Psychoneuroimmunology

Psychoneuroimmunology

Second Edition

ROBERT ADER

Department of Psychiatry, University of Rochester Medical Center, Rochester, New York

DAVID L. FELTEN

Department of Neurobiology and Anatomy, University of Rochester Medical Center, Rochester, New York

NICHOLAS COHEN

Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York

Table of Contents

Cover image

Title page

Dedication

Copyright

Contributors

Preface

PART I: Neurochemical Links between the Nervous and Immune Systems

Chapter 1: Central Neural Circuits Involved in Neural–Immune Interactions

Publisher Summary

I Introduction

II Effects of CNS Lesions on the Immune System

III CNS Responses to Immunization

IV Mediators of Immune–Neural Communication

V Immunologic Effects on Behavior

VI Conclusions

Chapter 2: Innervation of Lymphoid Tissue

Publisher Summary

I Introduction1

II Bone Marrow

III Thymus

IV Spleen

V Lymph Nodes

VI Other Lymphoid Accumulations

VII Interpreting Neuroanatomical Data

VIII Summary

Acknowledgments

Chapter 3: Ontogeny and Senescence of Noradrenergic Innervation of the Rodent Thymus and Spleen

Publisher Summary

I Introduction1

II Ontogeny of Sympathetic Neurotransmission in the Thymus

III Ontogeny of Sympathetic Neurotransmission in the Spleen

IV NORADRENERGIC INNERVATION OF THE MATURE AND AGING THYMUS

V Noradrenergic Innervation of the Mature and Aging Spleen

VI β-Adrenergic Receptors on Cells of the Immune System with Age

VII Significance of Age-Related Alterations in Noradrenergic Sympathetic Innervation of Lymphoid Organs: Possible Relationship to an Age-Related Decline in Immune Function

VIII Summary

Chapter 4: Neocortex Lateralization of Immune Function and of the Activities of Imuthiol, a T-Cell-Specific Immunopotentiator

Publisher Summary

I Introduction

II Lateralized Influence of Neocortex on Immune Function

III Immunoenhancing Effects of Imuthiol Are under Lateralized Neocortical Control

IV Conclusions

Chapter 5: T-Lymphocyte Entry and Antigen Recognition in the Central Nervous System

Publisher Summary

I Introduction1

II T-Lymphocyte Entry into the Central Nervous System

III Antigen Presentation in the Central Nervous System

IV Summary

Chapter 6: Interaction of the Mucosal Immune and Peripheral Nervous Systems

Publisher Summary

I Introduction

II Mucosal Architecture

III Innervation of Immune Cells in Mucosal Sites

IV Nerve Growth Factor

V Intersystem Communication

VI Possible Mucosal Neuroimmunological Pathways

VII Conclusions

Acknowledgements

Chapter 7: Immunologie Properties of Substance P

Publisher Summary

I Introduction1

II Substance P and Human Inflammatory Disorders

III Cellular Interactions with Substance P

IV Substance P Receptors

V Conclusions

Chapter 8: Vasoactive Intestinal Peptide and Immune Function

Publisher Summary

I Introduction

II Structure and Biosynthesis

III Availability and Distribution

IV Binding of Vasoactive Intestinal Peptide to Lymphoid Cells

V Opportunity of Lymphoid Cells to Bind Vasoactive Intestinal Peptide

VI Effects of Vasoactive Intestinal Peptide on Lymphoid Cells

VII Vasoactive Intestinal Peptide Receptor

VIII Future Directions

Chapter 9: Production and Recognition of Neuropeptides by Cells of the Immune System

Publisher Summary

I Introduction

II Neuroendocrine Peptides from Immunological Cells

III Conversion and Degradation of Neuropeptides by Immune Cells

IV Neuropeptide Mediation of Immunological Reactions, Inflammation, and Tissue Repair Processes

V Human Lymphocyte Receptors for Neuropeptides

VI Pathogenetic Roles of Neuropeptides in Immune Diseases

VII Summary

Chapter 10: Catecholamine Action and Immunologic Reactivity

Publisher Summary

I Introduction1

II Catecholamines and Lymphocyte Responsiveness in Vitro

III Catecholamines and Lymphocyte Activity in Vivo

IV Discussion: Role of Catecholamines in the Regulation of Immune Reactivity

V Conclusions

Acknowledgments

Chapter 11: Neurotransmitters and Molecular Signaling in the Immune Response

Publisher Summary

I Introduction1

II Role of Catecholamines in Modulating Immunity

III Modulation of T-Cell Function by Stimulation of β-Adrenergic Receptors

IV Molecular Neuroimmunomodulation—Consequences of Dual Receptor Signaling

V Concluding Remarks

PART II: Neuroendocrine–Immune System Interactions

Chapter 12: Effects of Hypophysectomy on Immune Function

Publisher Summary

I Introduction1

II The Pituitary Gland

III Methods of Hypophysectomy and Pituitary Grafting

IV Hypophysectomy, Hemopoiesis, and Immunity

V Discussion

VI Summary

Acknowledgments

Chapter 13: Growth Hormone in Immunobiology

Publisher Summary

I Introduction

II A Look at the Past

III Growth Hormone Deficiency

IV Growth Hormone, Thymic Involution, and Aging

V Growth Hormone and Lymphocytes

VI Growth Hormone and Hemopoiesis

VII Growth Hormone and Phagocytic Cells

VIII Growth Hormone in the Immune Response

IX A Look to the Future

Chapter 14: Prolactin and Immune Function

Publisher Summary

I Introduction

II Physiological and Pharmacological Regulation of Prolactin Secretion

III Effects of Prolactin on Immune Function

IV Cellular Effects of Prolactin in Immune Tissues

V Questions for Future Research

VI Summary

Acknowledgments

Chapter 15: Corticotropin-Releasing Hormone and Proopiomelanocortin-Derived Peptides in the Modulation of Immune Function

Publisher Summary

I Introduction

II Induction of Proopiomelanocortin-Derived Peptides by Corticotropin-Releasing Hormone

III Influence of Proopiomelanocortin-Derived Peptides on Immune Function

IV Epilogue

Chapter 16: Glucocorticoids and Immune Function

Publisher Summary

I Introduction1

II Molecular Mechanisms of Glucocorticoid Actions

III Glucocorticoid Modulation of Mediators of Immune and Inflammatory Reactions

IV Glucocorticoid Effects on Mononuclear Phagocytes

Chapter 17: Sex Hormones and Immune Function

Publisher Summary

I Introduction

II Male/Female Differences in Immunity

III Effect of Sex Steroids on the Immune System

Chapter 18: Role of the Pineal Neurohormone Melatonin in the Psycho–Neuroendocrine–Immune Network

Publisher Summary

I Introduction

II Immunologic Relevance of Endogenous Melatonin

III Immunologic Effect of Exogenous Melatonin

IV Mechanism of Action

V Preliminary Clinical Studies

VI Conclusions and Perspectives

Chapter 19: Thymic Hormones and Immune Function: Mediation via Neuroendocrine Circuits

Publisher Summary

I Introduction1

II Thymic Hormones and Reproductive Function

III Thymic Hormones and the Pituitary–Adrenal Axis

IV Discussion

Acknowledgments

Chapter 20: First and Second Messengers in the Development and Function of Thymus-Dependent Lymphocytes

Publisher Summary

I Introduction

II First Messengers

III Second Messengers

IV Conclusion

Chapter 21: Long-Term Effects of Neuroendocrine–Immune Interactions during Early Development

Publisher Summary

I Introduction1

II Interactions between the Immune System and the Central Nervous System

III Critical Periods in Development

IV Endocrine Influence on Immunity

V Immune System Modulation of Endocrine Pathways in Early Development

Acknowledgments

Chapter 22: Neuropeptide Hormones and Receptors Common to the Immune and Neuroendocrine Systems: Bidirectional Pathway of Intersystem Communication

Publisher Summary

I Introduction1

II Neuropeptide Hormone Production by Cells of the Immune System

III Neuropeptide Hormone Receptors on Cells of the Immune System

IV Discussion

Acknowledgments

Chapter 23: Physiological Implications of the Immune–Neuro–Endocrine Network

Publisher Summary

I Introduction1

II The Immune System as a Receptor Sensorial Organ

III Immune–Neuro–Endocrine Regulatory Circuits

IV Host Metabolic Adjustments Mediated by the Immune System

V Summary and Overview

Acknowledgments

PART III: Behavior–Immune System Interactions

Chapter 24: The Influence of Conditioning on Immune Responses

Publisher Summary

I Introduction1

II Modern Studies of Conditioning and Immune Function

III Dissociation of Conditioned Behavioral and Immune Responses

IV Adrenocortical Responses and Conditioned Immune Responses

V Summary

Acknowledgments

Chapter 25: Conditioned Immunosuppression: Analysis of Lymphocytes and Host Environment of Young and Aged Mice

