Psychiatric Annals

CME Article 

The Sickness Response: An Adaptive Brain–Body Reaction to Medical Illness

Claudia Troesch Viamontes, MD, PhD

Abstract

In general, sickness behavior tends to be adaptive. It limits activity, motivates rest, and temporarily suppresses appetite and libido, allowing the body to focus its resources on fighting illness. In certain cases, especially those that involve autoimmune disorders, medication side effects, or chronic disease, sickness behavior can be maladaptive, because it promotes gradual disengagement from the physical and social environment with dysphoria and anhedonia, induces sleep disturbances, limits motivation and productivity, and decreases quality of life (see Figure 2, page 986). Under extreme circumstances, sickness behavior can be complicated by cognitive impairment and may evolve into major depressive disorder (MDD).1 This article reviews the mechanisms that underlie the subjective and objective aspects of the sickness response. These mechanisms are remarkable because they bring to consciousness a series of events that are occurring at cellular and molecular levels as the immune system addresses an infection. Sickness phenomena even make it possible for the conscious mind to know whether infection-fighting is progressing successfully or not by determining “how sick” one feels. An understanding of this phenomenon, whose brain-body origin emphasizes the inseparability of psychiatry and medicine, can be invaluable for helping patients with chronic illness to manage the incapacitating complications of prolonged or exaggerated sickness reactions.

Abstract

In general, sickness behavior tends to be adaptive. It limits activity, motivates rest, and temporarily suppresses appetite and libido, allowing the body to focus its resources on fighting illness. In certain cases, especially those that involve autoimmune disorders, medication side effects, or chronic disease, sickness behavior can be maladaptive, because it promotes gradual disengagement from the physical and social environment with dysphoria and anhedonia, induces sleep disturbances, limits motivation and productivity, and decreases quality of life (see Figure 2, page 986). Under extreme circumstances, sickness behavior can be complicated by cognitive impairment and may evolve into major depressive disorder (MDD).1 This article reviews the mechanisms that underlie the subjective and objective aspects of the sickness response. These mechanisms are remarkable because they bring to consciousness a series of events that are occurring at cellular and molecular levels as the immune system addresses an infection. Sickness phenomena even make it possible for the conscious mind to know whether infection-fighting is progressing successfully or not by determining “how sick” one feels. An understanding of this phenomenon, whose brain-body origin emphasizes the inseparability of psychiatry and medicine, can be invaluable for helping patients with chronic illness to manage the incapacitating complications of prolonged or exaggerated sickness reactions.

Claudia T. Viamontes, MD, PhD, is Regional Medical Director, MHNet Behavioral Health, St. Louis, Missouri.

Dr. Viamontes has disclosed no relevant financial relationship.

A note from the editors: All illustrations in this article have been created by George I. Viamontes, MD, PhD, for specific use in this issue of Psychiatric Annals.

Copyright C. Viamontes 2009; copyright is transferred to the publisher; used with permission.

Address correspondence to: Claudia T. Viamontes, MD, PhD, viamontes@sbcglobal.net.

Brain–body communication is a continuous, two-way process that monitors the internal milieu and guides adaptive responses to perceived disruptions of homeostasis. The sickness response is a brain-based phenomenon that underlies the subjective experiences and unique behaviors that characterize medical illness. The invasion of the body by pathogens is a serious event that is addressed at many levels. The first response is usually by cells of the innate immune system. Initial responders, which include neutrophils, macrophages, and dendritic cells, engage invading pathogens and secrete signaling molecules that attract other immune system cells, begin activation of adaptive immunity, and alert the brain that an infection is being addressed at the cellular level (see Figure 1).

Summary of the Sickness Response. Sickness Symptoms Are Caused by the Action of Cytokines Produced by Immune Responses on Specific Regions of the Brain. All Illustrations Are Copyright George I. Viamontes, 2009; Copyright Is Transferred to the Publisher.; Used with Permission. A Note from the Editors: All Illustrations in This Article Have Been Created by Dr. Viamontes for Specific Use in This Issue of Psychiatric Annals. Images of Blood Vessels and Immune System Cells Used Throughout the Article Were Licensed from Zygote, Inc. Images of the Cytokines and Other Molecules Were Downloaded as Data Files from the Research Collaborative for Structural Informatics Protein Data Bank (RSCB PDB).22 Used with Permission.

Figure 1. Summary of the Sickness Response. Sickness Symptoms Are Caused by the Action of Cytokines Produced by Immune Responses on Specific Regions of the Brain. All Illustrations Are Copyright George I. Viamontes, 2009; Copyright Is Transferred to the Publisher.; Used with Permission. A Note from the Editors: All Illustrations in This Article Have Been Created by Dr. Viamontes for Specific Use in This Issue of Psychiatric Annals. Images of Blood Vessels and Immune System Cells Used Throughout the Article Were Licensed from Zygote, Inc. Images of the Cytokines and Other Molecules Were Downloaded as Data Files from the Research Collaborative for Structural Informatics Protein Data Bank (RSCB PDB).22 Used with Permission.

