Reginald M. Gorczynski, The Toronto Hospital, Department of Surgery and Immunology, CCRW 2-855, 200 Elizabeth Street, Toronto, Ontario, Canada

Published by: Elsevier Science
ISBN:0-444-50754-X
NeuroImmune Biology: Vol.1: New Foundation of Biology

Advisory Board:

B.G. Arnason, Chicago, IL
P.J. Barnes, London, UK
T. Bartfai, La Jolla, CA
L. Bertok, Budapest, Hungary
H.O. Besedovsky, Marburg , Germany
J. Bienenstock, Hamilton, Canada
C.M. Blatteis, Memphis, TN
J. Buckingham, London, UK
C. Chang, Rochester, NY
M. Dardenne, Paris, France
R.C. Gaillard, Lausanne, Switzerland
R. Good, Tampa, FL
R.M. Gorczynski, Toronto, Canada
C. Heijnen, Utrecht, The Netherlands
T. Hori, Fukuoka, Japan
G. Jancso, Szeged, Hungary
M.D. Kendall, Cambridge, UK
E.A. Korneva, St. Petersburg, Russia
K. Kovacs, Toronto, Canada
G. Kunkel, Berlin, Germany
L. Matera, Turin, Italy
D. Nance, Winnipeg, Canada
H. Ovadia, Jerusalem, Israel
C.P. Phelps, Tampa, FL
L.D. Prockop, Tampa, FL
R. Rapaport, New York, NY
S. Reichlin, Tucson, AZ
K. Skwarlo-Sonta, Warsaw, Poland
E.M. Sternberg, Bethesda, MD
D.W. Talmage, Denver, CO
S. Walker, Columbia, MO
A.G. Zapata, Madrid, Spain

Description

A new scientific discipline, acknowledged 65 years after its discovery, was the focus of the first Conference on Neuroimmune Biology in Canada. The papers presented at the conference, and in this volume, are dedicated to Dr. Hans Selye who is recognized as discovering the existence of a hypothalamic-pituitary-adrenal-thymus axis. This axis plays an important role in the adaptation of higher animals and man to various physical, chemical, biological and emotional challenges.

The conference and participants also honored Dr. Andor Szentivanyi whose opening paper, "Studies on the hypothalamic regulation of histamine synthesis", is contained in the introduction to this book. Dr. Szentivanyi has dedicated his long research career to the clarification of the role of the central nervous system in immune and inflammatory reactions, and his experimental results are presented here.

With an ultimate goal to achieve a more thorough understanding of higher organisms in their entire complexity, this book, the first in the series NeuroImmune Biology presents a coordinated and integrated view of the growing body of knowledge rapidly accumulating in this area.

Contents

Editorial
Andor Szentivanyi, Istvan Berczi

Preface
Istvan Berczi, Reginald M. Gorczynski

List of Corresponding Authors

I. Introduction

Neuroimmune Biology - An introduction (PDF)
Istvan Berczi

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Neuroimmune Biology - An introduction (HTML)
Istvan Berczi

Studies on the Hypothalamic Regulation of Histamine Synthesis.
Andor Szentivanyi, Istvan Berczi, Denyse Pitak, Allen Goldman

II. Neuroimmune Regulatory Mechanisms

Introduction: II. Neuroimmune Regulatory.
Reginald M. Gorczynski

Dynamics of Immune Responses: Historical Perspectives in our Understanding of Immune Regulation.
Kent T. HayGlass

Cell-to-cell Interaction and Signaling within the Immune System: Towards Integrating Mechanism and Physiology.
Peter A. Bretscher, Nahed Ismail, Nathan. Peters, Jude Uzonna

Regulation of the Immune Response within the Central Nervous System. 
Jack Antel

Regulatory Circuits of the Pituitary Gland.
Lucia Stefaneanu

Neuroendocrine Stress and Inflammatory disease: From Animal Model to Human Disease.
Esther M. Sternberg, Mojdeh Moghaddam

Immunoregulation by the Sympathetic Nervous System.
Dwight M. Nance, Brian J. MacNeil

