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Psychoneuroimmunology
- 1. Immunology and Immunotherapy in Psychiatry Presenter : Dr. Amit Chail (JR-2) Moderator : Dr. Ranveer Singh (Asst Prof, Psychiatry) 1
- 2. Case Vignette-1 • 34yr old Lady • Fever, Behavioral abnormalities and altered sensorium • O/E - • PR : 82 – 96 / min • BP- 138/ 90 <--> 180/110 mm Hg • Disoriented to time & place • Not obeying verbal commands • Echolalia & palilalia • Delusion of persecution, grandeur present • CSF study : Increased WBC, RBC and Protein Autoimmune Marker : Anti-NMDA receptor Ab : POSITIVE 2
- 3. Case Vignette-1 • Initial Management • IV Anitibiotics, Anti-viral and Sod Valproate • To control violent , agitated behavior • Inj Haloperidol 5mg and Phenargan 25 mg im sos • Tab Olanzapine 10 mg HS • Inj Lorazepam added, when developed catatonic excitation
- 4. • FURTHER MANAGEMENT: After Anti-NMDA reports- – Inj Methylprednisolone 1 gm 24 hrly started – IVIG started 2 Gm/kg slow i.v. – In divided doses 50gm – Day 1 50gm – Day 2 40gm – Day 3 – Inj Sodium Valproate 500 mg 8 hrly • In view of partial response: Inj IVIG repeated on Day 37 Case Vignette-1
- 5. Case Vignette-2 • 44 Year /M, no known comorbidities • Depressive episode – severe • On D5 - Herpes Zoster – multiple dermatomes • Investigations – Hematological – WNL • Treatment: – Acyclovir – 800mg x 5 times/day – L-cetrizine- 5mg OD – Desvenclfaxine (100mg/day) – Olanzapine 2.5 HS 5
- 6. Scope • Introduction - Immunology • Basics of Immunoneuropsychiatry • Introduction to immunological basis • Depression / Schizophrenia / Autism • Treatment Modalities • Cox Inhibitors / Antibiotics / Monoclonal Ab • Vaccines • Conclusion • Take home message • References 6
- 8. Immune system • Protect from infections • Detect and eliminate neoplastic cells • Survey and maintain self and commensals 8 Kumar V., & Robbins, S.L. (2015). Pathologic basis of disease (9th ed.). Philadelphia, PA: Saunders/Elsevier
- 9. 9 Innate Acquired Physico chemical barriers Skin, mucous membranes Cutaneous and mucosal immune systems Cells Phagocytes (macrophages, neutrophils, NK cells) Lymphocytes (B and T cells) Soluble mediators Macrophage-derived cytokines, i.e., IL-1, IL-6, TNF-α, IFN-α Lymphocyte-derived cytokines, i.e., IL-2, IL-4, IL-5, IL-6, IL-10, IFN-γ Memory None Yes Circulating molecules Complement, acute- phase reactants Antibodies Kumar, V., & Robbins, S. L. 1. (2015). Pathologic basis of disease (9h ed.). Philadelphia, PA: Saunders/Elsevier
- 10. 10 Weickert,CS; Weickert TW, Psychiatr Clin N Am - (2016) Kumar V., & Robbins, SL (2015). Pathologic basis of disease (9h ed.). Philadelphia, PA: Saunders/Elsevier
- 11. 11 Barbara Sperner-Unterweger, Immunological Aetiology of Major Psychiatric
- 12. 12 Barbara Sperner-Unterweger, Immunological Aetiology of Major Psychiatric
- 13. 13 Kumar V., & Robbins, SL (2015). Pathologic basis of disease (9h ed.). Philadelphia, PA: Saunders/Elsevier
- 14. 14 Sadock BJ, Comprehensive Textbook of Psychiatry, 10th edn, LWW, 2017,
- 15. Acquired Immunity 15 Janeway CA et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001 Sadock BJ, Sadock VA, Comprehensive Textbook of Psychiatry, 10th edn, LWW, 2017, Recognition Activation Effector
- 17. History of Psychoneuroimmunology Ladilas J Meduna, 1934 Epilepsy and Schizophrenia 17 Karl Menninger, 1920’s Schizophrenia – seasonality and Influenza Hermann Lehmann-Facius (1937) Anti brain Auto- Ab in CSF of Schizophrenia patients RS Smith (1992-93) Immunological hypotheses: • Depression • Schizophrenia
- 18. Cytokines and CNS • Immuno-modulators and neuro-modulators • Hormones of the immune system • Signals between cells to regulate the immune response to injury and infection Ziad Kronfol et al; Cytokines and the brain: implications for clinical psychiatry, Am J Psychiatry 2000; 157:683–694 18
- 19. 19 Ziad Kronfol et al; Cytokines and the brain: implications for clinical psychiatry, Am J Psychiatry 2000; 157:683–694
- 20. Immune-CNS Interaction in Psychiatric Disorders 21
- 21. Immune Variable Ac Stress Chronic Stress Major Depression Leukocytes ↑/↑ ↑/↑ ↑/↑ Lymphocytes ↑/↑ ↔ ↓/↓ Monocytes 0 ↔ 0 T lymphocytes 0 ↓/↓ ↔ B lymphocytes ↓/↓ ↓/↓ ↔ CD4+ cells 0 ↓/↓ ↔ CD8+ cells ↑/↑ ↓/↓ ↔ NK cells ↑/↑ ↓/↓ 0 IFN-γ ↑/↑ ? ? IL-1 ↑/↑ ? ↑ IL-2 ? ↓/↓ ↑ IL-4 ↓/↓ ? ? IL-6 ↑/↑ ↑ ↑/↑ CRP ↑/↑ ↑ ↑ 22
- 22. Depression • Inflammatory response (?Evolutionary advantage) • Increased circulatory cytokines (?) – Dysregulated – Increased PGE2 - Saliva, serum & CSF – Lymphocytes – IL- 6 – Sickness Behaviour 23 Müller N, Schwarz MJ, COX-2 Inhibition in Schizophrenia and Major Depression, Current Pharmaceutical Design, 2008, 14, 1452-1465
- 23. 24 Hernandez ME, Effect of SSRIs and immunomodulator on Cytokines Levels: An Alternative Therapy for Patients with Major Depressive Disorder, Clinical and Developmental Immunology, Volume 2013
- 24. Depression – Immune system • Evolutionary Perspective 25 Kinney, D. K. & Tanaka, M. An evolutionary hypothesis of depression and its symptoms, adaptive value, and risk factors. J. Nerv. Ment. Dis. 197, 561–567 (2009).