Publisher Summary

I Introduction1

II Conditioned Immunosuppression in Mice

III T Cells, Aging, and Conditioned Immunosuppression

IV Summary and Future Research

Chapter 26: Immunopharmacological Tolerance as a Conditioned Response: Dissecting the Brain–Immune Pathways

Publisher Summary

I Introduction1

II Conditioning Analysis of Drug Tolerance

III Immunopharmacological Tolerance: Associative Parameters

IV Immunopharmacological Tolerance: Mechanisms

V Summary and Conclusions

Acknowledgments

Chapter 27: Behavioral Adaptations in Autoimmune Disease-Susceptible Mice

Publisher Summary

I Introduction1

II Taste Aversion Learning in Lupus-Prone Mice

III Voluntary Consumption of Cyclophosphamide by Lupus-Prone Mice

IV Discussion

Acknowledgements

Chapter 28: Autoimmunity and Cognitive Decline in Aging and Alzheimer’s Disease

Publisher Summary

I Introduction1

II Immunologic Perturbation of Central Nervous System Function

III The Blood—Brain Barrier and Neuroimmunopathology

IV Brain-Reactive Antibodies and Aging

V Brain-Reactive Antibodies and Alzheimer’s Disease

VI Autoimmunity and Neurobehavioral Alterations in Aging Rodents

VII General Discussion and Conclusions

Acknowledgments

Chapter 29: Behavioral Consequences of Virus Infection

Publisher Summary

I Introduction

II A Viral Model of Hyperactivity

III Ways in Which Viruses May Alter Behavior

Chapter 30: Stress-Induced Changes in Immune Function in Animals: Hypothalamo–Pituitary–Adrenal Influences

Publisher Summary

I Introduction

II Stress Effects on Lymphoid Cells

III Stress Effects on in Vivo Immune Responses

IV Hypothalamo–Pituitary–Adrenal Influences

V Conclusion

Chapter 31: Stress-Induced Immune Modulation in Animals: Opiates and Endogenous Opioid Peptides

Publisher Summary

I Stress, Immunity, and Cancer

II Stress-Induced Analgesia

III Opiates, Opioid Peptides, Immunity, and Tumors

IV Summary

Acknowledgments

Chapter 32: Psychoimmunology of Social Factors in Rodents and Other Subprimate Vertebrates

Publisher Summary

Introduction

II Humoral Immunity and Social Factors

III Cell-Mediated Immunity and Social Factors

IV Diseases, Resistance to Disease, and Social Factors

V Social Factors in Tumor Growth and Survival

VI Concluding Comments

Acknowledgments

Chapter 33: Behavior and the Major Histocompatibility Complex of the Mouse

Publisher Summary

I Introduction1

II Methods

III Technical Notes

IV Determination of Odortypes, the Olfactory Image

V Reception of the Odortype

VI Behavior

VII Summary

Note Added in Proof

PART IV: Psychosocial Factors, Stress, Disease, and Immunity

Chapter 34: Stress and Immune Function in Humans

Publisher Summary

I Introduction1

II Major Stressful Life Changes

III Depression and Chronic Stressors

IV Academic Stress

V Intervention Studies

VI Social Relationships and Immune Function

VII Psychosocial Stressors, Immunity, and Health Consequences

Chapter 35: Exercise and Human Immune Function

Publisher Summary

I Introduction

II Exercise Physiology

III Exercise, Neuroendocrine Factors, and Psychological Function

IV Exercise and Immunity

V Functional Significance of Immune Alterations

VI Conclusions and Implications for Further Studies

Chapter 36: Depression and the Immune System

Publisher Summary

I Introduction

II Neuroimmunology

III Psychosocial Influences on Immunocompetence and Health and Illness

IV The Nosology of Depression

V Depressive Disorders and Immune Function

VI Immunocytes as Peripheral Models of Central Nervous System Alterations in Depression

VII Immunologic Influences on Central Nervous System Function in Depression

VIII Conclusion

Acknowledgments

Chapter 37: Immunosuppression by Marijuana and Components

Publisher Summary

I Introduction1

II Background and Historical Observations

III Blastogenic Responses of Lymphocytes from Marijuana Users

IV Administration of Δ9-Tetrahydrocannabinol to Experimental Animals

V Marijuana and Disease

VI Resistance to Infection

VII Effects of Marijuana and Components on Immune System Parameters

VIII Conclusions and Summary

Chapter 38: Social and Psychobiological Factors in Autoimmune Disease

Publisher Summary

I The Concept of Autoimmunity1

II Autoimmune Diseases

III Role of Genetic Factors in Autoimmune Disease

IV Role of Gender in Autoimmune Disease

V Psychosocial Factors in Autoimmune Disease

VI Psychosocial Factors in Specific Autoimmune Diseases

VII Conclusion

Chapter 39: Asthma: Psychoneuroimmunologic Considerations

Publisher Summary

I Introduction

II The Genetic Premise

III Mechanisms of Bronchoconstriction

V Research Issues

Chapter 40: Behavioral Sequelae of Autoimmune Disease

Publisher Summary

I Introduction

II Multiple Sclerosis—A Clinical Model of Cellular Autoimmunity and Behavioral Change

III Lupus—A Clinical Model of Antibody-Mediated Behavioral Disturbance

IV Animal Models and Mechanisms

V Concluding Remarks

Chapter 41: Psychosocial Interventions and Immune Function

Publisher Summary

I Introduction1

II Psychosocial Interventions and Immunity

III Adverse Consequences of Psychosocial Interventions

IV Discussion

Acknowledgments

Chapter 42: Psychoneuroimmunologic Aspects of Human Immunodeficiency Virus Infection

Publisher Summary

I Introduction

II HIV Infection and the Central Nervous System: Neuroimmune Connections

III Immunobiology of HIV Infection

IV Psychosocial Responses to the AIDS Epidemic

V Potential Pathways for the Influence of Psychosocial Factors on Progression of HIV Infection

VI Psychoimmunologic Research on HIV, AIDS-Related Complex, and AIDS

VII Conclusion

PART V: Epilogue

Chapter 43: A Personal Perspective on Psychoneuroimmunology

Author Index

Subject Index

Dedication

This volume is respectfully dedicated to our friend and colleague

George Freeman Solomon, M.D.

an imaginative and pioneering investigator who has contributed in the field of psychoneuroimmunology for the past 25 years

Copyright

Copyright © 1991 by Academic Press, Inc.

All Rights Reserved.

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher.

Academic Press, Inc.

San Diego, California 92101

United Kingdom Edition published by

Academic Press Limited

24–28 Oval Road, London NW1 7DX

Library of Congress Cataloging-in-Publication Data

Psychoneuroimmunology, Second Edition / edited by Robert Ader, David L.

Felten,

Nicholas Cohen.

p. cm.

Includes bibliographical references.

ISBN 0-12-043782-1 (alk. paper)

1. Neuroimmunology. 2. Psychoneuroimmunoendocrinology. I. Ader, Robert. II. Felten, David L. III. Cohen, Nicholas, Date.

IV. Title: Psychoneuroimmunology. 2. V. Title: Psychoneuroimmunology two.

[DNLM: 1. Psychoneuroimmunology. QW 504 P974]

QP356.47.P79 1990

616.07′9–dc20

DNLM/DLC

for Library of Congress 90–216

CIP

Printed in the United States of America

90 91 92 93 9 8 7 6 5 4 3 2 1

Contributors

Numbers in parentheses indicate the pages on which the authors’ contributions begin

Kurt Ackerman(71),     Department of Neurobiology and Anatomy, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

Robert Ader(3, 611, 685),     Department of Psychiatry, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

Rudy E. Ballieux(429),     Department of Clinical Immunology, University Hospital, Utrecht, The Netherlands

Judith Bard(831),     Department of Microbiology and Immunology, University of Arizona, Tucson, Arizona 85724

Gary K. Beauchamp(831),     Monell Chemical Senses Center, Philadelphia, Pennsylvania 19104

Denise Bellinger(71),     Department of Neurobiology and Anatomy, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

Istvan Berczi(339),     Department of Immunology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada R3T 2N2

