It is now well recognized that the brain, and especially the hypothalamus, plays an important role in the regulation of immune reactions and inflammation. This book aims to review our current state of knowledge of this important field. Key historical findings are presented, and the reciprocal interactions between the brain and the immune system are examined. Particular emphasis is placed on inflammation, a critical host defense reaction that serves as an effector response for both the adaptive and innate immune systems.
Mechanisms implicated in brain defense, as well as in more general host defense, are discussed. The regulatory influences of the brain on inflammatory responses are included with particular reference to the role of the hypothalamus, which is also the main director the hormonal regulation of immune/inflammatory. Gender-related differences in immune responsiveness, circadian modulator of immune responses, and evidence that behavioral conditioning (e.g. reward) of immune responses is possible are used as examples to reinforce the notion that the neuroendocrine system exerts a fundamental and complex regulatory influence on the immune system.
* Presents timely issues such as immunological aspects of the blood-brain-barrier and the role of inflammatory mediators in the evolution of strokes and degenerative diseases
* Includes analysis of the role of the brain in the adaptive responses to disease
* Evaluates the argument that further knowledge of the influence of the brain on the immune system will provide new insights to the pathophysiology infectious and autoimmune diseases
1. 1. Introduction 2. 2. Signaling the Hypothalamus by the Immune System 3. 3. Neuroimmunoregulation During Homeostasis 4. 4. Neurogenic Inflammation (NIF) 5. 5. The Acute Phase Response (APR) 6. 6. Healing 7. 7. Conclusions 8. Leech Neuroimmune Signaling 9. 1. Introduction 10. 2. Neuroimmune Modulation by Opioids 11. 3. Neuroimmune Modulation by Opiates 12. 4. Neuroimmune Modulation by Cannabinoids 13. 5. Brain Innate Immune Response 14. 6. Conclusions 15. Acknowledgements 16. Morphogenesis of the Hypothalamus and Hypophysis 17. 1. Introduction 18. 2. Morphological Aspects of Pituitary Development 19. 3. The Pituitary Primordium as a Member of the Cranial Placodes 20. 4. Molecular Aspects of the Development of Adenohypophyseal Placode 21. 5. Signaling Molecules Acting Before and after the Formation of “Rathke's Pouch” 22. 6. Transcription Factors Working in Developing Pituitary Cells 23. 7. Adenohypophysis and its Homologs in Agnathan Vertebrates and Protochordates 24. A Novel Genus of Specialized Anti-Inflammatory and Pro-Resolution Lipid Mediators 25. 1. Inflammation 26. 2. Resolution of Self-Limited Acute Inflammation 27. 3. Anti-Inflammatory and Pro-Resolution Lipid Mediators 28. 4. Resolvins 29. 5. Protectins and D-Series Resolvins 30. 6. Maresins 31. 7. Conclusions 32. 8. Summary 33. Acknowledgements 34. Neural and Non-Neural Stem Cells as Novel Therapeutic Modalities for Brain Injury 35. 1. Introduction 36. 2. Neural Stem Cells 37. 3. Non-Neuronal (Adult) Stem Cells in the CNS 38. The Role of the Toll-Like Receptors in Neuropathology 39. 1. Introduction 40. 2. Immune-Linked Receptors in the Brain 41. 3. Structure of TLRS 42. 4. TLR Adaptor Proteins 43. 5. Stroke/Ischemic Brain Damage 44. 6. Invading Pathogens 45. 7. Cancer 46. 8. Spinal Cord Injury 47. 9. Alzheimer's Disease 48. 10. Multiple Sclerosis 49. 11. Neuropathic Pain 50. 12. Conclusions 51. Cytokines and the Immune–Neuroendocrine Network 52. 1. Introduction 53. 2. Pro-Inflammatory Cytokines il-1, il-6 and TNFα in the Neuroimmune Network 54. 