In general, sickness behavior tends to be adaptive. It limits activity, motivates rest, and temporarily suppresses appetite and libido, allowing the body to focus its resources on fighting illness. In certain cases, especially those that involve autoimmune disorders, medication side effects, or chronic disease, sickness behavior can be maladaptive, because it promotes gradual disengagement from the physical and social environment with dysphoria and anhedonia, induces sleep disturbances, limits motivation and productivity, and decreases quality of life (see Figure 2, page 986). Under extreme circumstances, sickness behavior can be complicated by cognitive impairment and may evolve into major depressive disorder (MDD).1 This article reviews the mechanisms that underlie the subjective and objective aspects of the sickness response. These mechanisms are remarkable because they bring to consciousness a series of events that are occurring at cellular and molecular levels as the immune system addresses an infection. Sickness phenomena even make it possible for the conscious mind to know whether infection-fighting is progressing successfully or not by determining “how sick” one feels. An understanding of this phenomenon, whose brain-body origin emphasizes the inseparability of psychiatry and medicine, can be invaluable for helping patients with chronic illness to manage the incapacitating complications of prolonged or exaggerated sickness reactions.

Elements of the Sickness Response. Sickness Responses Are Complex, with a Variety of Vegetative, Behavioral, and Cognitive Effects. A Note from the Editors: All Illustrations in This Article Have Been Created by George I. Viamontes, MD, PhD, for Specific Use in This Issue of Psychiatric Annals.

Figure 2. Elements of the Sickness Response. Sickness Responses Are Complex, with a Variety of Vegetative, Behavioral, and Cognitive Effects. A Note from the Editors: All Illustrations in This Article Have Been Created by George I. Viamontes, MD, PhD, for Specific Use in This Issue of Psychiatric Annals.

Proinflammatory Cytokines

Sickness behavior is a genetically encoded response to infection. It is triggered by soluble mediators that are released by cells of the immune system as they engage invading pathogens (see Figure 3). These mediators are known as proinflammatory cytokines because they initiate the local and systemic inflammatory reactions that characterize immune responses (see Figure 1, page 985). The immune system and the brain share a common language implemented by cytokines because cytokine receptors are found not only on immune system cells, but on neurons, astrocytes, and microglia.1 This arrangement delivers a continuous stream of information to the brain on the status of ongoing immune reactions. Often, through the perception of a cytokine signature that manifests itself through such signs as body aches and malaise, it is possible to sense an incipient infection before overt symptoms appear. The proinflammatory cytokines that act on the brain to produce sickness responses include interleukin-1-alpha (IL-1alpha), interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), and interleukin-6 (IL-6). The interferons, whether innately generated or exogenously introduced, also produce significant sickness responses.

TNF-alpha Is an Early Mediator of Immune Responses. It Is Secreted Primarily by Cells of Innate Immunity, Namely Macrophages, Mast Cells, and Natural Killer Cells. TNF-alpha Recruits Immune System Cells to Sites of Infection by Activating the Cells and Promoting the Expression of Specialized Proteins that Make Immune System Cells Adhere to Endothelium. TNF-alpha Is a Pyrogen, and Therefore Causes Fever. It also Mediates Anorexia and a Variety of Other Sickness Symptoms. when It Is Present in the Circulation at High Concentrations, TNF-alpha Can Precipitate Extremely Low Glucose Levels. It Can Cause the Decreases in Cardiac Contractility and Blood Pressure that Characterize Septic Shock. TNF-alpha Induces the Production of IL-1. A Note from the Editors: All Illustrations in This Article Have Been Created by George I. Viamontes, MD, PhD, for Specific Use in This Issue of Psychiatric Annals.

Figure 3. TNF-alpha Is an Early Mediator of Immune Responses. It Is Secreted Primarily by Cells of Innate Immunity, Namely Macrophages, Mast Cells, and Natural Killer Cells. TNF-alpha Recruits Immune System Cells to Sites of Infection by Activating the Cells and Promoting the Expression of Specialized Proteins that Make Immune System Cells Adhere to Endothelium. TNF-alpha Is a Pyrogen, and Therefore Causes Fever. It also Mediates Anorexia and a Variety of Other Sickness Symptoms. when It Is Present in the Circulation at High Concentrations, TNF-alpha Can Precipitate Extremely Low Glucose Levels. It Can Cause the Decreases in Cardiac Contractility and Blood Pressure that Characterize Septic Shock. TNF-alpha Induces the Production of IL-1. A Note from the Editors: All Illustrations in This Article Have Been Created by George I. Viamontes, MD, PhD, for Specific Use in This Issue of Psychiatric Annals.