- 25. Pathogen Host Defence Hypothesis of Depression • Microbial interactions have been a primary driver of human evolution. • Immune activation - depression promoted survival in pathogenic environments while increasing mortality in sanitary conditions (developed world) • Pro-inflammatory and/or anti-pathogen protective effects or have been implicated in social behaviours that are likely to reduce pathogen exposure 27 Raison CL et al, The evolutionary significance of depression in Pathogen Host Defense (PATHOS-D), Molecular Psychiatry (2013) 18, 15–37
- 26. Pathogen Host Defence Hypothesis of Depression • Environmental risk factors for the development of depression – pro-inflammatory • Pro-inflammatory cytokines - sickness syndrome - ameliorated by treatment with antidepressants. • Chronic cytokine exposure produces a combination of withdrawal and/or energy conservation, anxiety and/or hypervigilance behaviours and emotions that commonly coexist in depression. 28 Raison CL et al, The evolutionary significance of depression in Pathogen Host Defense (PATHOS-D), Molecular Psychiatry (2013) 18, 15–37
- 27. Depression and Inflammation Peripheral blood and CSF Increased expression of pro-inflammatory cytokines and their receptors and increased levels of acute-phase reactants, chemokines and soluble adhesion molecules Peripheral blood gene expression Pro-inflammatory ‘M1’ macrophage phenotype and an over-representation of IL-6, IL-8 Post- mortem brain samples Increased expression of a variety of innate immune genes and proteins, including IL-1β, IL-6, TNF, Toll-like receptor 3 (TLR3) and TLR4 29 Miller AH et al The role of inflammation in depression: from evolutionary imperative to modern treatment target, Nature Reviews | Immunology, vol 16 | January 2016
- 28. Depression and Inflammation Inj- (IFNα) or their inducers Symptoms of depression Blockade of cytokines, such as TNF, or of inflammatory signalling pathway components, such as COX Reduce depressive symptoms in patients with medical illnesses, including rheumatoid arthritis, psoriasis and cancer, as well as in patients with major depressive disorder 30 Miller AH et al The role of inflammation in depression: from evolutionary imperative to modern treatment target, Nature Reviews | Immunology, vol 16 | January 2016
- 29. Transmitting stress-induced inflammatory signals 31 Miller AH et al The role of inflammation in depression: from evolutionary imperative to modern treatment target, Nature Reviews | Immunology, vol 16 | January 2016 Golam M Khandaker , Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment , Lancet Psychiatry , 2015; 2: 258–70
- 30. Cytokines, Neurotransmitters and Neurocircuits 32 Miller AH et al The role of inflammation in depression: from evolutionary imperative to modern treatment target, Nature Reviews | Immunology, vol 16 | January 2016
- 31. 33
- 32. Schizophrenia • Brain – Immune to immune system • Infection Hypothesis – Influneza Pandemics – Ab – EBV, CMV, HSV, Influenza virus – Retrovirus (?) High variability • Prevalence – universal – Immunity/Virus • Reduced risk of Cancer/RA- immunological basis • Seasonality of birth- winter/spring 34 Barbara SU, Immunological Aetiology of Major Psychiatric Disorders Evidence and Therapeutic Implications, Drugs 2005; 65
- 33. Predisposition to immune dysfunction –Genetic: GWAS- common risk - schizophrenia - chr 6.22p1 (MHC) class II proteins – Proposed: gene polymorphism – IL-10, IL -1 & TNF a • Maternal Infections during pregnancy • Maternal immune response - fetal brain dev - cytokines 35 Purcell SM, Wray NR, Stone JL, et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009;460(7256):748-52. Miller BJ, The Case for Adjunctive Monoclonal Antibody Immunotherapy in Schizophrenia, Psychiatr Clin N Am - (2016)
- 34. Schizophrenia • Ab pattern – Non specific – Auto-ab – Sub group – Non specific High variability • Cytokines – Local production / BBB • IL-1, IL-6, TNF –a (CSF/ Blood) • Th1 / Th2 cell balance. 36 Barbara SU, Immunological Aetiology of Major Psychiatric Disorders Evidence and Therapeutic Implications, Drugs 2005; Miller BJ, The Case for Adjunctive Monoclonal Antibody Immunotherapy in Schizophrenia, Psychiatr Clin N Am - (2016)
- 35. Current status • Cytokines Innate immunity • Microglia • Anti Neuronal cell Ab (NMDA) • T Lymphocytes Acquired • eCB • Gut Brain axis 37
- 36. Cytokines in Schizophrenia • Meta-analysis- Schizophrenia – – proinflammatory (IL-1, IL -6, TNF α, INF-γ) and – anti-inflammatory ( IL-10) – Normalised- symptom remission -with antipsychotic • Increased serum concentration – IL-6 at age 9 years - 2 x risk of psychotic disorder at age 18 years. • Dose response relationship Golam M Khandaker , Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment , Lancet Psychiatry , 2015; 2: 258–70 38
- 38. Anti-neuronal Cell Surface Auto-antibodies • NMDA R • Anti- NMDA receptor encephalitis, • Progressive illness starts with psychotic symptoms or seizures, and subsequently neurological and autonomic features • Pathogenic , If + in patients with encephalitis • Removal of Ab clinical improvement • Clinical significance - blood–brain barrier function • VG K Channel Ab - hallucinations, depression, and memory deficits 40 Hammer, C et al.2013). Neuropsychiatric disease relevance of circulating anti-NMDA receptor autoantibodies depends on blood–brain barrier integrity. Molecular Psychiatry, 19(10), 1143–1149.