3. Th1 Cytokines in the Neuroimmune Network 55. 4. Regulatory Cytokines in the Neuroimmune Network 56. 5. Cytokines and Major Depression 57. 6. Concluding Remarks 58. Acknowledgements 59. Orexin-Containing Neurons and the Immune System 60. 1. Introduction 61. 2. Orexin and Orexinergic Neurons 62. 3. Orexinergic Neuron Projections 63. 4. Orexin Receptors 64. 5. Hypothalamic Orexin-Containing Neurons and Cyclophosphamide Administration 65. 6. Orexin-Containing Neurons Respond to Antigenic Challenges 66. Conclusion 67. Central Pathways of Immunoregulation 68. 1. Central Pathways of Immunoregulation 69. 2. The Paraventricular Nucleus and IL-1β-Induced HPA Axis Responses 70. 3. Transduction of IL-1β Signals from the Periphery to the Brain 71. 4. Ascending Neural Pathways to the PVN Important in IL-1β Signaling 72. 5. Descending Neural Pathways from the PVN to Immune End Organs 73. 6. Recruitment of Pre-Sympathetic Nuclei 74. 7. Descending Connections from Pre-Sympathetic to Preganglionic Cells 75. 8. Innervation of Immune Organs by Sympathetic Projections 76. 9. Conclusions 77. Brain Responses to Antigenic Challenges 78. 1. Introduction 79. 2. Neurophysiological Processes in Hypothalamic Structures During Immune Response Development 80. 3. THE C-FOS Gene as a Marker of Activation of Neuronal Cells 81. 4. C-FOS Gene Expression in the CNS after Antigenic Challenges 82. 5. Conclusions 83. Acknowledgement 84. Role of the Endocrine System 85. 1. Introduction 86. 2. HPA Axis and the Immune Response 87. 3. Other Neuroendocrine axes and the Immune Response 88. 4. Conclusions 89. Conditioning of Immune Reactions 90. Introduction 91. 1. Evidence for CNS and Immune System Interactions 92. 2. Conditioning of Immunity in Animal Model Systems 93. 3. Possible Mechanisms for Mediating Classical Conditioning of Immune Responses 94. 4. Summary and Discussion 95. Acknowledgement 96. Gender Issues in Host Defense 97. 1. Introduction 98. 2. Host Defense 99. 3. Gender Issues in Host Defense Mechanisms 100. 4. Immune-Depressive Effects of Male Sex Steroids 101. 5. Potential Immune-Modulatory Mechanisms of Sex Steroids 102. 6. Therapeutic Options 103. 7. Conclusions 104. Glial Cells in Brain Defense Mechanisms 105. 1. Introduction: Glial Cells in the Brain 106. 2. Microglia 107. 3. Candidate Neuron–Microglia Signaling Factors 108. 4. Conclusions 109. Immunologic Privilege and the Brain 110. 1. Introduction 111. 2. Defining the Brain as an Immunologically Privileged Site: Historical Roots 112. 3. Components of Immunologic Privilege 113. 4. Lymphocyte Trafficking 114. 5. Downregulation of Intra-CNS Immune Responses 115. 6. Conclusion 116. Immune Aspects of the Blood–Brain Barrier 117. 1. Introduction to the Blood–Brain Barrier 118. 2. Endothelial Cell Activation 119. 3. Pericytes: The Second Line of Defense 120. 4. Astrocyte–Barrier Inductive Effects 121. 5. Conclusion 122. Neuroprotective Activities of CD4+CD25+ Regulatory T Cells 123. 1. Introduction 124. 2. Historical Perspective 125. 3. Development of Tregs 126. 4. Mechanisms of Regulation 127. 5. Interplay Between TH1, TH2, TH17 and Treg Cells 128. 6. Adaptive Immunity and Neuroprotection 129. 7. Tregs Are Protective in Models of Neurodegeneration 130. 8. Tregs and Mononuclear Phagocyte Activation 131. 9. Tregs Regulate Protective Immunity 132. 10. Induction of Tregs with Adjunctive Therapy 133. 11. Conclusion 134. Fever as a Host Defense Mechanism 135. 1. Introduction 136. 2. Definition of Fever 137. 3. Fever: An Old Weapon of Mass Protection 138. 4. The Course and Character of Fever 139. 5. Thermoeffector Mechanisms of Febrigenesis and Febrilysis 140. 