A few notes on cytokine nomenclature, origins, and functions can be helpful in clarifying this important topic. Cytokines are specialized polypeptides that are secreted by cells of the innate and adaptive immune systems, as a response to stimulation by antigens. Cytokines mediate intercellular communication by activating receptors on a variety of cells, including other immune system cells, endothelial cells, and neurons. Cytokines bind to their receptors with exceptionally high affinity, and their dissociation constants (Kd) are in the 10−10 to 10−12 M range.2 As a result, relatively low amounts of circulating cytokines can trigger significant responses in target cells.

The specific names given to individual cytokines have, in some cases, been determined by historical reasons rather than functional or relational considerations. TNF-alpha, for example, is the major mediator of acute inflammatory responses to gram-negative bacteria and other pathogens. It is secreted primarily by macrophages that have been activated by microbial antigens. TNF-alpha can also be secreted by mast cells and natural killer (NK) cells. A slightly different version of tumor necrosis factor, TNF-beta, can be produced by activated lymphocytes.2 TNF-alpha is a significant mediator of the sickness response, as discussed below. It is initially secreted as a membrane-bound protein, which can be cleaved by an intrinsic metal-loproteinase into the soluble form of TNF-alpha, which is a trimer of three cleaved chains.

TNF-alpha recruits immune system cells to sites of infection. It accomplishes this by inducing the expression of adhesion molecules on vascular endothelial surfaces, as well as on neutrophils, monocytes, and lymphocytes.2 TNF-alpha also stimulates the secretion of chemokines by endothelial cells and macrophages, which induce the immune cells that have attached to endothelial surfaces to move through the spaces between endothelial cells into infected tissue. TNF-alpha also induces the production of IL-1 by macrophages2 and causes relaxation of vascular smooth muscle, which leads to tissue inflammation. TNF-alpha is considered an endogenous pyrogen because it is secreted by the body’s own cells and promotes fever through its actions on the hypothalamus. In contrast, microbial products, such as lipopolysaccharide (LPS), a fever-causing bacterial cell wall component that is not found in mammalian cells, are considered exogenous pyrogens. In very severe infections, TNF-alpha can spill into the circulation and cause serious systemic effects. These include:2

  1. Shock, marked by a drop in blood pressure and decreased cardiac contractility as a result of TNF-alpha’s inhibition of muscle contraction;

  2. Cachexia, or muscle and fat-cell wasting, which results from appetite suppression and decreased levels of lipoprotein lipase, an enzyme that is needed for cleaving fatty acids from lipoproteins;

  3. Intravascular thrombosis, resulting from activation of endothelium, leading to production of coagulants and activation of neutrophils, which can clog small vessels. The tumor necrosis that gave this factor its name is the result of its ability to thrombose tumor vessels; and

  4. Precipitous drops in plasma glucose to levels incompatible with life, resulting from glucose utilization by muscles without replacement by the liver.

As the summary above indicates, the actions of TNF-alpha, although protective in a localized manner, can have disastrous effects if they spread systemically. For this reason, there are automatic mechanisms that normally limit the spread of inflammation, including the actions of the hypothalamic-pituitary-adrenal (HPA) axis, which results in the production of the anti-inflammatory hormone cortisol, and the actions of the sympathetic and parasympathetic nervous systems, which inhibit the production of inflammatory cytokines at a systemic level.3

The other immune system mediators that induce sickness responses include the interleukins and interferons. The interleukins are a heterogeneous group of cytokines that received their name because they were thought to be substances secreted exclusively by leukocytes (such as macrophages or lymphocytes) that act on other leukocytes. Unfortunately, the term is not strictly correct because interleukins can be secreted by non-leukocytes and act on a wide variety of cells. The interleukins are numbered sequentially in the order in which they were discovered. IL-1 is an important mediator of inflammation that usually acts in parallel with TNF-alpha. It exists in two forms, alpha and beta, which have only about 30% sequence homology.1 Both forms are originally secreted as a 33 kD polypeptide, and cleaved into 17 kD subunits. Only the 17 kD form of IL-1-beta is active, whereas both forms of IL-1-alpha have activity. IL-1 is primarily secreted by activated macrophages as a response to TNF-alpha or to bacterial products, such as LPS. IL-1 can also be produced by other types of cells, including neutrophils, keratinocytes, and endothelial cells. IL-1, such as TNF-alpha, causes the production of adhesion molecules on endothelial surfaces and immune cells, and promotes the latter’s entry into infected tissues (see Figure 4, page 987). In addition, IL-1 induces fever, triggers the release of other cytokines, including IL-6, and stimulates the production of neutrophils and platelets in bone marrow. Although IL-1 can induce the synthesis of acute-phase plasma proteins in the liver, it is normally not present in plasma at high enough concentrations to accomplish this.4