Behavioral and Central Neurochemical Consequences of Cytokine Challenge: Relationship to Stressors.
Zul Merali, Hymie Anisman, Shawn Hayley

Proinflammatory Signal Transduction Pathways in the CNS During Systemic Immune Response.
Serge Rivest, Sylvain. Nadeau, Steve Lacroix, Nathalie Laflamme

Nitric oxide in Neuroimmune Feedback Signaling.
Teresa L. Krukoff, Wendy W. Yang

III. Neuroimmune Mechanisms in Physiology

Introduction: III. Neuroimmune Mechanisms in Physiology.
Reginald M Gorczynski

A Model of Neuroimmune Communication: Mast Cells and Nerves.
John  Bienenstock

Immunomodulation by the Submandibular Gland.
A. Dean Befus, Paul Forsythe, Rene E. Déry, Ronald Mathison, Joseph S. Davison

Glandular Kallikrein in Immunoregulation.
Edris Sabbadini, Eva Nagy, Alexander Vörös, Gertrude Vörösova, Fred T. Kisil, Istvan Berczi

Understanding Classical Conditioning of Immune Responses.
Reginald M. Gorczynski

Sleep, Health and Immunocompetence.
Harvey Moldofsky, Wah-Ping Luk, Jodi Dickstein

Interactions Between the Immune System and the Testis.
David K. Pomerantz

Leptin and Cytokines: Actions and Interactions in Fever and Appetite Control.
Giamal N. Luheshi

IV. Neuroimmune Host Defence

Introduction: IV. Neuroimmune Host Defence.
Reginald M. Gorczynski

Fever and Antipyresis.
Quentin J. Pittman, Abdeslam Mouihate, Marie-Stephanie Clerget

The Salivary Gland Peptides: Their Role in Anaphylaxis and Lipopolysaccharide (LPS)-Induced Inflammation.
Joe S. Davison, Dean Befus, Ronald Mathison

Olfactory Stimuli and Allo-Recognition.
Malcolm G. Baines

Natural Immune Regulation of Activated Cells.
Donna A. Chow, Ricky Kraut, Xiaowei Wang

V. Neuroimmune Pathology

Introduction: V. Neuroimmune Pathology.
Istvan Berczi

Stress, Health and the Immune Response: Reciprocal Interactions Between the Nervous and Immune Systems.
Alexander W. Kusnecov, Alba Rossi-George, Scott Siegel

Cytokines in the Brain: From Localization and Function to Clinical Implications.
Julio Licinio, Ma-Li Wong

Neurogenic Inflammation: Role of Substance P.
Andrew M. Stanisz

Lupus as a Model of Neuroimmune Interactions.
Judah A. Denburg, Boris Sakic, Henry Szechtman, Susan D. Denburg

The Pathogenesis of Encephalitis.
Trevor Owens, Elise H. Tran, Mina Hassan-Zahraee, Alicia Babcock, Michelle L. Krakowski, Sylvie Fournier, Micheal B. Jensen, Bente Finsen

VI. Clinical Neuroimmune Biology

Introduction: VI. Clinical Neuroimmune Biology.
Istvan  Berczi

Growth Hormone Therapy and Immune Function.
Robert Rapaport, Robert Moghaddas

The Role of Prolactin in Systemic Lupus Erythematosus.
Richard Warrington, Tim McCarthy, Eva Nagy, Kingsley Lee, Istvan Berczi

Combination immunotherapy of Cance.
Eva Nagy, Istvan Berczi, Edward Baral, John Kellen

The Influence of Reproductive Hormones on Asthma.
Gordon T. Ford, Candice L. Bjornson, Ian Mitchell, M.Sarah Rose

Neuro-Immunopathgenesis in Autism.
Vijendra K. Singh

Skin Inflammation and Immunity after Spinal Cord Injury.
Brian J. MacNeil, Dwight M. Nance

(Article reprint used with permission,NIB 2001;1:vii-xii) )
Editorial to Volume I:  Why Neuroimmune Biology?