6. The Pyrogenic Stimulus 141. 7. The Neural Substrate of Fever Production And Lysis 142. 8. Putative Mediators of Fever 143. 9. Immunoneuromodulation of Fever: Updated Concept 144. 10. Conclusions 145. Acknowledgements 146. Leukocytes as Mediators of Pain and Analgesia 147. 1. Introduction 148. 2. Proalgesic Mechanisms 149. 3. Analgesic Mechanisms 150. Tumor Necrosis Factor as a Neuroinflammatory Mediator in Alzheimer's Disease and Stroke: Molecular Mechanisms and Neuroinflammatory Imaging 151. 1. Introduction 152. 2. Some Basic Aspects of Cerebral Inflammation 153. 3. Common Inflammatory Features in Normal Brain 154. 4. Inflammatory Signals in Neurodegenerative Disorders and Stroke: Markers for Damage or Protection? 155. 5. Neuroinflammatory Imaging 156. 6. Inflammatory Molecules as Possible Drug Targets for Novel Therapeutic Strategies 157. 7. Neuroinflammation, Microglial Activation and Neurodegeneration: Additional Pathways 158. 8. Neuroinflammation: Can Inflammation Lead to Improvements in Diagnosis and Treatment of Neurodegenerative Diseases? 159. Multiple Sclerosis and Depression: A Neuroimmunological Perspective 160. 1. Introduction 161. 2. Frequency of Depression in MS 162. 3. Depression Prior to Onset of MS 163. 4. Family History of Depression in MS 164. 5. Depression at Onset of MS 165. 6. Depression in Elderly MS Patients 166. 7. Clinical Features of Depression in MS 167. 8. Symptoms Shared Between Depression and MS 168. 9. Clinical Correlations 169. 10. Suicide in MS 170. 11. Migraine and MS 171. 12. Brain Metabolism in Depression 172. 13. Brain Metabolism in MS 173. 14. MRI, Depression and MS 174. 15. The Hypothalamic–Pituitary–Adrenal (HPA) Axis in Depression 175. 16. The HPA Axis in MS 176. 17. Bipolar Disease 177. 18. The Immunology of Multiple Sclerosis 178. 19. Cytokines in Depression and the Effect of Antidepressants on Cytokines 179. 20. Brain-Derived Neurotrophic Factor (BDNF) in Depression and in MS 180. 21. Corticotrophin-Releasing Hormone (CRH) in Peripheral Tissues 181. 22. Does Depression Complicate Treatment of MS with Immunomodulatory Drugs? 182. 23. Management of Depression in People with MS 183. Acknowledgements 184. Infection and Sepsis 185. 1. Host Immune Responses During Infection and Sepsis 186. 2. Brain-to-Immune Pathways that Regulate Host Responses During Infection 187. 3. Summary and Conclusion 188. Acknowledgements 189. Restoration of Neuroimmune Disturbances in Rats by Extra-High-Frequency Electromagnetic Irradiation of the Skin 190. 1. Introduction 191. 2. NK Cell Activity and Expression of the C-Fos Gene in Hypothalamic Structures Of rats after Painful Electric Stimulation of the Limbs: The Effect of EHF Skin Irradiation 192. 3. C-Fos Gene Expression, Morphofunctional Changes in Orexin-Containing Neurons in Hypothalamic Structures and NK Cell Activity in rats Treated with Cyclophosphamide and with EHF Irradiation of the Skin 193. 4. Lipopolysaccharide-Induced Activation of Hypothalamic Orexin-Containing Neurons in rats, Natural Kiler Cell Cytotoxicity and the Effects of EHF Irradiation of the Skin 194. 5. Conclusions 195. Acknowledgements
It is now well recognized that the brain, and especially the hypothalamus, plays an important role in the regulation of immune reactions and inflammation. This book aims to review our current state of knowledge of this important field. Key historical findings are presented, and the reciprocal interactions between the brain and the immune system are examined. Particular emphasis is placed on inflammation, a critical host defense reaction that serves as an effector response for both the adaptive and innate immune systems.