- 39. Anti-NMDAR encephalitis Investigations • MRI WNL in 50% – Remaining T2, FLAIR hyper-intensities in Hippocampus, cerebral and cerebellar cortex, basal ganglia, Insula • EEG-WNL • CSF-80% WNL – Moderate lymphocytosis – Mildly elevated protein levels • Brain biopsy-Non specific 41 Lakhan SE, Caro M, Hadzimichalis N. NMDA Receptor Activity in Neuropsychiatric Disorders. Front Psychiatry. 2013;4:52.
- 40. NMDA-R Ab • Major Psychiatric illnesses – 3X more likely to have elevated NMDAR antibody titers – Increased antibody titers in first episode presentations itself – M:F = 1: 4 – Ovarian Cancer 42 Pearlman DM, , Meta-analysis of the association between N-methyl-d-aspartate receptor antibodies and schizophrenia, schizoaffective disorder, bipolar disorder, and major depressive disorder, Schizophr Res. 2014.
- 41. 43 Golam M Khandaker , Infl ammation and immunity in schizophrenia: implications for pathophysiology and treatment , Lancet Psychiatry , 2015; 2: 258–70
- 42. Autism • Neurodevelopmental disorder • Uncertain etiology • Persistent deficits in social communication and social interaction • Restricted, repetitive patterns of behavior, interests, or activities 44 American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.)
- 43. Autism • Similarities with autoimmune disorders – Genetic susceptibility – Assoc with viral infections – Immunological dysfunction – Gender differences – M:F = 3-4:1 • Inconsistent results 45 Barbara Sperner-Unterweger, Immunological Aetiology of Major Psychiatric
- 44. Autism • Findings: — T cell mediated immune deficiencies — Altered NK cell function — Increased monocyte count — Abnormal CD4: CD 8 — Increased Monocyte/ TLC — Increased Th2 activity Increased IL-2 and INF-γ — Auto-Ab against Myelin Basic protein, Neuro- filament proteins and %-HT1A receptors — IgM & IgG – Anti brain auto-Ab (caudate nucleus) 46 Barbara Sperner-Unterweger, Immunological Aetiology of Major Psychiatric
- 45. 47
- 46. 48
- 47. 49
- 48. 50
- 50. 52
- 52. COX-2 Inhibitors - Schizophrenia • Celecoxib • Restores immune dysregulation in Schizophrenia • Inhibit the Production of Kynurenic Acid, • Balance the Type-1 / Type-2 Immune Response, • Therapeutic Effects in Early Stages of Schizophrenia 54 Norbert Müller, COX-2 Inhibition in Schizophrenia and Major Depression Current Pharmaceutical Design, 2008, 14, 1452-1465
- 53. COX-2 Inhibitors - Depression • Celecoxib and rofecoxib • Anti-inflammatory • Inhibit PGE2, IL-1, IL-6 • Balance b/w Kynurenic Acid & 5 HT • HPA axis stabilisation • Sickness behaviour • Therapeutic Effects in Early Stages 55 Norbert Müller, COX-2 Inhibition in Schizophrenia and Major Depression Current Pharmaceutical Design, 2008 Kohler et al, Inflammation and depression: combined use of SSRIs and NSAIDs or paracetamol and psychiatric outcomes, Brain and Behavior, 2015
- 54. COX-2 Inhibitors – current status • Adjunct • Certain forms • Side effects- CVS • Worsen – with no serum inflammatory markers • Not FDA approved • Neither supports nor discourages • Further research needed 56 Norbert Müller, COX-2 Inhibition in Schizophrenia and Major Depression Current Pharmaceutical Design, 2008 Kohler et al, Inflammation and depression: combined use of SSRIs and NSAIDs or paracetamol and psychiatric outcomes, Brain and Behavior, 2015
- 55. Monoclonal Anti-bodies • FDA Approved for auto-immune and inflammatory conditions • Directly neutralising cytokines or by binding cytokine receptors. • Clinical trial phase for psychiatric disorders • Only acute phase of illness • Schizophrenia and depression • Adalimumab, Infliximab, tocilizumab 57 N Kappelmann et al Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions, Molecular Psychiatry (2016) 00, 1–9 Miller BJ, Monoclonal Antibody immunotherapy in psychiatric disorders, The Lancet, March 2017
- 56. 58 Miller BJ, Monoclonal Antibody immunotherapy in psychiatric disorders, The Lancet, March 2017
- 57. 59
- 58. Monoclonal Anti-bodies • Advantages • No off-target (ie, nonimmune) effects. • More potent anti-inflammatory properties than other agents. • Intravenous route of administration obviates issues of medication adherence that may confound findings in research clinical trials. 60 Psychiatric Clinics of North America; Jun 2016: Volume 39, Issue 2, p165-360
- 59. Monoclonal Anti-bodies • Disadvantages • Serious potential adverse effects because of profound immunosuppression, including life threatening infections, Demyelinating disorders, ulcers, and malignancy. • High cost (potentially >$1000 per dose) may limit more widespread use. • Intravenous route of administration poses a myriad of logistical issues for patients and clinicians 61 Psychiatric Clinics of North America; Jun 2016: Volume 39, Issue 2, p165-360
- 60. Anti- cytokine treatment • Etanercept – Anti- TNFα – Dimeric, human, soluble TNF receptor that binds tightly and specifically to circulating and cell- bound TNF • Minocycline- tetracyclic antibiotic • Adjunctive role • No guidelines / Clinical trials 62 N Kappelmann et al Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions, Molecular Psychiatry (2016) 00, 1–9 Dean et al, Adjunctive minocycline treatment for major depressive disorder: A proof of concept trial, ANZJP, 2017