     The importance of proper mindset for the maintenance of health and for general well-being has been known since prehistoric times [1].  Jesus Christ actually practiced, perhaps unknowingly, healing of the sick and miserable, simply by giving them hope for recovery.  References to faith healing are also present in the Koran and in other religious texts.  Similar practices exist in primitive societies, where the "medicine man" provides spiritual and physical support to the sick.

     Darwin described the theory of evolution of the species over a hundred years ago [2], which is now regarded as scientifically proven [3], yet religion is still going strong, satisfying the "spiritual need" of enormous masses of people, especially in poor societies.  Although there are suggestions for emotions similar to religion in animals, it is reasonably safe to suggest that the true religious mindset is only present in homo sapiens.

     Why this seemingly obligatory dependence on religion?  Why spiritual satisfaction seems to be a compulsive need for so many people?  The most fundamental difference between higher animals and man lies in intellectual capacity.  Only man has to survive and prosper with the knowledge of certain death.  Even today for most people on our planet life poses enormous difficulties that may include starvation, homelessness, devastating diseases, and no hope for improvements in the future.  One may suggest that religion was, and still is, essential for providing hope for all those people who need help to maintain a balanced mindset that enables them to cope with the harsh realities of life.  It appears that an optimistic mindset for these people is only possible through believing in God and Heaven, where there is eternal life and happiness without any suffering.

     Throughout history severe crisis situations, such as war, created terrible epidemics of infectious disease.  Although not proven, the epidemics of deranged mindset may have contributed significantly to the spread of disease under these conditions.  It is now emerging that emotional crisis may lead to severe depression, which is associated with disturbed neuroendocrine and immune functions.  If these conditions persist, disease may follow [4-7].  Therefore, there is scientific evidence to indicate that the "spiritual need" of many people may actually stem from the enormous regulatory power of the human neuroimmune regulatory system over bodily functions.  It needs to be set properly, in spite of unfavourable circumstances, so that maintenance of health and survival is maximally supported.  That a strong belief in recovery from a serious illness has survival value stands the rigor of scientific scrutiny.  Modern clinical trials of new drugs are conducted with control groups of patients that receive ineffective substances (placebo).  Repeatedly it has been observed on the basis of objective parameters, that a significant percentage of placebo-treated patients show clinical improvements [8].  This may be interpreted as proof for the healing power of the proper mindset.

     Pathologists observed first that emotional factors and hormonal alterations have a major influence on the size of the thymus [9].  In 1936 Hans Selye discovered that noxious agents, when injected into rats, activate the ACTH-adrenal axis, which leads to the shrinkage of the thymus and of lymphoid organs [11, 12].  He produced evidence that glucocorticoids released by the adrenal gland caused the thymus atrophy.  A similar "stress response" could be observed in rats by the emotional upset of being restrained from movement.  Selye established that the hypothalamus-pituitary-adrenal-thymus axis was always activated under stressful conditions.  Therefore, it was postulated by him that this axis was involved in the adaptation of animals to survive life-threatening challenges by various 'nocuous' agents [10-12].  It is only now that we are beginning to understand that indeed he was right.  What he saw was the acute phase response (APR), which may indeed be regarded as an emergency defense reaction.

     Selye’s legacy has been extended by our studies on the role of the pituitary gland in the regulation of the immune system.  Growth hormone and prolactin was shown to maintain immunocompetence, whereas the ACTH-adrenal axis was found to exert an immunosuppressive effect.  Sex steroid hormones have been designated as immunomodulators.  These conclusions were made in reference to the adaptive immune response [13, 14].  It is now emerging that during febrile illness there is immunoconversion from the adaptive mode of immune reactivity to boosting natural immune mechanisms.  The activation of the hypothalamus-pituitary-adrenal axis and the sympathetic outflow actually help the production of acute phase proteins by the liver and of natural antibodies by CD5+ B lymphocytes, which in turn command the immune system during acute illness [15, 16].  These developments fully support Selye’s conclusion that the bodies defense mechanisms are mobilized after stress.