Edward W. Bernton(403),     Neuropharmacology Branch, Department of Medical Neurosciences, Division of Neuropsychiatry, Walter Reed Army Institute of Research, Washington, D.C. 20307-5100

Hugo O. Besedovsky(589),     Division of Neurobiology, Department of Research, University Hospital, Basel, Switzerland

John Bienenstock(177),     Department of Pathology, McMaster University, Hamilton, Ontario, Canada L8N 3Z5

Kathleen Biziere(127),     F. Hoffman La Roche & Cie, Bale, Switzerland

J. Edwin Blalock(573),     Department of Physiology and Biophysics, University of Alabama at Birmingham, UAB Station, Birmingham, Alabama 35294

Béla Bohus(807),     Department of Animal Physiology, University of Groningen, Center for Biological Sciences, Haren, The Netherlands

Edward A. Boyse(831),     Department of Microbiology and Immunology, University of Arizona, Tucson, Arizona 85724

Henry U. Bryant(403),     Department of Immunology, Pulmonary and Leukotriene Research, Eli Lilly and Co., Indianapolis, Indiana 46285

Sonia L. Carlson(3, 311),     Department of Microbiology and Immunology, University of Kentucky Medical Center, Lexington, Kentucky 40536

Daniel J.J. Carr(573),     Department of Physiology and Biophysics, University of Alabama at Birmingham, UAB Station, Birmingham, Alabama 35294

Ronald G. Coffey(529),     Departments of Medicine and Pharmacology and Therapeutics, University of South Florida College of Medicine, Tampa, Florida 33612

Nicholas Cohen(3, 611, 685),     Departments of Microbiology and Immunology and Psychiatry, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

Ario Conti(495),     Laboratory for Experimental Pathology, Istituto Cantonale di Patologia, 6604 Locarno, Switzerland

Linda S. Crnic(749),     Departments of Pediatrics and Psychiatry, University of Colorado School of Medicine, Denver, Colorado 80262

Ken Croitoru(177),     Department of Pathology, McMaster University, Hamilton, Ontario, Canada L8N 3Z5

Melissa K. Demetrikopoulos(771),     Department of Neuroscience, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey 07103

Dennis G. Dyck(663),     Department of Psychology, University of Manitoba, Winnipeg, Manitoba, Canada R3T 2N2

David L. Felten(3, 27, 71, 1117),     Departments of Neurobiology and Anatomy and Psychiatry, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

Suzanne Y. Felten(3, 27, 71),     Department of Neurobiology and Anatomy, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

Michael J. Forster(709),     Department of Pharmacology, Texas College of Osteopathic Medicine, Fort Worth, Texas 76107-2690

Herman Friedman(1081),     Department of Medical Microbiology and Immunology, University of South Florida College of Medicine, Tampa, Florida 33612

Ronald Glaser(849),     Department of Medical Microbiology and Immunology, The Ohio State University College of Medicine, Columbus, Ohio 43210

Edward J. Goetzl(263),     The Howard Hughes Medical Institute and Department of Medicine and Microbiology—Immunology, University of California Medical Center, San Francisco, California 94143-0724

Reginald M. Gorczynski(647),     Departments of Surgery and Immunology, University of Toronto, Toronto, Ontario, Canada M5G 1X5

Arnold H. Greenberg(663),     Manitoba Institute of Cell Biology, Winnipeg, Manitoba, Canada R3E 0V9

Lee J. Grota(685),     Department of Psychiatry, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

Paul M. Guyre(447),     Department of Physiology, Dartmouth Medical School, Hanover, New Hampshire 03756

Elba M. Hadden(529),     Departments of Medicine and Pharmacology and Therapeutics, University of South Florida College of Medicine, Tampa, Florida 33612

John W. Hadden(529),     Departments of Medicine and Pharmacology and Therapeutics, University of South Florida College of Medicine, Tampa, Florida 33612

Nicholas R.S. Hall(515, 561, 1067),     Departments of Psychiatry and Behavioral Medicine and Medical, Microbiology & Immunology, University of South Florida College of Medicine, Tampa, Florida 33613

Cobi J. Heijnen(429),     Department of Pediatric Immunology, University Hospital for Children and Youth, Het Wilhelmina Kinder-Ziekenhuis, Utrecht, The Netherlands

William Hickey(149),     Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110

Steven A. Hoffman(1037),     Department of Microbiology, Arizona State University, Tempe, Arizona 85287-2701

John W. Holaday(403),     Neuropharmacology Branch, Department of Medical Neurosciences, Division of Neuropsychiatry, Walter Reed Army Institute of Research, Washington, D.C. 20307-5100

Annemieke Kavelaars(429),     Department of Pediatric Immunology, University Hospital for Children and Youth, Het Wilhelmina Kinder-Ziekenhuis, Utrecht, The Netherlands

Steven E. Keller(771),     Department of Psychiatry and Neuroscience, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey 07103

Keith Kelley(377),     Department of Animal Sciences, University of Illinois, Urbana, Illinois 61801

Margaret E. Kemeny(1081),     Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, Los Angeles, California 90024

Janice K. Kiecolt-Glaser(849),     Department of Psychiatry, The Ohio State University College of Medicine, Columbus, Ohio 43210

Thomas Klein(931),     Department of Medical Microbiology and Immunology, University of South Florida College of Medicine, Tampa, Florida 33612

Mary Klinnert(1013),     National Jewish Center for Immunology and Respiratory Medicine, University of Colorado School of Medicine, Denver, Colorado 80206

Jaap Koolhaas(807),     Department of Animal Physiology, University of Groningen, Center for Biological Sciences, Haren, The Netherlands

Harbans Lal(709),     Department of Pharmacology, Texas College of Osteopathic Medicine, Fort Worth, Texas 76107-2690

Shmuel Livnat(283),     University of Rochester, Department of Microbiology and Immunology, School of Medicine and Denistry, Rochester, New York 14642

Kelley S. Madden(283),     University of Rochester, Department of Microbiology and Immunology, School of Medicine and Dentistry, Rochester, New York 14642

Georges J.M. Maestroni(495),     Laboratory for Experimental Pathology, Istituto Cantonale di Patologia, 6604 Locarno, Switzerland

Jean Marshall(177),     Department of Pathology, McMaster University, Hamilton, Ontario, Canada L8N 3Z5

Alan B. McCruden(475),     Department of Bioscience and Biotechnology, University of Strathclyde, Glasgow G4 0NR, Scotland

Joseph P. McGillis(209),     Department of Microbiology and Immunology and Sanders–Brown Center on Aging, University of Kentucky College of Medicine, Lexington, Kentucky 40536-0084

Andrew H. Miller(897),     Department of Psychiatry, Mount Sinai School of Medicine, City University of New York, New York, New York 10029-6574

Masato Mitsuhashi(209),     Department of Medicine and Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, California 94143

Jan A. Moynihan(685),     Department of Psychiatry, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

David A. Mrazek(1013),     National Jewish Center for Immunology and Respiratory Medicine, University of Colorado School of Medicine, Denver, Colorado 80206

Allan Munck(447),     Department of Physiology, Dartmouth Medical School, Hanover, New Hampshire 03756

Eva Nagy(339),     Department of Immunology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada R3T 2N2

Maureen P. O’Grady(515, 561, 1067),     Departments of Psychiatry and Behavioral Medicine and Medical, Microbiology & Immunology, University of South Florida College of Medicine, Tampa, Florida 33613

Clifford A. Ottaway(225),     Department of Medicine, St. Michael’s Hospital, University of Toronto, Toronto, Ontario Canada

Donald G. Payan(209),     Department of Medicine and Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, California 94143

Mary Perdue(177),     Department of Pathology, McMaster University, Hamilton, Ontario, Canada L8N 3Z5

Paola Pezzati(177),     Department of Pathology, McMaster University, Hamilton, Ontario, Canada L8N 3Z5

Gérard Renoux(127),     Laboratories d’Immunologie, Faculty de Medicine, Tours, France

Adriana Del Rey(589),     Division of Neurobiology, Department of Research, University Hospital, Basel, Switzerland

Thomas L. Roszman(3, 311),     Department of Microbiology and Immunology, University of Kentucky Medical Center, Lexington, Kentucky 40536

Randolph B. Schiffer(1037),     Departments of Neurology and Psychiatry, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

Steven J. Schleifer(771),     Department of Psychiatry, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey 07103

Yehuda Shavit(789),     Department of Psychology, The Hebrew University of Jerusalem, Mount Scopus, Jerusalem 91905, Israel