- 61. Miscellaneous Immunomodulators • hDLE- human Dialyzable Leukocyte Extract • Peptides – immuno-modulators • Adjuvant – infectious diseases & deficient CMI • Adjunctive • Pro-inflammatory • Significant reduction in depressive symptoms 63 Hernandez ME, Effect of SSRIs and mmunomodulator on Cytokines Levels: An Alternative Therapy for Patients with Major Depressive Disorder, Clinical and Developmental Immunology, Volume 2013
- 62. Vaccines in SUD • TA-CD vaccine • Induce formation of anti-cocaine antibodies • Haptenated – succinyl-nor-cocaine (SNC) to rCTB • Phase III trials – completed (2014-15) • Safe • Efficacy – lesser than earlier trials – Drop outs • Not significantly greater that psychosocial interventions • No FDA approval 64 Kosten, T.R., et al., Vaccine for cocaine dependence: A randomized double-blind placebo-controlled efficacy trial. Drug Alcohol Depend. (2014)
- 63. Alternative Medicine • Curcumin, Green tea & Ginkgo biloba • Circumin – Haldi • Immuno-modulatory and anti-oxidant • Anti-inflammatory – – Decreased IL-1β , TNFα & salivary cortisol – Acute phase of depression and schizophrenia • No guidelines • Further research needed 65 Jana Trebatická, Review Article, Psychiatric Disorders and Polyphenols: Can They Be Helpful in Therapy?Oxidative Medicine and Cellular Longevity Volume 2015,
- 64. Yoga • Downregulation HPA axis and SNS • Reduces – HRV, blood glucose, S Cholestrol – Salivary cortisol and oxidative stress • Subjective measures of fatigue, pain, and sleep • Additional studies - to distinguish between the different types of yoga and their various techniques 66 Ross A, The Health Benefits of Yoga and Exercise: A Review of Comparison Studies, The Journal Of Alternative And Complementary Medicine Volume 16,, 2010, pp. 3–12
- 65. Unanswered Questions • Proinflammatory cytokines- a cause /coincidence or consequence? • Identification of prodromal cases of schizophrenia • Predict disease progression, response to antipsychotic treatment and recovery? • Classification ? On immunological basis 67
- 66. 68
- 67. • CSF- lymphocytic pleocytosis or CSF- specific oligoclonal bands without evidence for infection • Epileptic seizures • Faciobrachial dystonic seizures • Suspected NMS • MRI abnormalities (mesiotemporal • hyperintensities, atrophy pattern) • EEG abnormalities (slowing, epileptic activity) 69 Herken J and Prüss H (2017) Red Flags: Clinical Signs for Identifying Autoimmune Encephalitis in Psychiatric Patients. Front. Psychiatry , 2017 Red Flag Signs- FEP
- 68. Summary • Growing evidence to support role of immune dysregulation in different psychiatric disorders • Cytokines and microglia • Depression – Early – Activation – Chronic – Suppressed • Schizophrenia - Immune dysregulation • Immune modulation – imp adjunct • Research phase • Low specificity 70
- 69. Take Home Message 71 • Immune hypothesis may provide answers to treatment resistant cases • From functionality to causality • Concepts – beyond psychopathology • Future – targeted and tailored treatment modalities • Red flag signs
- 70. References • Weickert,CS; Weickert TW, Psychiatr Clin N Am - (2016) • Kumar V., & Robbins, S. L. 1. (2015). Robbins basic pathology (9h ed.). Philadelphia, PA: Saunders/Elsevier • Barbara S U, Immunological Aetiology of Major Psychiatric Disorders: Evidence and Therapeutic Implications, Drugs, 2005, ; • Janeway CA et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001 • Sadock BJ, Sadock VA, Comprehensive Textbook of Psychiatry, 10th edn, LWW, 2017
- 71. • Müller N, Schwarz MJ, COX-2 Inhibition in Schizophrenia and Major Depression, Current Pharmaceutical Design, 2008 • Hernandez ME, Effect of SSRIs and mmunomodulator on Cytokines Levels: An Alternative Therapy for Patients with Major Depressive Disorder, Clinical and Developmental Immunology, Volume 2013 • Kinney, D. K. & Tanaka, M. An evolutionary hypothesis of depression and its symptoms, adaptive value, and risk factors. J. Nerv. Ment. Dis. 197, 561–567 (2009). • Miller AH et al The role of inflammation in depression: from evolutionary imperative to modern treatment target, Nature Reviews | Immunology, vol 16 | January 2016 73 References
- 72. • Miller BJ, The Case for Adjunctive Monoclonal Antibody Immunotherapy in Schizophrenia, Psychiatr Clin N Am - (2016) • Golam M Khandaker , Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment , Lancet Psychiatry , 2015; 2: 258–70 • Hammer, C et al.2013). Neuropsychiatric disease relevance of circulating anti-NMDA receptor autoantibodies depends on blood–brain barrier integrity. Molecular Psychiatry, 19(10), 1143–1149. • Lakhan SE, Caro M, Hadzimichalis N. NMDA Receptor Activity in Neuropsychiatric Disorders. Front Psychiatry. 2013;4:52 74 References
- 73. Thank you
Notes de l'éditeur
- Good afternoon everyone.