IL-1beta Is Primarily Secreted by Activated Macrophages as a Response to TNF-alpha or to Bacterial Products, Such as LPS. It Can also Be Produced by Other Types of Cells, Including Neutrophils, Keratinocytes, and Endothelial Cells. IL-1, Such as TNF-alpha, Causes the Production of Adhesion Molecules on Endothelial Surfaces and Immune Cells, and Promotes the Latter’s Entry into Infected Tissues. in Addition, IL-1 Beta Induces Fever, Social Withdrawal, and Anorexia and Stimulates the Production of Neutrophils and Platelets in Bone Marrow. Although IL-1 Can Induce the Synthesis of Acute-Phase Plasma Proteins in the Liver, It Is Normally not Present in Plasma at High Enough Concentrations to Accomplish This. A Note from the Editors: All Illustrations in This Article Have Been Created by George I. Viamontes, MD, PhD, for Specific Use in This Issue of Psychiatric Annals.

Figure 4. IL-1beta Is Primarily Secreted by Activated Macrophages as a Response to TNF-alpha or to Bacterial Products, Such as LPS. It Can also Be Produced by Other Types of Cells, Including Neutrophils, Keratinocytes, and Endothelial Cells. IL-1, Such as TNF-alpha, Causes the Production of Adhesion Molecules on Endothelial Surfaces and Immune Cells, and Promotes the Latter’s Entry into Infected Tissues. in Addition, IL-1 Beta Induces Fever, Social Withdrawal, and Anorexia and Stimulates the Production of Neutrophils and Platelets in Bone Marrow. Although IL-1 Can Induce the Synthesis of Acute-Phase Plasma Proteins in the Liver, It Is Normally not Present in Plasma at High Enough Concentrations to Accomplish This. A Note from the Editors: All Illustrations in This Article Have Been Created by George I. Viamontes, MD, PhD, for Specific Use in This Issue of Psychiatric Annals.

IL-6 (see Figure 5) is produced by a variety of cell types that have been activated by IL-1, TNF, or microbial products. Macrophages, endothelial cells, fibroblasts, and activated T-cells produce IL-6. In addition, IL-6 can be secreted by several types of tumor cells, including cardiac myxomas, as well as bladder and cervical cancers.5 IL-6 is pyrogenic. It induces the production of acute-phase proteins by hepatocytes and stimulates the growth of differentiated, antibody-producing B-cells.1

IL-6 Is Produced by a Variety of Cell Types that Have Been Activated by IL-1, TNF, or Microbial Products, Including Macrophages, Endothelial Cells, Fibroblasts, and Activated T-Cells. in Addition, IL-6 Can Be Secreted by Tumor Cells, Including Cardiac Myxomas, as Well as Bladder and Cervical Cancers. IL-6 Is Pyrogenic. It Induces the Production of Acute-Phase Proteins by Hepatocytes and Stimulates the Growth of Differentiated, Antibody-Producing B-Cells. IL-6 Amplifies the Sickness Reaction to Other Cytokines and Can Induce Hippocampus-Mediated Memory Deficits. A Note from the Editors: All Illustrations in This Article Have Been Created by George I. Viamontes, MD, PhD, for Specific Use in This Issue of Psychiatric Annals.

Figure 5. IL-6 Is Produced by a Variety of Cell Types that Have Been Activated by IL-1, TNF, or Microbial Products, Including Macrophages, Endothelial Cells, Fibroblasts, and Activated T-Cells. in Addition, IL-6 Can Be Secreted by Tumor Cells, Including Cardiac Myxomas, as Well as Bladder and Cervical Cancers. IL-6 Is Pyrogenic. It Induces the Production of Acute-Phase Proteins by Hepatocytes and Stimulates the Growth of Differentiated, Antibody-Producing B-Cells. IL-6 Amplifies the Sickness Reaction to Other Cytokines and Can Induce Hippocampus-Mediated Memory Deficits. A Note from the Editors: All Illustrations in This Article Have Been Created by George I. Viamontes, MD, PhD, for Specific Use in This Issue of Psychiatric Annals.

The interferons comprise another important family of cytokines that can cause behavioral symptoms. These immunoregulatory proteins are secreted by a variety of cell types after stimulation with viral proteins and nucleic acids, as well as other antigens, mitogens, and lectins.3 The interferons are generally classified as type I and type II. Type I interferons include interferons alpha, beta, epsilon, kappa, and omega.2 The most clinically important of these are interferons alpha and beta. Type I interferons are classified together because they bind to the same receptor. Type II interferon refers to gamma interferon, which is also known as immune interferon. It binds to a unique receptor whose components fully assemble only after interferon gamma has bound to one of the elements.

Interferon alpha (IFN-alpha) is a 189 amino acid protein, with at least 13 variants, which is made primarily by plasmacytoid dendritic cells and mononuclear phagocytes (see Figure 6). Plasmacytoid dendritic cells are present in the blood and tissues, and are specialized for viral recognition.2 Viral nucleic acids are the strongest stimulator of IFN-alpha production.