Harvey B. Simon(869),     Harvard Medical School, Cardiovascular Health Center and Infectious Disease Unit, Massachusetts General Hospital, Boston, Massachusetts 02114

George Freeman Solomon(1081),     Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, Los Angeles, California 90024

Steven Specter(931),     Department of Medical Microbiology and Immunology, University of South Florida College of Medicine, Tampa, Florida 33612

Sunil P. Sreedharan(263),     The Howard Hughes Medical Institute and Departments of Medicine and Microbiology–Immunology, University of California Medical Center, San Francisco, California 94143-0724

Andrzej Stanisz(177),     Department of Pathology, McMaster University, Hamilton, Ontario, Canada L8N 3Z5

Ronald Stead(177),     Department of Pathology, McMaster University, Hamilton, Ontario, Canada L8N 3Z5

Marvin Stein(897),     Department of Psychiatry, Mount Sinai School of Medicine, City University of New York, New York, New York 10029-6574

William H. Stimson(475),     Department of Bioscience and Biotechnology, University of Strathclyde, Glasgow G4 0NR, Scotland

Lydia Temoshok(1081),     Henry M. Jackson Foundation, Walter Reed Army Medical Center, Washington, D.C. 20307

Motoaki Tomioka(177),     Department of Pathology, McMaster University, Hamilton, Ontario, Canada L8N 3Z5

Robert L. Trestman(897),     Department of Psychiatry, Mount Sinai School of Medicine, City University of New York, New York, New York 10029-6574

Christoph W. Turck(263),     The Howard Hughes Medical Institute and Departments of Medicine and Microbiology–Immunology, University of California Medical Center at San Francisco, San Francisco, California 94143-0724

Herbert Weiner(955),     Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles School of Medicine, Los Angeles, California 90024

Kunio Yamazaki(831),     Monell Chemical Senses Center, Philadelphia, Pennsylvania 19104

Preface

The nervous and immune systems have evolved with an exquisite capacity to receive and respond to specific forms of stimulation originating from the internal or external milieu. The neurosciences and immunology developed and matured without seriously considering that there might be communication networks between these systems that could mutually influence their respective functions. When, in 1981, Psychoneuroimmunology was published, the notion that the immune system was not totally autonomous, but represented another specialized adaptive mechanism that was integrated with other homeostatic processes, was not a generally accepted conceptualization that influenced the strategy of immunologic research. Although it still may not be a universally accepted conceptualization, research conducted over the past 10 years has made it increasingly apparent that there are complex interrelationships among behavioral, neural, endocrine, and immune processes. At the same time, progress over the past 10 years has highlighted how much we do not yet know.

It would appear that all major organ systems or homeostatic defense mechanisms are, to a greater or lesser extent, subject to the influence of environmental circumstances and psychosocial factors as these are processed, integrated, and evoke adaptive behavioral responses that are ultimately regulated by the brain. The mechanisms underlying such psychobiological interactions, particularly the consequences of such interactions for health and disease, are imperfectly understood, and the most imperfectly understood mechanisms, perhaps, are the immunologic changes that may mediate between psychosocial factors and the susceptibility to or progression of disease, or both. Psychoneuroimmunology was intended to communicate the developing awareness that there was, in fact, an intimate and relatively unexplored relationship between the nervous and immune systems, the analysis of which might reveal new information about the operation of the immune system—and the brain. Psychoneuroimmunology, Second Edition confirms these projections.

There are now abundant data documenting neuroanatomical, neuroendocrine, and neurochemical links to the immune system. We do not know the nature of all the channels of communication linking the nervous and immune systems—or the functional significance of the connections that have been established. We do know, however, that the immune system is capable of receiving neural and neuroendocrine signals. Conversely, we now have compelling evidence that neural and endocrine responses can be influenced by products of an activated immune system. The existence of bidirectional pathways of communication between nervous and immune systems provides an experimental foundation for the observation of behavioral and stress-induced influences on immune function and, conversely, the effects of immune processes on behavior. It is no longer speculative to propose that the immune system is modulated by feedback mechanisms mediated via neural and endocrine processes, and by feedforward mechanisms, as well. The consequences of these reciprocal relations between neuroendocrine and immune processes for health and disease have not been established but are now beginning to attract the attention of clinical investigators.

Each of these general areas of research is represented in sections of this volume. The first section brings together chapters detailing the role of neural structures and neurotransmitter signals in communication with the immune system. These reviews document the extensive neural connections with organs of the immune system, provide a developmental perspective on the dynamics of noradrenergic sympathetic innervation of spleen and thymus, describe the influence of the cerebral cortex on immune function, and detail the evidence for immune signaling of the CNS. In addition, several chapters are devoted to specific neuropeptides as immunomodulating signal molecules. Part II consists of several chapters elaborating the role of hormones in the modulation of immune functions, the basis for bidirectional communication between the neuroendocrine and immune systems, and the potential physiological implications of these neuroendocrine–immune system interactions. Part III addresses behavioral influences on immune response. The effects of conditioning and the effects of stress and social interactions in modulating immune responses are discussed, and conversely, the behavioral consequences of experimentally altered or genetically determined immunologic states are reviewed. The final section documents the effects of psychosocial factors (including stress) on immune responses in humans and touches on the potential impact of behavioral interventions in modulating immunity in healthy human subjects and in patients with AIDS.

Individual chapters vary as a function of the biopsychosocial level of organization with which the authors are dealing and the state of the art that characterizes that subfield. All the chapters, however, are relatively focused treatments that reflect the progress that has been made during the past several years. It is particularly true of a new interdisciplinary field that major advances derive from what we know that we don’t know, and these several reviews do point out directions for future research. In short, this volume is not a collection of definitive reviews or a simple collation of established facts; it is a progress report, an incomplete map of some of the territories that are being explored for the first time, and an intriguing glimpse of an extraordinarily complex landscape.

Psychoneuroimmunology, Second Edition was prepared, in part, as an updated, substantive contribution to the future research of those behavioral and neuroscientists, endocrinologists, and immunologists who already are contributing to an analysis of neural–immune relationships, who are learning to communicate with each other, and who have found such communication to be mutually rewarding. It is also an invitation to other experimental and clinical investigators in these and other disciplines of the biological and biomedical sciences to become informed about this new field of interdisciplinary research and to add their special expertise to an analysis of behavior-neural-endocrine-immune system interactions and an understanding of the role of these interactions in the maintenance of health and in the development and the treatment of disease.

The editing and organization of any compilation of papers requires the dedicated attention of several individuals besides the editors, and there are several individuals to whom we owe thanks. Jaime Cohen helped us manage last minute details and, as secretary, Marge Ralph was persistent and methodical in keeping things in order and keeping us (and many of the contributors) alerted to a myriad of details throughout the process of editing this volume. Drs. Nancy Costello, Kimberly Kelly, and Alexander Kusnecov, postdoctoral fellows in our laboratories, assumed primary responsibility for preparing the index. The assistance of all these individuals is most gratefully acknowledged. In addition, Academic Press was both supportive and patient throughout the inevitable delays.

R.A., D.L.F. and N.C.

PART I

Neurochemical Links between the Nervous and Immune Systems

Outline

Chapter 1: Central Neural Circuits Involved in Neural–Immune Interactions

Chapter 2: Innervation of Lymphoid Tissue

Chapter 3: Ontogeny and Senescence of Noradrenergic Innervation of the Rodent Thymus and Spleen

Chapter 4: Neocortex Lateralization of Immune Function and of the Activities of Imuthiol, a T-Cell-Specific Immunopotentiator

Chapter 5: T-Lymphocyte Entry and Antigen Recognition in the Central Nervous System

Chapter 6: Interaction of the Mucosal Immune and Peripheral Nervous Systems

Chapter 7: Immunologie Properties of Substance P

Chapter 8: Vasoactive Intestinal Peptide and Immune Function

Chapter 9: Production and Recognition of Neuropeptides by Cells of the Immune System

Chapter 10: Catecholamine Action and Immunologic Reactivity

Chapter 11: Neurotransmitters and Molecular Signaling in the Immune Response

Central Neural Circuits Involved in Neural–Immune Interactions

DAVID L. FELTEN, NICHOLAS COHEN, ROBERT ADER, SUZANNE Y. FELTEN, SONIA L. CARLSON and THOMAS L. ROSZMAN

Publisher Summary

This chapter discusses the involvement of the central nervous system circuitry in the modulation of immune responses. The immune system is capable of modulating both neuroendocrine responses and behavior of the organism. Immunologically altered neuroendocrine and behavioral responses may affect immunity. The inescapable conclusion is the existence of a complex network that must expand the definition of a self-regulatory immune system. The data revealing bidirectional links between the nervous and immune systems question the notion of an autonomous immune system. The immune system is capable of considerable self-regulation, and, adopting classic reductionist strategies, immune responses can be made to take place in vitro, removed from the variability that characterizes integrated adaptive phenomena. The functions of the immune system that are of ultimate concern, however, are those that take place in vivo. The presence of receptors for cytokines, neurotransmitters, and hormones on cells of the immune system, the ready availability of these signal molecules in the lymphoid microenvironment, and the direct demonstration of functional bidirectional communication reveal a dynamic process of interaction between the nervous and immune systems with profound influences on the ability of an animal to respond to external and internal challenges, and to maintain homeostasis through bidirectional signaling.