     It was discovered in 1949 by Szentivanyi and colleagues that the hypothalamus regulates the anaphylactic response in guinea pigs.  Subsequent observations revealed that in laboratory animals, where the hypothalamus was imbalanced by lesions or by electrical stimulation, anaphylactic reactivity and antibody formation were altered significantly [17-21].  These experiments revealed that the nervous system has a dominant regulatory power over immune reactivity.  In 1964 Korneva and Khai made similar observations [22].

     The potential of sensory nerves to induce inflammation has been discovered by Jancso and co-workers [23].  This discovery ties in nicely with the above findings, indicating that the nervous system is capable of both causing and inhibiting inflammatory reactions.  A compelling body of experimental evidence is available today, indicating the regulatory role of nerves in the inflammatory process.  There is little doubt that inflammatory diseases have a significant input from the nervous system.  The task is now to understand the mechanisms involved and to use the insights gained to the benefit of patients.

     The work of Pavlov called attention to the role of the mind in alimentary physiology by demonstrating that in dogs the expectation of receiving food leads to salivation (conditioned reflex). Later, the phenomenon of conditioning has been extended to numerous other bodily functions.  In 1926 Metalnikov and Chorine showed that the  Pavlovian rules of conditioning also apply to the immune system [24].  In modern times Ader and co-workers [25], MacQuin et al., [26] and Gorczynski and colleagues [27] provided rigorous scientific proof, indicating that the expectation of an immunological insult has a significant modulatory effect on subsequent immune responses. Therefore, immune responses may be conditioned in the classical Pavlovian sense.  Moreover, it is now emerging that saliva itself has major immunoregulatory substances.  In laboratory rodents the submandibular gland is a major site of production of these substances, which participate in the regulation of both mucosal and systemic immune reactions [28, 29].

     In Persia, in Egypt and in the Roman Empire a healing power was attributed to fever.  This view, which was supported by empirical observations, persisted till modern times.  During the early nineteen hundreds an active search has been done by scientists for pyrogenic substances that could be used for fever therapy of diseases [30].  Such a substance was isolated by Boivin and colleagues from gram-negative bacteria [31], which is now known as bacterial lipopolysaccharide (LPS), or endotoxin.  Now it is clear that LPS, a harmless substance by itself, is instantaneously recognized by the immune system.  LPS induces cell activation, proliferation, cytokine production and the activation of immune-effector mechanisms.  It also affects directly the central nervous system.  If given systemically, LPS induces APR and boosts host defense.  Clearly, there is evidence to support the idea that LPS has many beneficial effects, and that it can be used to good advantage in many life-threatening situations [15].  Similar homologous epitopes (homotopes) that are capable of instantaneous activation of the innate immune system exist in other microorganisms and in self-components [15, 16].

     In 1975 Wannemacker and co-workers isolated the leukocyte endogenous mediator (LEM) of fever [32].  This was the first immune-derived molecule that mediated feedback signals towards the central nervous system.  Later LEM was found to be identical with interleukin-1.  It is now clear that IL-1 also serves as a feedback signal for pituitary hormone release [33-38].  Subsequently other cytokines, especially IL2, IL6, TNF-alpha and interferon gamma were shown to regulate the secretion of pituitary hormones during systemic immune/inflammatory reactions [39].  It is also clear by now that the nerves have immunoregulatory function and provide feedback signals from lymphoid organs and from sites of immune/inflammatory reactions towards the central nervous system [40-43].

     The Science of Immunology has evolved from observations that higher animals and man will acquire specific immunity after previous exposure to an infectious agent or toxin.  Naturally microbiologists were most interested in this phenomenon as their major concern has been to fight infectious diseases.  In order to take advantage of the body’s phenomenal capability to develop specific resistance against pathogenic microbes after exposure, Jenner developed vaccination. This was a major advance in preventing infectious diseases and even today, still is a very important part of preventive medicine.  Therefore, the traditional thinking in Immunology has revolved around the specific stimulus (antigen) that is capable of inducing immunity and it’s interaction with the cells (lymphocytes) that are able to produce antibodies [44, 45].  It took some time to realize that cells, not antibodies, mediated some forms of immunity.  With the advent of Cellular Immunology it has been discovered that lymphocytes are capable of producing antibodies in culture systems [46].  This fortified the view that the immune system was a largely autonomous system that went about the business of fighting ‘foreign’ intruders, while sparing ‘self’ from immune attack [45].  Seemingly there was no need for other control mechanisms, nor did it occur to the scientists pre-occupied with the prevention of infectious disease, that higher regulation of the immune system is in order, or actually it is required for normal function. Clearly, this system was mysteriously intelligent, capable of deciding with remarkable precision what to do.  No other tissues/organs/systems were capable of self-non-self discrimination with such a remarkable precision and to display memory when stimulated by the same antigen/pathogen for the second time.