Interferon Alpha (IFN-alpha) Is a 189 Amino Acid Protein that Is Made Primarily by Plasmacytoid Dendritic Cells and Mononuclear Phagocytes. Viral Nucleic Acids Are the Strongest Stimulator of IFN-alpha Production. IFN-alpha Produces Fever and Other Sickness Responses. It also Induces Production of MHC I and II Molecules, Potentiates Macrophages, Stimulates the Development of Helper T Cells Along the TH1 Pathway, and Induces the Production of Inflammatory Cytokines (TNF-alpha, IL-1-Beta, and IL-6). A Note from the Editors: All Illustrations in This Article Have Been Created by George I. Viamontes, MD, PhD, for Specific Use in This Issue of Psychiatric Annals.

Figure 6. Interferon Alpha (IFN-alpha) Is a 189 Amino Acid Protein that Is Made Primarily by Plasmacytoid Dendritic Cells and Mononuclear Phagocytes. Viral Nucleic Acids Are the Strongest Stimulator of IFN-alpha Production. IFN-alpha Produces Fever and Other Sickness Responses. It also Induces Production of MHC I and II Molecules, Potentiates Macrophages, Stimulates the Development of Helper T Cells Along the TH1 Pathway, and Induces the Production of Inflammatory Cytokines (TNF-alpha, IL-1-Beta, and IL-6). A Note from the Editors: All Illustrations in This Article Have Been Created by George I. Viamontes, MD, PhD, for Specific Use in This Issue of Psychiatric Annals.

Interferon beta (IFN-beta) is a 187 amino acid protein that is made by fibroblasts and many other cell types, which have been infected by a virus. When type I interferons bind to their receptor, they trigger a phosphorylation cascade, which generates activated complexes that bind to special DNA sequence known as IFN-stimulated transcription elements.2 These DNA sequences are present in the genes whose protein products implement the interferon response, and their activation leads to gene transcription.

Type I interferons have a variety of actions that serve to eradicate viral infections and strengthen immunity against phagocytosed pathogens. The activation of interferon type I receptors results in the synthesis of several substances that interfere with the transcription of viral proteins and with viral replication. In addition, type I interferons stimulate the development of helper T cells along the TH1 pathway, which promotes cellular immunity and induces the expression of class I major histocompatibility complex (MHC) molecules (see Figure 6). These molecules, when expressed by virally infected cells, “mark” the expressing cell for destruction by natural killer cells or cytotoxic T lymphocytes (CTLs). This is accomplished by the display of viral antigens in the peptide-binding grooves of the MHC class I molecules (see Figure 7, page 989), which also contain a binding site for the CD8 antigen displayed by CTLs.2 Type I interferons also induce the production of the inflammatory cytokines IL-6, IL-1-beta and TNF-alpha.6

A Class II MHC Molecule Complexed with a Peptide from the HIV, Which Is Represented as a Space-Filling Model Within a Groove in the MHC Molecule.

Figure 7. A Class II MHC Molecule Complexed with a Peptide from the HIV, Which Is Represented as a Space-Filling Model Within a Groove in the MHC Molecule.

IFN-gamma is secreted by TH1 helper cells and natural killer cells as a response to antigen-presenting cells that are actively displaying an antigen. IFN-gamma activates macrophages and induces production of nitric oxide and reactive oxygen intermediates. This enhances the macrophage’s ability to kill phagocytosed pathogens.2 IFN-gamma also promotes differentiation of CD4+ cells along the TH1 helper pathway and inhibits the generation of the TH2 cells that mediate allergic reactions. In addition, it stimulates the expression of class I and class II MHC molecules on antigen-presenting cells.

How Cytokines Reach the Brain

Access to the brain is restricted by the blood-brain barrier, which is implemented by the tight junctions between the endothelial cells that line brain capillaries. These tight junctions prevent the diffusion of large or hydrophilic molecules into the brain. Four major mechanisms (see Figure 8; Figure 9; Figure 10, page 991; and Figure 11, page 992) have been identified that allow information about ongoing immune responses to be carried into the brain.7

Peripheral Nerves, Such as the Vagus, Can Detect Cytokines Products by Immune Responses and Signal the Brain. Images of Cells and Bacteria Licensed from Zygote, Inc. A Note from the Editors: All Illustrations in This Article Have Been Created by George I. Viamontes, MD, PhD, for Specific Use in This Issue of Psychiatric Annals.

Figure 8. Peripheral Nerves, Such as the Vagus, Can Detect Cytokines Products by Immune Responses and Signal the Brain. Images of Cells and Bacteria Licensed from Zygote, Inc. A Note from the Editors: All Illustrations in This Article Have Been Created by George I. Viamontes, MD, PhD, for Specific Use in This Issue of Psychiatric Annals.