Introduction

Effects of CNS Lesions on the Immune System

Hypothalamus

Limbic Forebrain Structures

Brain Stem Central Autonomic Nuclei

Cerebral Cortex

CNS Responses to Immunization

Neuronal Firing Rates

Central Monoamine Metabolism

Mediators of Immune–Neural Communication

Hormones Produced by the Thymus

Lymphocyte Products

Immunologic Effects on Behavior

Conclusions

References

I Introduction

Evidence from a number of fields points toward a link between neural activity and altered immune responses (Ader, Cohen, & D. L. Felten, 1987). As discussed in other chapters in this book, psychosocial factors such as bereavement, marital separation, depression, and examination stress in medical students are associated with altered measures of immune reactivity, and in some instances with altered health status, although these two processes have not yet been linked causally. Experimental studies in rodents have shown a causal relationship between a variety of stressors and subsequent suppression or enhancement of immune responses. These studies point toward the participation of neural circuitry in the modulation of immune reactivity, but do not reveal the specific circuitry that may be involved (D. L. Felten & S. Y. Felten, 1987). Similarly, studies in animals using classic conditioning of immune responses reveal suppression or enhancement of these responses, requiring the involvement of neural circuitry. These conditioning studies suggest that the central nervous system (CNS) is able to detect alterations in immune reactivity (a molecular sensory input to the CNS) and, subsequent to detection, is able to initiate a change in immune response with exposure to the conditioned stimulus (Ader & Cohen, 1985). Irwin and colleagues (Irwin, Hauger, Brown, & Britton, 1988) have shown that intracerebraventricular administration of corticotropin-releasing factor (CRF) can evoke reduced splenic natural killer (NK) cell responses via the sympathetic noradrenergic projections to the spleen, but the central neural circuitry for regulating this autonomic outflow to the spleen has not yet been identified.

The involvement of CNS circuitry in modulation of immune responses was tested directly in lesioning studies (discussed in detail in Section II). Discrete lesions in hypothalamic areas (particularly anterior/preoptic regions), limbic forebrain structures (amygdala, hippocampus, septum), brain stem autonomic or reticular regions (raphe nuclei, reticular formation areas, parabrachial nuclei), and the cerebral cortex result in alterations in specific immune reactivity in the direction of either enhancement or suppression that can be observed either transiently or chronically depending on the site and extent of the lesion (Roszman & Brooks, 1985; Roszman, Cross, Brooks, & Markesbery, 1985). This direct evidence for involvement of CNS circuitry in immune modulation points toward an integrated circuitry of limbic cortex/limbic forebrain/hypothalamus/brain stem autonomic nuclei that regulates both autonomic outflow and neuroendocrine outflow (D. L. Felten & S. Y. Felten, 1987). The immune system appears to be modulated not only by feedback mechanisms mediated through neural and endocrine processes, but by feedforward mechanisms as well. The immunologic effects of learning, an essential feedforward mechanism, can, under appropriate circumstances, serve an immunoregulatory function in vivo. Conceptually, the capacity to suppress or enhance immune responses by conditioning raises many questions about the normal operation and modifiability of the immune system via neural and endocrine processes.

We do not yet know the nature of all the channels of communication between the brain and the immune system or the functional significance of the interrelationships that have been established. However, we do know the basic outlines of the central control of neuroendocrine and autonomic outflow (S. Y. Felten, Carlson, Bellinger, & D. L. Felten, 1986). Neuroendocrine outflow from the brain is achieved through both the posterior and anterior pituitary (D. L. Felten, Sladek, & Sladek, 1985). Nerve terminals from cell bodies in the magnocellular paraventricular and supraoptic nuclei secrete neurohormones such as vasopressin and oxytocin directly into the systemic circulation in the posterior pituitary. Nerve terminals from a number of hypothalamic and other visceral nuclei secrete releasing factors, inhibiting factors, and other hormones into the hypophyseal portal blood at the median eminence; these hormones bathe cells of the anterior pituitary in high concentrations, and they influence the secretion of the anterior pituitary hormones such as adrenal corticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), leutinizing hormone (LH), growth hormone (GH), and prolactin. These key nuclei that act as neuroendocrine transducing elements for the anterior and posterior pituitary are regulated mainly through the hypothalamus, limbic forebrain, and brain stem circuitry, which control this so-called hypothalamo–pituitary–endocrine target-organ axis.

Autonomic neural connections link the spinal cord and brain stem, through a two-neuron chain of the sympathetic and parasympathetic subdivisions, with target organs that classically have included cardiac muscle, smooth muscle, and exocrine (secretory) glands, and more recently also viscera related to metabolism, such as the liver and brown fat cells. We have proposed that organs of the immune system be included as target organs of direct autonomic innervation (D. L. Felten et al., 1987; D. L. Felten, S. Y. Felten, Carlson, Olschowka, & Livnat, 1985; S. Y. Felten et al., 1986, 1988). The autonomie preganglionic neurons in the spinal cord and lower brain stem receive direct fiber projections from brain stem nuclei (nucleus solitarius, raphe nuclei, tegmental noradrenergic nuclei), hypothalamic nuclei (paraventrivular nucleus oxytocin and vasopressin neurons, lateral hypothalamus, posterior hypothalamus, dorsal hypothalamus), limbic forebrain structures (central amygdaloid nucleus), and regions of the cerebral cortex (frontal, cingulate, and insular cortical areas, mainly zones of limbic cortex) (D. L. Felten & S. Y. Felten, 1987; Swanson & Sawchenko, 1983). In addition, indirect regulation of these systems arises from regions such as the parabrachial nuclei, central gray, and reticular formation of the brain stem, numerous hypothalamic nuclei and cell groups, limbic forebrain areas such as the hippocampal formation and septum, and cortical association areas. These structures interconnect with the hypothalamus, the structure that lies at the crossroads of the limbic forebrain and brain stem visceral nuclei.

This integrated circuitry has extensive ascending and descending connections among the regions cited. These regions also share many similarities. They are sites intimately involved in visceral, autonomic, and neuroendocrine regulation. The cortical and limbic forebrain regions mediate both affective and cognitive processes, and they may be involved in the response to stressors, in affective states and disorders such as depression, in aversive conditioning, and in the emotional context of sensory inputs from the outside world as well as the inside world. From a immunologic perspective, these regions are the sites in which lesions result in altered responses of cells of the immune system. They are the regions that respond to immunization or cytokines by altered neuronal activity or altered monoamine metabolism. They are the regions that possess the highest concentration of glucocorticoid receptors and link some endocrine signals with neuronal outflow to the autonomic and neuroendocrine systems. Thus, this circuitry is the major system of the CNS suspected to play a key role in responding to immune signals and regulating CNS outflow to the immune system.

It is now apparent that the immune and nervous systems communicate bidirectionally through short, intermediate, and long communication loops. These loops are achieved through mediators, such as hormones, neurotransmitters, and cytokines, that interact with receptors found on cells of both systems. These mediators utilize common second messenger systems, probably interacting directly or indirectly to alter the responsiveness or expression of receptors for these signal molecules, providing for integrated responses when acting on neurons or lymphocytes. The data reviewed in this book provide compelling evidence that the immune system, like any other system operating in the interests of homeostasis, is integrated with other physiological processes and is therefore influenced by, and is capable of influencing, the brain. The following sections summarize some of the evidence for direct CNS interactions with the immune system.