- 34yr old Lady Fever x 12 days Behavioral abnormality x 12 days Fever 10 -12 days duration, Moderate - high grade, Asso with severe global headache at onset associated with chills and rigor, h/o associated pain abdomen & burning sensation in urine Took oral antibiotics for UTI Deffervescence of fever for about 3-4 days, but Brought back to the medical facility with - Recurrence of Fever after 3- 4 days - Associated behavioral abnormality Abnormal behavior was in form of hallucination, hyper salivation, tremulousness, agitation, insomnia, mutism followed by indiscernible speech & loss of social inhibition Examination-- Average built and nourishment Afebrile Pulse- 82 / min. regular, normal volume B.P.- 138/ 90 <--> 180/110 mm Hg Right Arm supine Features of dysautonomia in form of Increased secretions, postural fall and labile blood pressure RR- 18/ min No neck rigidity SpO2 - 99 % on room air Catatonic posturing at times conscious; disoriented to time , place & person Not obeying verbal commands Moving all four limbs Patient was conscious Disoriented to time & place Recognizing husband Not cooperative, limited attention time present Associated echolalia & palilalia was present in speech Delusion of persecution, grandeur present SpO2 - 99 % on room air
- Admitted to ICU Started on undermentioned regimen in view of suspected viral encephalitis (NMDA reports not available): Inj Ceftriaxone 2 gm iv 12 hrly Inj Acyclovir 750 mg iv 8 hrly Inj Sodium Valproate 500 mg 8 hrly To control violent , agitated behavior Inj Haloperidol 5mg im stat & sos Inj Phenargan 25 mg im stat & sos Tab Olanzapine 10 mg HS Inj Lorazepam added, when developed catatonic excitation on antipsychotics
- Admitted to ICU on DIL
- I will be presenting the topic under the following headings
- immune system has the capacity to protect the body from the invasion of foreign pathogens, such as viruses, bacteria, fungi, and parasites. In addition, the immune system can detect and eliminate cells that have become neoplastically transformed. Finally, it has emerged recently that the immune system surveys, controls, and maintains the various symbiotic and commensal microbiota, notably in the gut. These functions are accomplished through highly specific receptors on immune cells for molecules derived from invading organisms and a rich intercellular communication network that involves direct cell-to-cell interactions and signaling between cells of the immune system by soluble factors called cytokines
- Ag Recognition -through specialized receptors for antigens on the surface of B & T lymphocytes B-cell antigen receptor - Can recognize the tertiary structure of specific proteins. T-cell antigen receptor recognizes only fragments of protein antigens. Fragments must be present in association with a class of cell surface molecules called major histocompatibility (MHC). Induction of T-cell response depends on the ability & effectiveness of MHC molecules to bind & present antigen. All MHC class I-restricted T cells express: An invariant surface glycoprotein- CD8 Different invariant surface glycoprotein-CD4 Most CD8+ T cells are cytolytic Ability to lyse cells to which they bind. Most CD4+ T cells are helper T cells- Secrete cytokines on activation Recent evidence indicates that two subclasses of Th cells secrete have different function on stimulation. T helper-1 (Th-1) cells: Involved in cell-mediated inflammatory reactions T helper-2 (Th-2) cells: Encourage antibody formation, particularly IgE responses Some undergo further growth & differentiation into mature effector cells Some activated B cells or T cells become memory cells Primed for activation on further stimulation Principal effector mechanisms of acquired immunity Mediated by antibodies (humoral immunity) secreted from B cells, and by cytolytic T cells (cellular immunity) Humoral immunity Especially effective in combating extracellular pathogens, such as bacteria and parasites Cellular immunity Effective in protecting against viral infection Natural killer cells- may provide some protection against tumor cells.
- Meduna made the observation that the brains of epileptics had greater than normal numbers of glial cells, while those of schizophrenics had fewer, and hypothesized that there might be a biologic antagonism between convulsions and schizophrenia
- Cytokines often act both as immuno-modulators and as neuromodulators. Regarded as the hormones of the immune system. Act as signals between cells to regulate the immune response to injury and infection.
- Both psychological stress (e.g., academic stress, depression) and physical stress (e.g., infection, trauma) can activate interleukin-1 . IL-1 activation is associated with various phenomena, both peripherally (e.g., cascade activation of other cytokines, induction of acute phase proteins) and centrally (e.g., various immunologic, neurochemical, neuroendocrine, and behavioral effects). Feedback mechanisms occur at several levels and include negative feedback exerted by cortisol. Only selected effects are shown as an example. IL=interleukin, TNF-α=tumor necrosis factor-α, CRH=corticotropinreleasing hormone, GnRH=gonadotropin-releasing hormone, NE= norepinephrine, 5-HT=serotonin, DA=dopamine, NK=natural killer. Immunologic effects- IL-1 stimulates the production of other cytokines by astrocytes and microglia. Colony-stimulating factor, TNF-α, additional IL-1 & IL-6. IL-1 directly injection into brain: stimulate astrogliosis and produce neovascularization Neuroendocrine effects: IL-1 was associated with increases in corticotropin-releasing hormone, ACTH, and corticosteroids. IL-6, TNF and interferon can stimulate HPA axis. Brain (Hypothalamus) plays a central role in this feedback loop Emotions and/or psychosocial stressors can tilt the balance one way or the other. Effects on the HPA Axis: cytokines activate HPA axis Involves stimulation of CRH production in the paraventricular nucleus of hypothalamus cytokine-induced depression/sickness behavior Blocking CRH reverses some of the behavioral sequelae of pro-inflammatory cytokine administration. Behavioral effects: several of the behaviors associated with infection: “sickness behavior” Increased sleep, decreased appetite & sexual drive. Dysphoria, anhedonia, cognitive dysfunction, somnolence and fatigue. IL-1, TNF-α and interferon interacts with specific neuro-hormones & neurotransmitters in brain to produce somnogenic activity
- g HRV,28 blood glucose,33,35 blood lipids,35,67 salivary cortisol,3 and oxidative stress
- Sickness behavior is a coordinated set of adaptive behavioral changes that develop in ill individuals during the course of an infection.[1] They usually (but not necessarily)[2] accompany fever and aid survival. Such illness responses include lethargy, depression, anxiety, malaise, loss of appetite,[3][4] sleepiness,[5]hyperalgesia,[6] reduction in grooming[1][7] and failure to concentrate The major cytokines, interleukin-1, tumor necrosis factor alpha, and others, all act on the hypothalamus to provoke alterations in the normal homeostatic condition. These include elevated body temperature, increased sleep, and loss of appetite as well as major alterations in lipid and protein metabolism leading to significant weight loss. Some of these changes are clearly directed towards enhancing the normal immune responses.