TNF-alpha, IL-1 Beta, and IL-6 Are Actively Transported into the Brain by Endothelial Cells. A Note from the Editors: All Illustrations in This Article Have Been Created by George I. Viamontes, MD, PhD, for Specific Use in This Issue of Psychiatric Annals.

Figure 9. TNF-alpha, IL-1 Beta, and IL-6 Are Actively Transported into the Brain by Endothelial Cells. A Note from the Editors: All Illustrations in This Article Have Been Created by George I. Viamontes, MD, PhD, for Specific Use in This Issue of Psychiatric Annals.

The Circumventricular Organs, Which Do not Have a Blood-Brain Barrier, Can Therefore Be Affected by Circulating Substances. 1. Subfornical Organ. 2. Organum Vasculosum of the Lamina Terminalis. 3. Median Eminence. 4. Middle Lobe of Pituitary. 5. Posterior Lobe of Pituitary. 6. Area Postrema. 7. Subcommisural Organ. 8. Pineal Gland. A Note from the Editors: All Illustrations in This Article Have Been Created by George I. Viamontes, MD, PhD, for Specific Use in This Issue of Psychiatric Annals.

Figure 10. The Circumventricular Organs, Which Do not Have a Blood-Brain Barrier, Can Therefore Be Affected by Circulating Substances. 1. Subfornical Organ. 2. Organum Vasculosum of the Lamina Terminalis. 3. Median Eminence. 4. Middle Lobe of Pituitary. 5. Posterior Lobe of Pituitary. 6. Area Postrema. 7. Subcommisural Organ. 8. Pineal Gland. A Note from the Editors: All Illustrations in This Article Have Been Created by George I. Viamontes, MD, PhD, for Specific Use in This Issue of Psychiatric Annals.

Cytokines Activate Endothelial Cells and Perivascular Macrophages and Incude Prostaglandin E2 Production. Image Licensed from Zygote, Inc. A Note from the Editors: All Illustrations in This Article Have Been Created by George I. Viamontes, MD, PhD, for Specific Use in This Issue of Psychiatric Annals.

Figure 11. Cytokines Activate Endothelial Cells and Perivascular Macrophages and Incude Prostaglandin E2 Production. Image Licensed from Zygote, Inc. A Note from the Editors: All Illustrations in This Article Have Been Created by George I. Viamontes, MD, PhD, for Specific Use in This Issue of Psychiatric Annals.

First, local cytokine activity can be detected by peripheral sensory nerves (see Figure 8). This has been demonstrated for the vagus nerve in the peritoneal cavity8 and the glossopharyngeal nerve in the oral cavity.9 Cutting regional sensory nerves diminishes the central febrile response induced by local injections of LPS, a bacterial cell wall component that activates the innate immune response and causes fever.

Second, cytokines are actively transported across the blood-brain barrier (see Figure 9).7 Saturable transport systems have been identified for IL-1-alpha, IL-1-beta, IL-6, and TNF-alpha.10 An experiment suggests that the observed sickness responses induced by IL-1 are mediated by direct entry of peripheral IL-1 into the brain and induction of additional IL-1 production within the brain.11 Mice were injected with human IL-1 (hIL-1), which is active in mice and humans. The cytokine was actively transported into the posterior division of the septum (PDS), where it acts to cause memory impairment.11 Anti-hIL-1 antibody and anti-mouse IL-1 antibodies injected directly into the PDS were able to inhibit about 70% of the memory impairment, suggesting that transported IL-1 not only acts directly on the brain, but also induces IL-1 synthesis and/or triggers its release.11

The third mechanism of information transfer from periphery to brain takes place at special sites called the circumventricular organs (see Figure 10, page 991).7 These brain structures are unique because they have an attenuated blood-brain barrier, and therefore allow passage of a variety of substances from the blood into the brain. They include the pineal gland, the subfornical organ, the organum vasculosum of the lamina terminalis, the choroid plexus, the area postrema, the median eminence, the subcommissural organ, and the middle and posterior pituitary. The circumventricular organs contain brain macrophages called microglia, which can react to cytokines or to pathogen-derived substances, such as LPS and viral DNA. These substances are recognized by specialized membrane proteins called toll-like receptors (TLRs). TLRs are pattern recognition molecules that are pre-programmed to detect common antigens present in viruses and bacteria, but not in mammalian cells.2 When TLRs are activated, they promote the production of a variety of transcription factors, including nuclear factor-kappa-B (NF-kappa-B). NF-kappa-B binds to special promoter DNA sequences contained in many genes that encode cytokines. As a result, the binding of bacterial or viral products triggers a chain of events that lead to cytokine production in brain microglia. Secreted cytokines can subsequently diffuse into the brain.7

The fourth way in which immune system information can be transmitted to the brain is through activation of IL-1 receptors that are present on endothelial cells and perivascular macrophages around brain venules (see Figure 11, page 992).7 Endothelial cell activation by IL-1 leads to the production of prostaglandin E2, a substance that can cause fever in the hypothalamus and may mediate other aspects of sickness responses.