II Effects of CNS Lesions on the Immune System

A HYPOTHALAMUS

A major strategy for studying central sites that may be involved in modulation of immune responses is the production of electrolytic lesions using stereotaxic procedures. Although this approach has limitations, and shows mainly what the rest of the CNS can do in the absence of specifically lesioned circuitry, it has provided a first insight into potential circuitry underlying brain-immune communication. The area most intensively studied is the preoptic/anterior hypothalamic region of the hypothalamus. Cross, Brooks, Roszman, and others found that anterior hypothalamic lesions resulted in a decrease in nucleated spleen cells and thymocytes (Brooks, Cross, Roszman, & Markesbery, 1982; Cross, Brooks, Roszman, & Markesbery, 1982; Markesbery, Brooks, & Roszman, 1980; Katayama, Kobayashi, Kuramoto, & Yokoyama, 1987), decreased proliferative T-cell responses to the mitogen concanavalin A (Con A) (Brooks et al., 1982; Cross et al., 1980, 1982; Roszman, Cross, Brooks, & Markesbery, 1982), decreased NK cell activity (Cross, Brooks, Roszman, & Markesbery, 1984; Cross, Markesbery, Brooks, & Roszman, 1984), decreased antibody production (Tyrey & Nalbandov, 1972), altered tumor cell growth (Sobue et al., 1981), and inhibited the development of a lethal anaphylactic response (Stein, Schleiffer, & Keller, 1981). These altered responses were mainly transient. Some of these effects were reversible with hypophysectomy, suggesting that the effects are mediated by neuroendocrine mechanisms (Cross et al., 1982; Tyrey & Nalbandov, 1972). The consensus from these studies is that the anterior hypothalamus is involved, either directly or indirectly, in the stimulation of both humoral and cell-mediated immune functions.

Lesions of the medical hypothalamus or posterior hypothalamus have yielded more variable results. Medial hypothalamic lesions have been reported by Katayama and colleagues (1987) to decrease T- and B-cell numbers and by Dann, Wachtel, and Rubin (1979) to enhance graft rejection, but Roszman and colleagues (1982) were unable to find any alterations from such lesions. Katayama and colleagues (1987) found that posterior hypothalamic lesions decreased the T helper/T suppressor cell ratio, whereas Sobue and colleagues (1981) found that such lesions enhanced tumor growth. However, Stein and colleagues (1981) found that neither medial nor posterior hypothalamic lesions affected the development of lethal anaphylaxis, a humoral immune response.

Studies of lesioning the hypothalamus are difficult to interpret for several reasons. The hypothalamic nuclei are small, difficult to lesion discretely, and often contain many subsets of chemically specific neurons. These functional groups of neurons may be compact or scattered. In addition, fibers of passage are abundant and are intertwined throughout the hypothalamus, making damage to them likely in the production of lesions. Therefore, although evidence points to the anterior hypothalamus as a major site of influence over many immune functions, the identification of the discrete projections and chemically specific neuronal systems involved awaits studies using techniques with a higher degree of resolution and specificity.

B LIMBIC FOREBRAIN STRUCTURES

Lesions in limbic forebrain structures also lead to alterations in immune functions, generally in the direction of enhancement. Roszman and colleagues (Brooks et al., 1982; Cross et al., 1982) found that lesions of the dorsal hippocampus or amygdaloid complex resulted in a transient increase in splenocytes and thymocytes, and in T-cell proliferative responses to the mitogen Con A, responses that can be reversed by hypophysectomy (Cross et al., 1982), suggesting that they are mediated through neuroendocrine mechanisms. Other studies found that cell-mediated processes such as experimental allergic encephalomyelitis and graft rejection were unaffected by such lesions. Nance, Rayson, and Carr (1987) reported chronic alterations in T-cell responses following lesions of the lateral septal area and its connections to the hippocampus. The limbic structures lesioned in these studies have extensive connections into the hypothalamus and can regulate both neuroendocrine and autonomic outflow.

C BRAIN STEM CENTRAL AUTONOMIC NUCLEI

Lesions of specific brain stem regions also resulted in alterations in immune responses. Masek, Kadlecova, and Petrovicky (1983) found that lesions of the caudal reticular formation in the medulla and caudal pons resulted in inhibition of delayed-type hypersensitivity responses, whereas lesions in the rostral medial reticular formation and raphe nuclei resulted in enhanced delayed-type hypersensitivity responses (Isakovic & Jankovic, 1973). Lesions of the reticular formation also are followed by thymic involution. Since many neuronal systemsinterconnect through the reticular formation, it is not possible to determine the identity of the chemically specific neurons involved in modulation of these immune responses. One clue, however, may lie in the possible involvement of monoaminergic systems with these reticular formation lesions. The caudal reticular formation contains the noradrenergic cell bodies that project extensively to the hypothalamus and some limbic structures, whereas the rostral raphe nuclei contain the serotonergic cell bodies that project to the hypothalamus and limbic system (D. L. Felten & Sladek, 1983). These two monoaminergic systems provide regulation of numerous visceral and neuroendocrine events and are involved in both affective and cognitive processes. In the hypothalamus, noradrenergic and serotonergic mechanisms often balance each other in the modulation of functions such as thermoregulation. In support of a role for central noradrenergic involvement in modulation of immune responses, Cross and colleagues (Cross, Brooks, & Roszman, 1987; Cross et al., 1986) showed that central administration of the noradrenergic toxin 6-hydroxydopamine into the cisterna magna inhibits the primary antibody response to sheep red blood cells, apparently as a result of enhanced suppressor T-cell activity after immunization. It is also possible that both the reticular formation/raphe lesions and the central depletion of norepinephrine alter descending monoaminergic projections to the autonomic preganglionic neurons, in addition to their removal of ascending monoaminergic inputs to the hypothalamus and limbic system.

Kadlecova and colleagues (1987) have found that discrete lesions in the parabrachial nuclei, particularly the ventral and medial components, resulted in decreased proliferative responses of thymocytes. These nuclei are integrated into the connections between brain stem autonomic nuclei, such as the nucleus solitarius, and the hypothalamic and limbic forebrain circuitry of the amygdala, and they probably are involved in processing both afferent and both afferent and efferent information related to the autonomic nervous system as well as in influencing hypothalamic and limbic circuitry that impinges on neuroendocrine circuits.

D CEREBRAL CORTEX

Renoux and colleagues (Renoux, Biziere, Renoux, Bardos, & Degenne, 1987; Renoux, Biziere, Renoux, Guillaumin, & Degenne, 1983; Renoux et al., 1984) have suggested that the cerebral cortex can modulate immune responses and that this system may be lateralized (see Renoux & Biziere, this volume). They found that large lesions in the left cerebral hemisphere of mice resulted in decreased T-cell numbers and responses, and in decreased NK-cell activity, with no effects on B cells or macrophages. The right cerebral cortex appeared to have the opposite influence, postulated to be due to modulation of efferent signals arising from the left cerebral cortex. Although such lesions are large and the mechanisms, pathways, and identity of chemically specific systems involved are not yet known, these data are of great interest. They have been confirmed by other investigators (Newlands, Huntley, & Miller, 1984). Since the cerebral cortex is suspected of being involved in the response to psychosocial factors, stressors, and conscious interpretation of the outside world, the possibility that the cerebral cortex can affect immune responses provides an important link between these phenomena impinging on the CNS and the outflow responses of the CNS that have direct access to the immune system. The cerebral cortex, especially frontal, cingulate, and temporal regions, have direct connections with the limbic forebrain, hypothalamus, brain stem, visceral nuclei, and even some autonomic preganglionic neurons.

III CNS Responses to Immunization

A NEURONAL FIRING RATES

Electrical recordings within discrete regions of the hypothalamus have provided evidence for immune influences, most likely via secretion of cytokines, over neuronal firing rates. Besedovsky, Sorkin, Felix, and Haas (1977) demonstrated increased neuronal firing rates in the ventromedial nucleus of the hypothalamus at the time of peak antibody response to primary immunization. Saphier, Abramsky, Mor, and Ovadia (1987) demonstrated increased neuronal firing rates in the preoptic/anterior hypothalamic area at the time of peak response during a primary antibody response (Day 5) and a decreased neuronal firing rate in the paraventricular nucleus (PVN) of the hypothalamus during the first 3 days following immunization followed by an increased firing rate by Day 6. The pattern of firing in the preoptic/anterior area during the secondary immune response was not as abrupt or high as that observed during the primary immune response. This may reflect a difference in cytokine secretion between primary and secondary responses.

