sleep + Pain - Food intake - Thermoregulation
- 16. Is autism inpart caused by a disruption of the immune-neuroendocrine network via elevation of pro-inflammatory mediators (cytokines)?
- 18. o We demonstratean active neuroinflammatory process in the cerebral cortex, white matter, and cerebellum of autistic patients. o Immunocytochemical studies showed marked activation of microglia and astroglia. o Chemokines and cytokines MCP–1, IL-6 and TGF-1, derived from neuroglia, were the most prevalent cytokines in brain tissues. o Cerebrospinal fluid showed a unique proinflammatory profile of cytokines, including a marked increase in MCP-1.
- 19. Which common peripheralimmune insults other than infections can induce the synthesis of pro-inflammatory cytokines in the brain and the activation of glial cells?
- 21. Duplicating the pediatricvaccine schedule with alum adjuvants in mice 2) Behavioral testing (social interaction) at 4-6 months of age 3) Sacrifice and collecting of brain tissue at 6 months of age 4) Semi-quantitative RT-PCR 5) Western blot for protein levels Treatment Group Mouse Age (days postnatal) Total Al injected 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 (ug/kg body weight) High aluminum (US) 170 150 110 80 20 20 550 Low aluminum (SCA) 90 80 50 20 240 Control (saline) X X X X X X 0 1) Aluminum injection schedule:
- 22. Gene expression changesin male mice brains
- 23. Protein level changesin male mice brains
- 24. Genes affected inmale mouse brains Gene Function NFKBIB NF-kappa-B inhibitor, which inhibits NF-kappa-B by complexing with, and trapping it in the cytoplasm. NF-κB is the central regulator of inflammation. Constitutive NF-κB activation is essential for macrophage survival. ACHE Neurotransmitter (Ach) degradative enzyme, acetylcholinesterase. Anti-depression/anxiety effect. Low AChE activity is associated with deficits in neurodevelopment, particularly in attention and memory. CCL2/ MCP-1 Chemokine secreted by a few cell types including macrophage. A cytokine involved in immunoregulatory and inflammatory processes. IFNG Interferon gamma, a secreted product and potent activator of macrophages. A soluble cytokine with antiviral, immunoregulatory and anti-tumor properties. TNF Tumor necrosis factor mainly secreted by macrophages. Multifunctional proinflammatory cytokine.
- 25. Gene expression changesin female mice brains
- 26. BEHAVIORAL TESTS: LIGHT-DARKBOX High aluminum group exhibits significantly increased anxiety & reduced exploratory behavior. Females are more severely affected, showing deficits even at low concentration of aluminum.
- 27. Males in thehigh aluminum group are significantly more lethargic than those in the low aluminum group & control mice. BEHAVIORAL TESTS: OPEN FIELD
- 28. 0 50 100 150 200 250 Object Mouse Sniffingtime(sec) CTRL females USfemales *** 0 20 40 60 80 100 120 140 160 Object Mouse Sniffingtime(sec) CTRL males US males BEHAVIORAL TESTS: SOCIAL INTERACTIONS
- 29. REPEATED VACCINATIONS = Stimulationof aberrant immune responses Increased levels of inflammatory cytokines in the brain IMPAIRED BRAIN DEVELOPMENT & FUNCTION
- 30. MOREOVER…. Repeated immunization withforeign antigen compounds causes systemic autoimmunity in mice otherwise not prone to spontaneous autoimmune diseases.
- 31. o CD4+ Tcells from repeatedly-immunized mice acquire the ability to induce autoantibodies which results in autoimmune tissue injury similar to that seen in human autoimmune diseases. o “SYSTEMIC AUTOIMMUNITY APPEARS TO BE THE INEVITABLE CONSEQUENCE OF OVER-STIMULATING THE HOST’S IMMUNE ‘SYSTEM’ BY REPEATED IMMUNIZATION WITH ANTIGEN.”
- 32. THE KEY PROBLEMIS NOT SINGLE VACCINES THE KEY PROBLEM IS:
- 34. Otherreasons why vaccinestend to adversely affect the centralnervous system o Vaccine-derived antigen-adjuvant (aluminum) complexes persist in the body long after injection (> 6 months) o They are capable of penetrating the blood-brain barrier and triggering abnormal immuno-inflammatory reactions in the brain 34
- 35. Penetration of theblood-brain barrier by aluminum can allow access of antibodies to the brain and cause unwanted autoimmune reactions
- 36. Testing the hypothesis: Isthere experimental evidence to indicate that antibodies induced by the HPV vaccine cross- react with neural antigens?
- 37. Gardasil Mouse serum Mouse brain proteinextract Gardasil antigens (HPV-16, 18, 11, 6) Anti-HPV antibody Anti – HPV antibody binds to HPV Brain extract inhibits Anti – HPV antibody binding to HPV Mouse serum
- 38. Brain extract m/ml %Inhibition 0 20 40 60 80 100 1020 30 40 50 Gardasil + pertussis Gardasil Aluminum Brain protein extract inhibits anti-HPV antibodies binding to HPV antigens
- 39.
- 40. SUMMARY: The neurotoxic riskof the HPV vaccine o Neurotoxic action of the aluminum adjuvant + o Immuno-inflammatory effect of the HPV-16L1 vaccine antigen + o Neuro-autoimmune effect of the cross-reactive HPV vaccine-induced anti-HPV-16L1 antibody 40
- 43. Some vaccines aswell as alum adjuvants can induce the release of IL-6 cytokine implicated in autism
- 45. o The wholecell pertussis vaccine induced high serum interleukin-6 levels in mice, while the acellular vaccine induced very low interleukin-6 levels, indicating that the whole bacterial cell is also important for interleukin-6 induction.
- 48. o Metals suchas chromium, arsenic and particularly aluminum were elevated in the blood of an autistic child, as compared to reference values of a normal child. o 70% of mothers took vaccine or injection and 80% of them ate canned food and fish during pregnancy. 90% babies received all recommended vaccines. o In this study was possible to identify two important data regarding exposure to toxic metals. In 80% of cases the autistic children have used or make use of controlled drug and 90% of them have taken all vaccines.
- 49. o Hair scalpanalysis of 1,967 subjects (0-15 years old, male and female), showed that 584 (29.7%) and 347 (17.6%) were deficient in zinc and magnesium. o 339 (17.2%), 168 (8.5%) and 94 (4.8%) individuals were found to suffer from high burdens of aluminum, cadmium and lead, respectively, and 2.8% or less from mercury and arsenic.
- 50. The risks associatedvaccine-derived Al are four-fold: 1) Al can persist in the body 2) Al can trigger pathological immunological responses 3) Al can make its way into the central nervous system where it can activate deleterious immuno-inflammatory and excitotoxic processes 4) Al can alter expression of numerous genes involved in the immuno-inflammatory responses and cell-to-cell signaling
- 52. o Effect ofIL1 and IL6 on synaptic plasticity, learning and memory. In healthy conditions, IL1β supports learning acquisition and consolidation of hippocampal-dependant memory, while IL-6 exerts the opposite effect. When the concentration of IL1β and IL6 in the brain is increased during peripheral and central diseases, both cytokines tend to inhibit these processes.
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