- Evolutionary legacy of an inflammatory bias. Early evolutionary pressures derived from human interactions with pathogens, predators and human conspecifics (such as rivals) resulted in an inflammatory bias that included an integrated suite of immunological and behavioural responses that conserved energy for fighting infection and healing wounds, while maintaining vigilance against attack. This inflammatory bias is believed to have been held in check during much of human evolution by exposure to minimally pathogenic, tolerogenic organisms in traditional (that is, rural) environments that engendered immunological responses characterized by the induction of regulatory T (TReg) cells, regulatory B (BReg) cells and immunoregulatory M2 macrophages as well as the production of the anti-inflammatory cytokines interleukin‑10 (IL‑10) and transforming growth factor-β (TGFβ). In modern times, sanitized urban environments of more developed societies are rife with psychological challenges but generally lacking in the types of infectious challenges that were primary sources of morbidity and mortality across most of human evolution. In the absence of traditional immunological checks and balances, the psychological challenges of the modern world instigate ancestral immunological and behavioural repertoires that represent a decided liability, such as high rates of various inflammation-related disorders including depression.
- anhedonia characteristic of depression serve to shunt energy resources to fighting infection and wound healing, whereas the hypervigilance characteristic of anxiety disorders, commonly co‑morbid with depression, subserves protection from attack and subsequent pathogen exposure
- Pathogen host defence hypothesis of depression Several lines of evidence support the notion that the evolution and persistence of depression risk alleles and depressive symptoms in human populations are based on their relevance to ‘pathogen host defence’. This evidence includes: Until recently, approximately 50% of humans died from infectious causes before adulthood, thereby providing strong selective pressure for genetic alleles that enhance host defence. As a result of strong selective pressure, microbial interactions have been a primary driver of human evolution. Patterns of inflammatory activation associated with depression promote survival in highly pathogenic environments while increasing mortality in sanitary conditions common in the developed world. The best replicated risk alleles for depression have pro-inflammatory and/or anti-pathogen protective effects or have been implicated in social behaviours that are likely to reduce pathogen exposure6. Environmental risk factors for the development of depression (that is, psychosocial stress, early life adversity, obesity and processed-food diet) are uniformly pro-inflammatory13. Exposure to pro-inflammatory cytokines produces a sickness syndrome with symptoms that overlap considerably with those seen in depression and that can be ameliorated by treatment with antidepressants23. In addition, the onset of depression is often mistaken with development of sickness, and symptoms associated with infections are often mistaken with the onset of depression127. Chronic cytokine exposure produces a combination of withdrawal and/or energy conservation, anxiety and/or hypervigilance behaviours and emotions that commonly coexist in depression6,9. Symptoms shared by depression and sickness behaviour — such as hyperthermia and reduced iron availability — that lack any conceivable social value have potent anti-pathogen effects6.
- Pathogen host defence hypothesis of depression The best replicated risk alleles for depression have pro-inflammatory and/or anti-pathogen protective effects or have been implicated in social behaviours that are likely to reduce pathogen exposure. Environmental risk factors for the development of depression (that is, psychosocial stress, early life adversity, obesity and processed-food diet) are uniformly pro-inflammatory Exposure to pro-inflammatory cytokines produces a sickness syndrome with symptoms that overlap considerably with those seen in depression and that can be ameliorated by treatment with antidepressants. In addition, the onset of depression is often mistaken with development of sickness, and symptoms associated with infections are often mistaken with the onset of depression. Chronic cytokine exposure produces a combination of withdrawal and/or energy conservation, anxiety and/or hypervigilance behaviours and emotions that commonly coexist in depression. Symptoms shared by depression and sickness behaviour — such as hyperthermia and reduced iron availability — that lack any conceivable social value have potent anti-pathogen effects.
- Meta-analyses - IL‑1β, IL‑6, TNF and (CRP) are the most reliable biomarkers of inflammation
- Inj- inflammatory cytokines (IFNα) or their inducers (typhoid vaccination)
- Transmitting stress-induced inflammatory signals to the brain. In the context of psychosocial stress, catecholamines (such as noradrenaline) released by activated sympathetic nervous system fibres stimulate bone marrow production and the release of myeloid cells (for example, monocytes) that enter the periphery where they encounter stress-induced damage-associated molecular patterns (DAMPs), bacteria and bacterial products such as microbial-associated molecular patterns (MAMPs) leaked from the gut. These DAMPs and MAMPs subsequently activate inflammatory signalling pathways such as nuclear factor-κB (NF‑κB) and the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. Stimulation of NLRP3 in turn activates caspase 1, which leads to the production of mature interleukin‑1β (IL‑1β) and IL‑18 while also cleaving the glucocorticoid receptor contributing to glucocorticoid resistance. Activation of NF‑κB stimulates the release of other pro-inflammatory cytokines including tumour necrosis factor (TNF) and IL‑6, which together with IL‑1β and IL‑18 can access the brain through humoral and neural routes. Psychosocial stress can also lead to the activation of microglia to a M1 pro-inflammatory phenotype, which release CC-chemokine ligand 2 (CCL2) that in turn attracts activated myeloid cells to the brain via a cellular route. Once in the brain, activated macrophages can perpetuate central inflammatory responses. ASC, apoptosis-associated speck-like protein containing a CARD; HMGB1, high mobility group box 1; HSP, heat shock protein; LPS, lipopolysaccharide; TLR, Toll-like receptor.