In summary, the last three pathways converge at the level of microglia. Specialized neurons, microglia, and endothelial cells transduce information about immune responses that are occurring in the periphery into the brain. This data transfer process is the first step in the generation of sickness responses.

The Sickness Response

Although the exact mechanisms for sickness response generation by the brain have not been fully elucidated, it is clear that this phenomenon is correlated with the presence of IL-1, TNF-alpha, and IL-6 in the circulation. For example, a study of humans with Epstein-Barr virus, Q fever, or Ross River virus infections has demonstrated that peripheral blood levels of IL-1-beta and IL-6 are correlated with core sickness symptoms, including fever, malaise, pain, fatigue, and poor concentration.12 In addition, animal experiments have shown that systemic or central administration of IL-1-beta or TNF-alpha induces sickness behaviors that are dose and time-dependent.7 In contrast, IL-6 administration, either central or systemic, does not produce measurable sickness effects in mice or rats, other than fever.7 Despite its lack of direct mediation of sickness behaviors, IL-6 has a significant effect on the induction of memory impairment by IL-1-beta or TNF-alpha. Sickness-related memory problems are a common feature of infections and can be particularly debilitating in the elderly.

The hippocampus, which mediates memory processes, has a high density of cytokine receptors.13 In addition, the presence of high levels of peripheral IL-1-beta or TNF-alpha induces the production of these same cytokines in the hippocampus.13 High levels of hippocampal cytokines are in turn associated with inhibition of long-term potentiation and induction of performance deficits in hippocampally mediated cognitive tests.13 IL-6 appears to be important for cytokine production in the hippocampus because IL-6 deficient mice injected with LPS show no hippocampally mediated cognitive deficits and very low levels of hippocampal cytokine RNA. In contrast, normal mice responding to LPS show elevated levels of hippocampal cytokine RNA and hippocampally mediated cognitive deficits. Both types of mice demonstrate other sickness responses.13

An important mediator of central cytokine effects is a structure called the nucleus of the solitary tract (NST; see Figure 12). The solitary tract is a long set of myelinated fiber bundles that extend from the caudal pons to the spinomedullary junction.14 It contains fibers from the facial and trigeminal nerves rostrally, from the glossopharyngeal nerve intermediately, and from the vagus nerve caudally, thus representing sensory inputs from the head, face, pharynx, and viscera.14 The NST, located in the dorsomedial medulla, is an important mediator of homeostatic reflexes. It receives and integrates an array of sensory inputs and coordinates visceral and autonomic responses, including parasympathetic activation. The NST projects to such important structures as the central nucleus of the amygdala, the parabrachial nuclei, the periaqueductal gray, the reticular formation, the nucleus ambiguus, and the area postrema.15 It also projects to vasomotor interneurons in the medulla that control blood pressure, to vagal parasympathetic premotor neurons that control heart rate, and to motor neurons of the nucleus ambiguus that innervate esophageal muscles.16 The NST’s projections to limbic, digestive, and autonomic regions may allow this structure to mediate a number of the commonly experienced, vegetative symptoms that characterize the sickness response.

The Nucleus Solitarius, or Nucleus of the Solitary Tract (NST). The NST Appears to Be an Important Element in the Central Detection of Peripherally Produced Cytokines and in the Generation of Physiological and Behavioral Responses. The Vagus and Glossopharyngeal Nerves Have Been Shown to Detect IL-1-Beta and to Mediate Activation of the NST.

Figure 12. The Nucleus Solitarius, or Nucleus of the Solitary Tract (NST). The NST Appears to Be an Important Element in the Central Detection of Peripherally Produced Cytokines and in the Generation of Physiological and Behavioral Responses. The Vagus and Glossopharyngeal Nerves Have Been Shown to Detect IL-1-Beta and to Mediate Activation of the NST.

The NST appears to be an important element in the central detection of peripherally produced cytokines and in the generation of physiological and behavioral responses. The vagus8 and glossopharyngeal9 nerves have both been shown to detect IL-1-beta and to mediate activation of the NST, as demonstrated by expression of cFos, which indicates early gene transcription.17 An important response by the NST to cytokine stimulation is the triggering of what has been called “the inflammatory reflex.”18 This reaction involves parasympathetic acetylcholine release in those organs that house the reticuloen-dothelial, or macrophage, system of the body. These include the heart, GI tract, liver, spleen, kidneys, and lungs.18 Released acetylcholine binds to a nicotinic receptor present on macrophages whose activation shuts down inflammatory cytokine production.18 This prevents the unrestrained progression of inflammation, which could prove fatal.