Mechanisms implicated in brain defense, as well as in more general host defense, are discussed. The regulatory influences of the brain on inflammatory responses are included with particular reference to the role of the hypothalamus, which is also the main director the hormonal regulation of immune/inflammatory. Gender-related differences in immune responsiveness, circadian modulator of immune responses, and evidence that behavioral conditioning (e.g. reward) of immune responses is possible are used as examples to reinforce the notion that the neuroendocrine system exerts a fundamental and complex regulatory influence on the immune system.
* Presents timely issues such as immunological aspects of the blood-brain-barrier and the role of inflammatory mediators in the evolution of strokes and degenerative diseases
* Includes analysis of the role of the brain in the adaptive responses to disease
* Evaluates the argument that further knowledge of the influence of the brain on the immune system will provide new insights to the pathophysiology infectious and autoimmune diseases
1. 1. Introduction 2. 2. Signaling the Hypothalamus by the Immune System 3. 3. Neuroimmunoregulation During Homeostasis 4. 4. Neurogenic Inflammation (NIF) 5. 5. The Acute Phase Response (APR) 6. 6. Healing 7. 7. Conclusions 8. Leech Neuroimmune Signaling 9. 1. Introduction 10. 2. Neuroimmune Modulation by Opioids 11. 3. Neuroimmune Modulation by Opiates 12. 4. Neuroimmune Modulation by Cannabinoids 13. 5. Brain Innate Immune Response 14. 6. Conclusions 15. Acknowledgements 16. Morphogenesis of the Hypothalamus and Hypophysis 17. 1. Introduction 18. 2. Morphological Aspects of Pituitary Development 19. 3. The Pituitary Primordium as a Member of the Cranial Placodes 20. 4. Molecular Aspects of the Development of Adenohypophyseal Placode 21. 5. Signaling Molecules Acting Before and after the Formation of “Rathke's Pouch” 22. 6. Transcription Factors Working in Developing Pituitary Cells 23. 7. Adenohypophysis and its Homologs in Agnathan Vertebrates and Protochordates 24. A Novel Genus of Specialized Anti-Inflammatory and Pro-Resolution Lipid Mediators 25. 1. Inflammation 26. 2. Resolution of Self-Limited Acute Inflammation 27. 3. Anti-Inflammatory and Pro-Resolution Lipid Mediators 28. 4. Resolvins 29. 5. Protectins and D-Series Resolvins 30. 6. Maresins 31. 7. Conclusions 32. 8. Summary 33. Acknowledgements 34. Neural and Non-Neural Stem Cells as Novel Therapeutic Modalities for Brain Injury 35. 1. Introduction 36. 2. Neural Stem Cells 37. 3. Non-Neuronal (Adult) Stem Cells in the CNS 38. The Role of the Toll-Like Receptors in Neuropathology 39. 1. Introduction 40. 2. Immune-Linked Receptors in the Brain 41. 3. Structure of TLRS 42. 4. TLR Adaptor Proteins 43. 5. Stroke/Ischemic Brain Damage 44. 6. Invading Pathogens 45. 7. Cancer 46. 8. Spinal Cord Injury 47. 9. Alzheimer's Disease 48. 10. Multiple Sclerosis 49. 11. Neuropathic Pain 50. 12. Conclusions 51. Cytokines and the Immune–Neuroendocrine Network 52. 1. Introduction 53. 2. Pro-Inflammatory Cytokines il-1, il-6 and TNFα in the Neuroimmune Network 54. 3. Th1 Cytokines in the Neuroimmune Network 55. 4. Regulatory Cytokines in the Neuroimmune Network 56. 5. Cytokines and Major Depression 57. 