There is a large early Soviet literature documenting electrophysiological alterations in evoked or spontaneous brain activity during the course of reaction to an antigen. The most important sites of such changes were found in the hypothalamus, limbic forebrain structures such as the hippocampus, and midbrain reticular formation. These studies were reviewed in English by E. A. Korneva, Klimenko, & Shkhinek (1985).

B CENTRAL MONOAMINE METABOLISM

Neurochemical measurements provide further support for the notion that the CNS can monitor immune status. Besedovsky et al. (1983) reported that norepinephrine levels in the hypothalamus were decreased 4 days after immunization, at the time of peak antibody response. No such changes were seen on Day 1, eliminating acute stress as the cause, and no changes were found in central dopamine or central norepinephrine in numerous other sites. They further found that the supernatants from cultures of Con A-stimulated lymphocytes induced a decrease in hypothalamic norepinephrine within 2 hours of administration, a situation that they considered to be analogous to cytokine secretion during the time of peak antibody response. Recent turnover studies from the laboratories of Dunn (1988) and Besedovsky (Kahiersh, del Rey, Honegger, & Besedovsky, 1988) suggest that decreased norepinephrine levels in the hypothalamus following immunological stimuli are accompanied by increased turnover of norepinephrine.

Carlson, D. L. Felten, Livnat, and S. Y. Felten (1987) also studied the response of CNS monoamines to immunization using microdissection of specific regions of the hypothalamus and other CNS sites. They found a specific decrease in norepinephrine in the PVN of the hypothalamus (but not in the supraoptic nucleus, the anterior hypothalamus, or the medial hypothalamus) at Day 4 following immunization, the time of peak antibody response and the time of peak secretion of glucocorticoids (Besedovsky, Sorkin, Keller, & Müller, 1975). Carlson et al. also found decreased norepinephrine and serotonin in the dorsal hippocampus and an increase in serotonin in the nucleus solitarius during the rising phase of the immune response. No changes in monoamine metabolism were seen in other discrete sites, and no alterations were found at the time of the declining phase of the immune response.

These studies suggest that one or more cytokines are able to communicate with specific hypothalamic, limbic forebrain, and brain stem autonomic sites, either directly or indirectly, and induce specific changes in the metabolism of central monoamines, which are key regulatory neurotransmitters over numerous visceral, autonomic, and neuroendcrine processes, and in electrical activity of neurons. This constitutes a further basis for bidirectional communication between the brain and the immune system. The changes in norepinephrine and in electrical activity in the PVN in response to immunization provides a potential mechanism for influencing outflow of the CRF-ACTH-glucocorticoid axis that, in turn, has a direct influence on the responsiveness of lymphocytes. The recent evidence that peripheral administration of interleukin-1 (IL-1) can alter the expression of CRF in the PVN of the hypothalamus (see Section IV,B,2) further strengthens the existence of a physiologically functional loop for this system. Whether the effects of immunization or IL-1 administration act directly on the CRF neurons, act through regulatory monoamine circuits such as the noradrenergic input to PVN, or act directly on the pituitary remains to be elucidated. It is highly likely that many such circuits and loops exist; the identification and elucidation of these circuits is one of the great challenges in this field.

IV Mediators of Immune–Neural Communication

The immune system is capable of modulating both neuroendocrine responses and behavior of the organism. Immunologically altered neuroendocrine and behavioral responses may, in turn, affect immunity. The inescapable conclusion is the existence of a complex network that must expand our definition of a self-regulatory immune system.

A HORMONES PRODUCED BY THE THYMUS

It has been known since the early 1900s that the thymus gland functions as an endocrine organ (Sajous, 1903). Various thymic peptides can modulate lymphocytes directly and/or mediate effects on the immune system via hormonal and neural pathways. For example, thymosin fraction 5(TF5), a partially purified extract from bovine thymuses, and two of its sequenced constituent peptides, thymosin α1 and thymosin β4 (Goldstein, Slater, & White, 1966; Spangelo, Hall, & Goldstein, 1987), exerted a variety of immunostimulatory effects (Spangelo, Hall, & Goldstein, 1987): (1) induction of lymphopoiesis; (2) stimulation of maturation of T cells; (3) restoration of full T-cell reactivity in adult thymectomized mice; (4) enhancement of in vitro mitogen responses, alloreactivity, and antibody production; and (5) increase in the production of lymphokines such as T-cell growth factor (Zatz, Oliver, Samuels, Skotnicki, Sztein, & Goldstein, 1984) and migration inhibition factor. In addition to these immunologic activities, these thymic peptides altered the activity of neuroendocrine circuits. TF5 increased secretion of ACTH, β-endorphin, corticosterone, GH, and prolactin (Spangelo, Hall, & Goldstein, 1987; Spangelo, Hall, Dunn, & Goldstein, 1987; Spangelo, Judd, Ross, Login, Jarvis, Badamchian, Goldstein, & MacLeod, 1987). TF5 and thymosin β4 stimulated secretion of luteinizing hormone-releasing hormone (LHRH) from the hypothalamus (Rebar, Miyake, Low, & Goldstein, 1981). Thymosin fraction 5 was also able to block binding of corticosteroids to their receptors on lymphocytes, thereby modulating the immunoregulatory effects of these adrenal hormones.

The intracerebroventricular injection of thymosin β4, but not thymosin α1, into the lateral ventricles of the mouse caused a significant increase in circulating LH (Hall et al., 1982). Injection of TF5 and thymosin α1, but not thymosin β4, into the lateral ventricles produced a significant increase in circulating corticosterone (Hall et al., 1982). Additionally, injections of TF5 elevated ACTH, β-endorphin, and cortisol in monkeys (Healy et al., 1983). A neuroendocrine site of action for the corticogenic activity of TF5 was indicated by the demonstration that this material did not stimulate glucocorticoid release from isolated adrenal fasciculata cells in vitro. These data argue strongly for a thymus-pituitary-adrenal axis modulated by thymosin α1 and a thymus–pituitary–gonadal axis modulated by thymosin β4.

B LYMPHOCYTE PRODUCTS

1 Neurohormones

Blalock and colleagues (Blalock, 1989; Blalock, Bost, & Smith, 1985; Blalock, Harbour-McMenamin, & Smith, 1985; Blalock & Smith, 1985; Smith & Blalock, 1981; Smith, Harbour-McMenamin, & Blalock, 1985; Smith, Meyer, & Blalock, 1982) have demonstrated that molecules antigenically, structurally, and functionally similar to α-, β-, and γ-endorphin are produced by leukocytes treated with bacterial lipopolysaccharide or Newcastle disease virus. Immunoreactive endorphin that bound to δ-opioid receptors are produced by B lymphocytes, and β-endorphin-like immunoreactive peptides and ACTH were produced by a subpopulation of macrophages (Lolait, Lim, Toh, & Funder, 1984; Lolait et al., 1986). Others have confirmed these observations and found that leukocytes produce mRNA for proopiomelanocortin (POMC) (Westly, Kleiss, Kelley, Wong, & Yuen, 1986), the precursor of ACTH and endorphins. Blalock’s laboratory (Blalock & Smith, 1985; Smith et al., 1982) reported that the leukocyte-derived ACTH is capable of eliciting corticosteroid responses in hypophysectomized animals injected with virus, but Dunn and colleagues (Dunn, Powell, Moreshen, Gaskin, & Hall, 1987) reported conflicting findings, which they attribute to incompleteness of the hypophysectomy in earlier studies. The important proposition of a lymphoid-adrenal axis in which lymphocytes serve a sensory function for stimuli such as viruses (Blalock, 1984) is provocative and awaits further confirmation. A critical point for future determination is whether these leukocyte-derived neurohormones reach threshold levels in the serum for communication with distant organs or mainly act locally, as paracrine or autocrine secretions.

Bernton and colleagues (Bernton, Bryant, & Holaday, this volume), using cDNA probes in lymphocyte hybridization studies, suggested that lymphocytes may produce prolactin-related peptides. Blalock, Smith, and colleagues reported that human lymphocytes cultured with staphylococcal enterotoxin A or allogeneic cells produced immunoreactive TSH (Smith, Phan, Kruger, Coppenhaver, & Blalock, 1983) or chorionic gonadotropin (Weigent & Blalock, 1987), respectively. These observations suggest that cells of the immune system may be able to produce hormones directly to modulate immunity, in addition to responding to the hormonal influences that occur via the clasiscal neuroendocrine channels.