     However, the case for Neuroimmune interaction, which was first advanced by pathologists a century ago, grew stronger and stronger and by the mid-seventies half a dozen, or so, laboratories were preoccupied with studies in this area.  The term ‘bi-directional communication’ between the Nervous and Immune Systems has been coined by Blalock and accepted enthusiastically by many people in the field.  At the same time, it became obvious that both the immune system (which was watching self integrity) and the nervous system, which innervated all tissues and organs, including the immune system, were in fact communicating with the entire organism.  Indeed, it seems clear by now, there is much more to this interaction than ‘bi-directional’.  It is now emerging, that we are dealing with a truly multi-directional, all-inclusive systemic regulatory network formed by the nervous-, endocrine- and immune systems, which  controls  all bodily functions of higher animals and man.  This system is involved in conception and in the entire process of reproduction, in the growth and development of the fetus and of the newborn, in aging, in the process of daily life rhythms, in the sleep-wake cycle, in seasonal adjustments and in most, if not all, pathological conditions, where defense, healing and regeneration are all influenced [47-49].  Clearly, the entire biology of higher organisms is based on this highly evolved and incredibly sophisticated regulatory system that is able to sense outside stimuli, including danger signs as well as to monitor and patrol the body for intruders, abnormalities and aberrations and correct, protect, heal and regenerate the organism as it may be required for the optimal maintenance of health and recovery from disease.

     Historic observations, the healing power of God and Jesus Christ, as well as every day events indicating the association of emotional difficulties and ill health maintain a very strong popular belief in the importance of mind-body interaction.  In contrast, scientists pride themselves to only accept phenomena as true when sufficient scientific data are available in support of their validity.  So far the scientific community at large does not fully appreciate the fundamental importance of the neuroimmune regulatory network.  However, the time has arrived, when the role of this fundamental regulatory system may be submitted to scientific scrutiny.  The human genome has been mapped and the experimental tools and sophistication, as well as the capacity of handling the vast amount of information that needs to be evaluated, are all available to undertake this task. There is little doubt, that fitting together the puzzle will soon become the next, and perhaps the last, frontier of Vertebrate Biology.  Clearly, what is also required is to organize and interpret the scientific data as we go along.  This is especially important because the relevant information is published in diverse specialty journals.

     The Science of Neuroimmune Biology deals with this systemic regulatory network, coordinating, organizing and interpreting the rapidly accumulating knowledge.  The ultimate goal is to understand the function of higher organisms, including man, in their entire complexity.  The objective of the book series, Neuroimmune Biology, is to provide regular assessments and interpretation of accumulated experimental evidence.  It is hoped that this publication will enable the scientific community to keep abreast with essential advancements of our knowledge in a quest for understanding the Biology of higher organisms.

     We are pleased to present to the interested readers the introductory volume of this publication series and our plans for the forthcoming issues.  We feel that it is high time to turn our attention to the organization and interpretation of the knowledge that has been accumulated in Biology.  A new scientific field called Genomics has emerged recently, as attention is focused on the interaction of individual genes in the genome.  In contrast with Genomics that still deals largely with events at the molecular and cellular level, our interest focuses on Integrative Physiology and Pathophysiology, never forgetting the milieu in which the cells (and their genes) of the body have to exert their functions.  The term Neuroimmune Biology expresses this overall objective.

Istvan Berczi and Andor Szentivanyi