6. Concluding Remarks 58. Acknowledgements 59. Orexin-Containing Neurons and the Immune System 60. 1. Introduction 61. 2. Orexin and Orexinergic Neurons 62. 3. Orexinergic Neuron Projections 63. 4. Orexin Receptors 64. 5. Hypothalamic Orexin-Containing Neurons and Cyclophosphamide Administration 65. 6. Orexin-Containing Neurons Respond to Antigenic Challenges 66. Conclusion 67. Central Pathways of Immunoregulation 68. 1. Central Pathways of Immunoregulation 69. 2. The Paraventricular Nucleus and IL-1β-Induced HPA Axis Responses 70. 3. Transduction of IL-1β Signals from the Periphery to the Brain 71. 4. Ascending Neural Pathways to the PVN Important in IL-1β Signaling 72. 5. Descending Neural Pathways from the PVN to Immune End Organs 73. 6. Recruitment of Pre-Sympathetic Nuclei 74. 7. Descending Connections from Pre-Sympathetic to Preganglionic Cells 75. 8. Innervation of Immune Organs by Sympathetic Projections 76. 9. Conclusions 77. Brain Responses to Antigenic Challenges 78. 1. Introduction 79. 2. Neurophysiological Processes in Hypothalamic Structures During Immune Response Development 80. 3. THE C-FOS Gene as a Marker of Activation of Neuronal Cells 81. 4. C-FOS Gene Expression in the CNS after Antigenic Challenges 82. 5. Conclusions 83. Acknowledgement 84. Role of the Endocrine System 85. 1. Introduction 86. 2. HPA Axis and the Immune Response 87. 3. Other Neuroendocrine axes and the Immune Response 88. 4. Conclusions 89. Conditioning of Immune Reactions 90. Introduction 91. 1. Evidence for CNS and Immune System Interactions 92. 2. Conditioning of Immunity in Animal Model Systems 93. 3. Possible Mechanisms for Mediating Classical Conditioning of Immune Responses 94. 4. Summary and Discussion 95. Acknowledgement 96. Gender Issues in Host Defense 97. 1. Introduction 98. 2. Host Defense 99. 3. Gender Issues in Host Defense Mechanisms 100. 4. Immune-Depressive Effects of Male Sex Steroids 101. 5. Potential Immune-Modulatory Mechanisms of Sex Steroids 102. 6. Therapeutic Options 103. 7. Conclusions 104. Glial Cells in Brain Defense Mechanisms 105. 1. Introduction: Glial Cells in the Brain 106. 2. Microglia 107. 3. Candidate Neuron–Microglia Signaling Factors 108. 4. Conclusions 109. Immunologic Privilege and the Brain 110. 1. Introduction 111. 2. Defining the Brain as an Immunologically Privileged Site: Historical Roots 112. 3. Components of Immunologic Privilege 113. 4. Lymphocyte Trafficking 114. 5. Downregulation of Intra-CNS Immune Responses 115. 6. Conclusion 116. Immune Aspects of the Blood–Brain Barrier 117. 1. Introduction to the Blood–Brain Barrier 118. 2. Endothelial Cell Activation 119. 3. Pericytes: The Second Line of Defense 120. 4. Astrocyte–Barrier Inductive Effects 121. 5. Conclusion 122. Neuroprotective Activities of CD4+CD25+ Regulatory T Cells 123. 1. Introduction 124. 2. Historical Perspective 125. 3. Development of Tregs 126. 4. Mechanisms of Regulation 127. 5. Interplay Between TH1, TH2, TH17 and Treg Cells 128. 6. Adaptive Immunity and Neuroprotection 129. 7. Tregs Are Protective in Models of Neurodegeneration 130. 8. Tregs and Mononuclear Phagocyte Activation 131. 9. Tregs Regulate Protective Immunity 132. 10. Induction of Tregs with Adjunctive Therapy 133. 11. Conclusion 134. Fever as a Host Defense Mechanism 135. 1. Introduction 136. 2. Definition of Fever 137. 