The immune system's role in anxiety disorders
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The document discusses the bidirectional relationship between the immune system and the central nervous system (CNS). It describes how immune activity in the body can influence psychological symptoms through various mechanisms, including the production of cytokines, effects on microglia and tryptophan metabolism, and alterations to the hypothalamic-pituitary-adrenal axis. The document also reviews evidence that psychological stress can impact immune functioning and that changes in immune markers correlate with anxiety levels, post-traumatic stress disorder, and other anxiety disorders.
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The immune system's role in anxiety disorders
- 1. The immune system and anxiety disorders David Christmas Cambridge and Peterborough NHS Trust
- 2. Agenda • Introduction to the immune system – The immune system and the CNS • How the immune system can influence psychological symptoms • Anxiety and immune changes – Stress and immune function – Anxiety disorders and immune function
- 3. Immune system in brief
- 4. How does peripheral immune activity influence the CNS? A. Active transport of cytokines across BBB B. Activation of vagus nerve C. Passage of cytokines through porous areas of BBB D. Direct migration of circulating immune cells E. All of the above A ctive transportofcy... A ctivation ofvagus n... Passage ofcytokines... D irectm igration ofci... A llofthe above 0% 0% 0%0%0%
- 5. How the immune system influences psychological symptoms Immune alterations Neuropsychiatric effects Activated microglia Direct neuronal/ monoaminergic effects Altered tryptophan metabolism Altered HPA axis functioning
- 6. How the immune system influences psychological symptoms Immune alterations Neuropsychiatric effects Activate microglia Direct neuronal/ monoaminergic effects Altered tryptophan metabolism Altered HPA axis functioning
- 7. • Physiological levels helpful – IL-1β – maintains plasticity and LTP – TNF-α – Upregulates AMPA and improves synaptic strength • High pathological levels – IL-1β – inhibits LTP – TNF-α – impaired LTP – IL-6 – inhibits LTP and glutamate release
- 8. Cytokine effects on hippocampusSynapticstrength/LTP Increasing IL-1, TNF, IL-6 Adapted from Khairova 2009 Correlates with “depression”
- 9. How the immune system influences psychological symptoms Immune alterations Neuropsychiatric effects Activated microglia Direct neuronal/ monoaminergic effects Altered tryptophan metabolism Altered HPA axis functioning
- 10. Aetiology of IFN-Induced Depression: Trp Metabolism Diet 5HT Aromatic amino acid decarboxylase Tryptophan Tryptophan hydroxylase 5-HTP 5-HT Tryptophan Metabolic Pathway
- 11. Aetiology of IFN-Induced Depression: Tryp/5-HT Depletion? Bonaccorso et al. J Clin Psychopharm. 2002 Capuron et al. Mol Psych. 2002 Indoleamine dioxygenase Diet 5HT Aromatic amino acid decarboxylase Tryptophan Tryptophan hydroxylase 5-HTP 5-HT L-Kynurenine IFNs Tryptophan Metabolic Pathway
- 12. Change in tryptophan correlates with increasing depression • Increase in K/Trp ratio (IDO): p = 0.017 • Assoc with depression: R2 =0.340, p = 0.001 IDO vs Mood -15 -10 -5 0 5 10 15 20 25 30 35 -20 -15 -10 -5 0 5 10 15 20 Change BDI ChangeIDO Christmas in preparation
- 13. How the immune system influences psychological symptoms Immune alterations Neuropsychiatric effects Activated microglia Direct neuronal/ monoaminergic effects Altered tryptophan metabolism Altered HPA axis functioning
- 14. HPA axis • Pro-inflammatory cytokines – Activate HPA axis – May downregulate Glucocorticoid receptors centrally – causes increased cortisol release • Glucocorticoids normally anti-inflammatory • But during prolonged stress are pro- inflammatory in CNS – increased IL-1b and TNFa
- 15. How the immune system influences psychological symptoms Immune alterations Neuropsychiatric effects Activated microglia Direct neuronal/ monoaminergic effects Altered tryptophan metabolism Altered HPA axis functioning
- 16. Activated Microglia • Produce increased: – IL-1b, IL-6, TNF-a, MCP-1 (more macrophages) – Cause damage through reactive oxygen species – Increased IDO expression • Some mice models lacking Hoxb8 – Display OCD-like grooming behaviour
- 17. Stress and Immune function
- 18. Anxiety and immune function – Psychological Stress Carpenter et al Neuropsychopharmacology 2010
- 19. Anxiety and immune system Immune stressor Wright Brain Behaviour Immunity 2005
- 20. Anxiety and immune response correlate during challenge TNF Reichenberg Archives of General Psychiatry 2001
- 21. Anxiety varies with immune markers in general population Pitsavos Atherosclerosis 2006
- 22. Immune changes and PTSD Gill Perspectives in Psych Care 2009
- 23. Immune and HPA changes in PTSD • Increased proinflammatory cytokines – IL-1b, TNFa, IL-6, CRP – Increased IL-6 response time of trauma may predict PTSD at 6 months • HPA dysfunction – Reduced CSF CRF – Increased circulating cortisol – Increased response/sensitivity to Dex
- 24. IL-1β reduced in OCD IL-1βPg/ml Brambilla Biological Psychiatry 1997 Denys Psychoneuroendicrinology 2006
- 25. Summary • Brain has constituent immune cells – Have many homeostatic functions in addition to traditional pathogen removal • Cross-talk between CNS and peripheral immune systems • Psychological stressors induce immune responses and vice versa • Much work is needed to delineate role of immune system in anxiety disorders