- Cytokine targets in the brain: neurotransmitters and neurocircuits. Once in the brain, the inflammatory response can affect metabolic and molecular pathways influencing neurotransmitter systems that can ultimately affect neurocircuits that regulate behaviour, especially behaviours relevant to decreased motivation (anhedonia), avoidance and alarm (anxiety), which characterize several neuropsychiatric disorders including depression. On a molecular level, pro-inflammatory cytokines including type I and II interferons (IFNs), interleukin‑1β (IL‑1β) and tumour necrosis factor (TNF) can reduce the availability of monoamines — serotonin (5‑HT), dopamine (DA) and noradrenaline (NE) — by increasing the expression and function of the presynaptic reuptake pumps (transporters) for 5‑HT, DA and NE through activation of mitogen-activated protein kinase (MAPK) pathways and by reducing monoamine synthesis through decreasing enzymatic co-factors such as tetrahydrobiopterin (BH4), which is highly sensitive to cytokine-induced oxidative stress and is involved in the production of nitric oxide (NO) by NO synthase (NOS). Many cytokines, including IFNγ, IL‑1β and TNF, can also decrease relevant monoamine precursors by activating the enzyme indoleamine 2,3‑dioxygenase (IDO), which breaks down tryptophan, the primary precursor for serotonin, into kynurenine. Activated microglia can convert kynurenine into quinolinic acid (QUIN), which binds to the N‑methyl-d‑aspartate receptor (NMDAR), a glutamate (Glu) receptor, and together with cytokine-induced reduction in astrocytic Glu reuptake and stimulation of astrocyte Glu release, in part by induction of reactive oxygen species (ROS) and reactive nitrogen species (RNS), can lead to excessive Glu, an excitatory amino acid neurotransmitter. Excessive Glu, especially when binding to extrasynaptic NMDARs, can in turn lead to decreased brain-derived neurotrophic factor (BDNF) and excitotoxicity. Inflammation effects on growth factors such as BDNF in the dentate gyrus of the hippocampus can also affect fundamental aspects of neuronal integrity including neurogenesis, long-term potentiation and dendritic sprouting, ultimately affecting learning and memory. Cytokine effects on neurotransmitter systems, especially DA, can inhibit several aspects of reward motivation and anhedonia in corticostriatal circuits involving the basal ganglia, ventromedial prefrontal cortex (vmPFC) and subgenual and dorsal anterior cingulate cortex (sgACC and dACC, respectively), while also activating circuits regulating anxiety, arousal, alarm and fear including the amygdala, hippocampus, dACC and insula. BH2, dihydrobiopterin; DAT, dopamine transporter; EAAT2, excitatory amino acid transporter 2; NET, noradrenaline transporter; NF-κB, nuclear factor-κB; SERT, serotonin transporter; TH, tyrosine hydroxylase; TPH, tryptophan hydroxylase. Copyrighted 2015. Advanstar. 120580:1115BN.
- TH2 chronic inflammation TH1 – acute inflammation
- Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort suggest that increased serum concentration of the proinflammatory cytokine interleukin 6 at age 9 years is associated with twofold increased risk of development of a psychotic disorder at age 18 years dose-response association between increased interleukin 6 concentrations in childhood and subsequent risk of subclinical psychotic experiences in young adulthood, which persists after several potential confounders are taken into account, including sex, body mass, and psychological and behavioural problems preceding the measurement of childhood interleukin 6. Antipsychotic-naive fi rst-episode psychosis30 and acute psychotic relapse16 are also associated with increased serum concentrations of interleukin 6 and other proinfl ammatory cytokines, such as tumour necrosis factor α (TNFα), interleukin 1β, interferon γ, and decreased serum concentrations of anti-infl ammatory cytokine interleukin 10, which are normalised after remission of symptoms with antipsychotic treatment
- 10 % of total cells Myeloid precursors/ Intrauterine M1 (activated and upregulated ) & M2 (resting, surveillance) Neuro-inflammation – PET/ TSPO Binding of ligand to Grey matter and hippocampus GM Volume loss & cognitive deterioration
- Antibodies against neuronal cell surface targets, N-methyl-D-aspartate (NMDA) receptor, and components of the voltage-gated potassium channel Complex Whether this finding applies for patients with antibodies and a purely psychiatric presentation remains to be tested, although a few case descriptions exist to support this. anti- NMDA receptor encephalitis, a progressive illness that often starts with psychotic symptoms or seizures, and subsequently manifests other neurological and autonomic features. When present in patients with encephalitis, the antibodies are deemed to be pathogenic, and removal of the antibodies is associated with clinical improvement
- 2. Postulates that psychotropic medications can induce serum autoantibody production 4.The found increased odds of NMDAR seropositivity can not be attributed to inadvertrent inclusion of undiagnosed anti NMDAR encephalitis
- Possible mechanism of immune etiology of schizophrenia
- Persistent deficits in social communication and social interaction across multiple contexts Social deficits, Communication difficulties, Stereotyped or repetitive behaviors, cognitive delays
- decreasing of maternal immune protection and child immune-system immaturity create an immune vulnerability to infection diseases that, especially if treated with antibiotics, could facilitate dysbiosis and GI disorders. This condition triggers a vicious circle between immune system impairment and increasing dysbiosis that leads to leaky gut and neurochemical compounds and/or neurotoxic xenobiotics production and absorption. This alteration affects the ‘gut–brain axis’ communication that connects gut with central nervous system via immune system. Thus, metabolic pathways impaired in autistic children can be affected by genetic alterations or by environment–xenobiotics interference. In addition, in animal models many xenobiotics exert their neurotoxicity in a sex-dependent manner
- The first periods of life (0–36 months) are particularly delicate for the makeup of the gut complex community, and for immunity and neurodevelopment The critical window for immune vulnerability of children. At about 12 months the maternal protection is disappeared as well as antibodies from breastfeeding (especially in early weaning). On the other hand, the functionality and stability of gut microbiota as well as child’s own antibodies formation are not yet reached.