3. Fever: An Old Weapon of Mass Protection 138. 4. The Course and Character of Fever 139. 5. Thermoeffector Mechanisms of Febrigenesis and Febrilysis 140. 6. The Pyrogenic Stimulus 141. 7. The Neural Substrate of Fever Production And Lysis 142. 8. Putative Mediators of Fever 143. 9. Immunoneuromodulation of Fever: Updated Concept 144. 10. Conclusions 145. Acknowledgements 146. Leukocytes as Mediators of Pain and Analgesia 147. 1. Introduction 148. 2. Proalgesic Mechanisms 149. 3. Analgesic Mechanisms 150. Tumor Necrosis Factor as a Neuroinflammatory Mediator in Alzheimer's Disease and Stroke: Molecular Mechanisms and Neuroinflammatory Imaging 151. 1. Introduction 152. 2. Some Basic Aspects of Cerebral Inflammation 153. 3. Common Inflammatory Features in Normal Brain 154. 4. Inflammatory Signals in Neurodegenerative Disorders and Stroke: Markers for Damage or Protection? 155. 5. Neuroinflammatory Imaging 156. 6. Inflammatory Molecules as Possible Drug Targets for Novel Therapeutic Strategies 157. 7. Neuroinflammation, Microglial Activation and Neurodegeneration: Additional Pathways 158. 8. Neuroinflammation: Can Inflammation Lead to Improvements in Diagnosis and Treatment of Neurodegenerative Diseases? 159. Multiple Sclerosis and Depression: A Neuroimmunological Perspective 160. 1. Introduction 161. 2. Frequency of Depression in MS 162. 3. Depression Prior to Onset of MS 163. 4. Family History of Depression in MS 164. 5. Depression at Onset of MS 165. 6. Depression in Elderly MS Patients 166. 7. Clinical Features of Depression in MS 167. 8. Symptoms Shared Between Depression and MS 168. 9. Clinical Correlations 169. 10. Suicide in MS 170. 11. Migraine and MS 171. 12. Brain Metabolism in Depression 172. 13. Brain Metabolism in MS 173. 14. MRI, Depression and MS 174. 15. The Hypothalamic–Pituitary–Adrenal (HPA) Axis in Depression 175. 16. The HPA Axis in MS 176. 17. Bipolar Disease 177. 18. The Immunology of Multiple Sclerosis 178. 19. Cytokines in Depression and the Effect of Antidepressants on Cytokines 179. 20. Brain-Derived Neurotrophic Factor (BDNF) in Depression and in MS 180. 21. Corticotrophin-Releasing Hormone (CRH) in Peripheral Tissues 181. 22. Does Depression Complicate Treatment of MS with Immunomodulatory Drugs? 182. 23. Management of Depression in People with MS 183. Acknowledgements 184. Infection and Sepsis 185. 1. Host Immune Responses During Infection and Sepsis 186. 2. Brain-to-Immune Pathways that Regulate Host Responses During Infection 187. 3. Summary and Conclusion 188. Acknowledgements 189. Restoration of Neuroimmune Disturbances in Rats by Extra-High-Frequency Electromagnetic Irradiation of the Skin 190. 1. Introduction 191. 2. NK Cell Activity and Expression of the C-Fos Gene in Hypothalamic Structures Of rats after Painful Electric Stimulation of the Limbs: The Effect of EHF Skin Irradiation 192. 3. C-Fos Gene Expression, Morphofunctional Changes in Orexin-Containing Neurons in Hypothalamic Structures and NK Cell Activity in rats Treated with Cyclophosphamide and with EHF Irradiation of the Skin 193. 4. Lipopolysaccharide-Induced Activation of Hypothalamic Orexin-Containing Neurons in rats, Natural Kiler Cell Cytotoxicity and the Effects of EHF Irradiation of the Skin 194. 5. Conclusions 195. Acknowledgements