2 Cytokines

Besedovsky and colleagues (Besedovsky, del Rey, & Sorkin, 1981; Besedovsky, del Rey, Sorkin, Lotz, & Schwulera, 1985; Besedovsky et al., 1975) and others (Shek & Sahiston, 1983) have demonstrated that blood levels of glucocorticoids increase at the time of peak immune response to several antigens. These glucocorticoid levels were immunosuppressive; this may explain the well-known phenomenon of antigenic competition. Adrenalectomy or hypophysectomy block the antigen-induced glucocorticoid increase and, as might be predicted, also abrogate antigenic competition. These investigators further demonstrated that supernatants from Con A-activated or alloantigen-activated cells can also elevate circulating glucocorticoids and ACTH. This increase has been attributed to a glucocorticoid-increasing factor (GIF) derived from lymphocytes (Besedovsky et al., 1985) and to macrophage/monocyte-derived IL-1 (Besedovsky, del Rey, Sorkin, & Dinarello, 1986).

Since IL-1β can stimulate a mouse pituitary cell line to release ACTH (Bernton, Beach, Holaday, Smallridge, & Fein, 1987), the in vivo effects may result from direct stimulation of ACTH-producing cells in the anterior pituitary, although this finding was not confirmed by other laboratories (Berkenbosch, van Oers, del Rey, Tilders, & Besedovsky, 1987; Sapolsky, Rivier, Yamamoto, Plotsky, & Vale, 1987; Uehara, Gottschall, Dalh, & Arimura, 1987). However, IL-1 was shown to work by stimulating release of CRF from the hypothalamus into the hypophyseal portal circulation, where it can evoke the release of ACTH from the anterior pituitary (Berkenbosch et al., 1987; Sapolsky et al., 1987). It is interesting to note that astrocytes in vitro and microglia in vitro and in vivo can produce IL-1 and also are in a favorable anatomical position to modulate hypothalamic CRF secretion (Nieto-Sampedro & Berman, 1987; Giulian, Baker, Shih, & Lachman, 1984; Fontana, Weber, & Dayer, 1984; Fontana, Kristensen, Dubs, Gemsa, & Weber, 1982).

An underlying assumption in this field is that IL-1 production eventually will be suppressed by the IL-1-pituitary-ACTH-glucocorticoid pathway just outlined, thus completing a neuroendocrine–immune loop. The situation actually may be more complex than this simple loop; Mathison and colleagues (Mathison, LaForest, & Ulevitch, 1984; Mathison, Schreiber, LaForest, & Ulevitch, 1983) have shown that a macrophage-derived factor also can inhibit ACTH-inhibited steroidogenesis, and Fairchild and Mishell (1982) have found a macrophage-derived factor that makes T-helper cells resistant to glucocorticoids. In addition, physiological concentrations of IL-1β were reported to stimulate the release of TSH, GH, and LH, while inhibiting prolactin secretion from the same population of pituitary cells and release ACTH in response to exogenous IL-1 (Bernton et al., 1987). Whether these activities are the result of stimulation of prostaglandin and leukotriene synthesis, and whether such activities play a physiological role in immunomodulation, remain to be determined.

Interleukin-1 has also been shown to induce fever (probably by inducing the hypothalamus to produce prostaglandins; Dinarello et al., 1986) and to induce the onset of slow-wave sleep (Shoham, Davenne, Cady, Dinarello, & Krueger, 1987). Ahmed, Llanos, Dinarello, and Blatteis (1985) reported that IL-1 can inhibit the binding of some opioid ligands to their specific receptors. Dafny and colleagues (Dafny, Prieto-Gomez, & Reyes-Vazquez, 1985; Reyes-Vazquez, Prieto-Gomez, Georgiades, & Dafny, 1984) reported that interferon-α (IFN-α) but not IFN-δ can alter the firing rates in cerebral cortex, hippocampus, and the ventromedial nucleus of the hypothalamus and, like IL-1, can interact with opioid binding sites. It is not yet known to what extent such cytokines can cross into the brain, although possibilities include crossing at the circumventricular organs [such as the organum vasculosum of the lamina terminalis (OVLT) and median eminence near the hypothalamus], crossing into the cerebrospinal fluid at the choroid plexus, and facilitated transport across the blood-brain barrier (capillary endothelium). Cytokines such as IL-1 also may be produced by glia within the CNS (Fontana et al., 1982; Johnson et al., 1986). Breder, Dinarello, and Saper (1988) reported the presence of IL-1-immunoreactive neurons in the hypothalamus, with fiber projections to numerous other hypothalamic sites and some nonhypothalamic autonomic regions. These investigators proposed that peripherally administered IL-1 binds at the OVLT, releases prostaglandin E2 (PGE2) (blockable by indomethacin, an inhibitor of prostagladin synthesis), which then stimulates the central IL-1 neuronal system. Saper’s laboratory also reported the presence of TNF-immunoreactive neurons in the CNS, while Schultzberg, Svenson, Unden, and Bartfai (1987) reported IL-1-immunoreactive peripheral axons in the spleen, probably colocalized in sympathetic noradrenergic neurons.

Interleukin-2 (IL-2), a cytokine produced mainly by the T-helper cell, appears to exert effects on neuroendocrine cells and neurons. Interleukin-2 stimulated the production of ACTH from pituitary cells and mouse AtT-20 cells (Smith, 1988). Administration of IL-2 to humans in clinical trials effected a subsequent rise in plasma ACTH and cortisol (Lotze, Frana, Sharrow, Robb, & Rosenberg, 1985), suggesting that IL-2 may affect the hypothalamo-pituitary-adrenal axis in vivo. Humans receiving IL-2 therapy also showed side effects that suggest some central action, including fever, hypotension, and neuropsychiatrie symptoms (West et al., 1987). Recombinant IL-2 therapy designed to increase lymphokine-activated killer (LAK) cells in cancer patients led to profound mental alterations (Denicoff et al., 1987). These effects dissipated when IL-2 was withdrawn. It appears that clinical use of IL-2 may be limited in part by neuropsychiatric complications. Although IL-2 receptors have been reported in the brain (Hoffman, et al., 1986), it remains to be demonstrated that IL-2 can cross the blood-brain barrier and bind to these receptors or that neuropsychiatrie effects of IL-2 therapy in humans are attributable to direct action of IL-2 on neurons.

Interferons, originally known as cytokines with antiviral activity, interact with specific receptors on numerous cells. Receptor studies suggest one subtype that binds IFN-α and IFN-β and one subtype that binds INF-γ (Celada & Shreiber, 1987; Chany & Chany-Fournier, 1982). Interferon-α/β can induce corticosteroid production in adrenal cells (Blalock & Harp, 1981), and IFN-α can inhibit stimulated testosterone production by Leydig cells (Orava, Cantell, & Vihko, 1985), possibly through cAMP as a second messenger (Smith, 1988).

Interferons may also act as neuromodulators. Interferon-α enhances the excitability of neurons in culture (Calvet & Gresser, 1979) and can alter the electrical activity of central neurons in several regions (cerebral cortex, dorsal hippocampus, ventromedial hypothalamus, and parafascicular thalamic nucleus) following iontophoretic application (Reyes-Vasquez et al., 1984). Interferon-α binds to opiate receptors both in vitro and in vivo (Blalock & Smith, 1981; Smith, 1988). In vivo studies demonstrated that IFN-α can induce analgesia and catatonia in mice and that IFN-α can prevent tolerance and dependence to endogenous opioid peptides and morphine (Dafny, 1984; see Smith, 1988, for discussion). Administration of IFN-α to humans was accompanied by side effects such as fever and drowsiness (Gutterman et al., 1982; Mattson et al., 1985); IFN-γ induced fever, malaise, and psychiatric complications in humans (Rinehart, Young, Laforge, Colburn, & Neidhart, 1987; van der Burg et al., 1985). The use of recombinant IFN-γ in breast cancer therapy revealed neurological side effects such as somnolence, confusion, parasthesias, and increased slow wave activity (Smedley, Katrak, Sikora, & Wheeler, 1983). Interestingly, Preble and Torrey (1985) found high titers of IFN in the serum of patients with psychoses. Thus, it appears that IFNs can act either directly or indirectly to exert central effects. Interferon-γ may also be made accessible to neurons by direct secretion from activated lympocytes that can cross the blood-brain barrier and immunosurvey the brain (see Hickey, this volume; Schluesener & Wekerle, 1985). It remains to be demonstrated that the effects of administration of IFNs are achieved by their crossing the blood-brain barrier and acting directly on neurons and that such communication occurs as a normal physiological cytokine–neural interaction.

Nerve growth factor (NGF) is a neuronotrophic peptide required for the survival and differentiation of