- Suggested pathogenesis for autism. Genetic/immunological susceptibility and environmental risk factors could enhance gut dysbiosis, leading to an aberrant inflammatory response, to an abnormal production of microbial end-products, and to leaky gut. The latter can enhance mal-absorption of both microbial and exogenous xenobiotics derived from diet. Once absorbed in the bloodstream, all these compounds can affect the normal brain development and function both directly and impairing the immune system: the latter creates a loop, of aberrant gut–brain axis communication that contributes to enhance these aberrant physiological responses. Finally, endogenous or exogenous stressors might have an impact in the development of senses, language, and higher cognitive functions developing and integrating in the first period of life
- Making human monoclonal antibodies (mAbs): XenoMouse Hybridoma Technology. 1. endogenous mouse immunoglobulin (Ig; heavy and light chain) gene loci were functionally inactivated in embryonic stem (ES) cells by gene-targeted deletion and used to generate mice homozygous for the necessary deletions. Crossbreeding of these mice resulted in mice homozygous for these deletions, rendering them incapable of producing mouse immunoglobulin. Then, yeast artificial chromosomes containing either human heavy- or light-chain DNA were introduced into ES cells. Crossbreeding of the mice derived from these ES cells resulted in transgenic mice producing both human and mouse antibodies. The mice incapable of producing mouse immunoglobulin were crossbred with the transgenic mice (containing both human and mouse antibodies), resulting in the XenoMouse strain that expresses fully human antibodies and is unable to produce mouse antibodies. Antibody-producing B cells, isolated from the spleen of an immunized XenoMouse, are used to produce hybridomas, wherein the B cells are fused with an immortal cell line. Finally, fully human mAbs are produced through the use of hybridoma technology. Results of this technology are favorable from a supply standpoint because each hybridoma can produce large quantities of identical fully human antibodies that can be cultured indefinitely and screened to identify antibodies of desired specificity, affinity, and target activity.
- Abagovomab – ovarian cancer Adalimumab – TNF –a – Rheumatoid arthritis, Psoriatic arthritis Infliximab – TNF a - Rheumatoid arthritis, Psoriatic arthritis Tocilizumab – IL 6 rececptor - RA
- The immune system responds to stressful stimuli by secreting proinflammatory cytokines [51], but when the rise in stress becomes chronic, the cytokines that are produced by immune cells activate the HPA axis, stimulating the adrenal cortex to synthesize and release glucocorticoids, which ultimately suppress proinflammatory gene expression [34]. For example, glucocorticoids upregulate IL-4, IL-10, and IL-13 production and can induce immunosuppression with higher and sustained glucocorticoid secretion
- The B subunit of cholera toxin (CTB) is a highly immunogenic protein known to elicit a potent antibody response. TA-CD vaccine is designed to induce formation of anti-cocaine antibodies. This cocaine vaccine covalently links succinylnorco-caine (SNC) to cholera toxin B (rCTB), which has a worldwide safety record for cholera immunization
- Studies show that curcumin could also potentially treat inflammation relating to mood disorders. The spice decreases levels of inflammatory interleukin 1β and tumor necrosis factor α, increases plasma brain-derived neurotrophic factor levels, and decreases salivary cortisol concentrations compared with placebo
- g HRV,28 blood glucose,33,35 blood lipids,35,67 salivary cortisol,3 and oxidative stress Acta Psychiatr Scand. 2007 Sep;116(3):226-32. Yoga therapy as an add-on treatment in the management of patients with schizophrenia--a randomized controlled trial. Duraiswamy G
- Is increased serum concentration of proinfl ammatory cytokines a cause or consequence of schizophrenia? • Could systemic infl ammatory markers be used to identify prodromal cases of schizophrenia, to predict disease progression, response to antipsychotic treatment and recovery? • Could infl ammatory processes explain cognitive defi cits, progressive cognitive decline and brain volume loss in some cases of schizophrenia? • Could infl ammatory processes explain the association between early-life adversity and risk of psychiatric disorders in adult life? • Does activation of microglia correspond with clinical severity of schizophrenia and response to antipsychotic treatment? • What is the role of neuronal cell surface autoantibodies in schizophrenia and other psychiatric disorders? • What is the prevalence of neuronal cell surface antibodies in schizophrenia, other psychiatric disorders, and healthy controls? • Does the prevalence of neuronal cell surface antibodies depend on the phase of the illness? Are there clinical signs that predict a positive test? • Are there other peripheral biomarkers associated with neuronal cell surface antibodies which could form therapeutic targets? • What is the association between intestinal microbiota and infl ammatory, behavioural, cognitive, and neurochemical phenotypes seen in schizophrenia and other psychiatric disorders? • What is the response of antibody-associated psychosis to immunosuppression or antipsychotic treatment? • Does control of infl ammation lead to clinical improvement in psychosis and other mental illness? • Is stratification of patients based on their immune phenotype helpful with respect to prediction of response to conventional and novel treatments?