Eccles19 has reviewed the specific mechanisms that cause the multiple symptoms of an upper respiratory infection (URI). His findings, which illustrate many of the principles of sickness-response signaling, form the basis of the discussion below. Upper respiratory tract infections are the most common diseases of humans. The mechanisms that generate the subjective symptoms of URIs illustrate how interactions between the central nervous system and the body’s defenses against pathogens generate many of the familiar sickness responses (see Figure 13, page 993).

Summary of Upper Respiratory Infection Symptoms and Their Immediate Causative Factors. A Note from the Editors: All Illustrations in This Article Have Been Created by George I. Viamontes, MD, PhD, for Specific Use in This Issue of Psychiatric Annals.

Figure 13. Summary of Upper Respiratory Infection Symptoms and Their Immediate Causative Factors. A Note from the Editors: All Illustrations in This Article Have Been Created by George I. Viamontes, MD, PhD, for Specific Use in This Issue of Psychiatric Annals.

Even before the respiratory symptoms of the common cold or influenza (see Figure 14, page 993) appear, there is often a prodromal phase characterized by muscle aches, malaise, and anorexia. These symptoms are a result of acute phase immune responses to infection, mediated by the action of cytokines, as described above. Anorexia is induced by the inhibition of hunger centers in the hypothalamus, which express cytokine receptors. Muscle aches (myalgia) are thought to be caused by the action of prostaglandin E2 (PE2), which is produced by cytokine-activated mononuclear phagocytes, on skeletal muscles. PE2 induces muscle breakdown, which releases substances that activate pain receptors. Theoretically, the mild muscle breakdown that is induced by immune responses can be beneficial because it generates amino acids that can be used by immune system cells. Eventually, in a prolonged illness, decrease in muscle mass can lower the body’s energy needs.

A Representation of the Influenza Virus. Image Licensed from Zygote, Inc. A Note from the Editors: All Illustrations in This Article Have Been Created by George I. Viamontes, MD, PhD, for Specific Use in This Issue of Psychiatric Annals.

Figure 14. A Representation of the Influenza Virus. Image Licensed from Zygote, Inc. A Note from the Editors: All Illustrations in This Article Have Been Created by George I. Viamontes, MD, PhD, for Specific Use in This Issue of Psychiatric Annals.

Among the first characteristic symptoms of a URI are a sore throat and a runny nose, either singly or in combination. The sore throat of a viral infection is thought to be produced by the actions of bradykinins and prostaglandins, which are released in the inflammatory response to the virus, on pharyngeal pain receptors. These receptors are part of the trigeminal nerve system. Inflammatory responses in the nasal epithelium and anterior nasopharynx are the underlying cause of rhinorrhea, sneezing, nasal congestion, and sinus pain. Specifically, rhinorrhea results from increased glandular and goblet cell secretions, combined with inflammatory capillary exudates. The fluid is initially thin and clear, but eventually, it may become thick, with a color that ranges from yellow to green. The thickness and coloration of the secretions reflect the extent of leukocyte involvement in the inflammatory process because neutrophils and monocytes have granules that contain myeloperoxidase, which is green. Contrary to popular opinion, the appearance of nasal secretions is not specifically related to the type of infection, such as bacterial or viral, but to the severity of the inflammatory reaction.19

Sneezing and coughing are specialized reflexes that are triggered by two cranial nerves. Sneezing is an adaptive reflex that expels nasal contents as a reaction to activation of the trigeminal nerve, which provides the sensory innervation of the nasal cavity. Foreign bodies or irritants, such as pepper and fine powders, can trigger sneezing. In a URI, the immune response to the invading virus releases histamine and other mediators of inflammation. These substances stimulate trigeminal nerve endings, transmitting an impulse that triggers sneezing through the activation of sneeze centers in the brainstem. Coughing is another specialized reflex that is commonly triggered by a URI, and it is mediated by the vagus nerve. A cough is an adaptive reaction that can clear the lower airways of secretions and foreign bodies. Initially, the cough of a URI is triggered by inflammatory activation of vagal nerve endings, and it is generally nonproductive. Eventually, as the infection spreads to the lower airways, the cough can become productive. The muscular action sequences of coughing are triggered by a pattern generator in the brainstem as a result of vagal activation. Coughing may persist for 3 weeks or longer after the resolution of other URI symptoms because the vagal nerve endings become hyperreactive and can be triggered by otherwise innocuous stimuli, such as the sudden influx of cold air. Coughing is the most common precipitant of a primary care consultation.19

The production of fever by pyrogens, which is one of the most common features of the sickness response, features a remarkable metabolic mechanism (see Figure 15). Circulating pyrogens activate brain endothelial cells and perivascular macrophages and induce them to secrete PE2.20 Pe2 diffuses within the brain and activates the medial preoptic nucleus of the hypothalamus, which regulates temperature in mammals.20 The medial preoptic nucleus then triggers a cascade of activation that culminates in the stimulation of selected fibers within the inter-mediolateral column, which provides sympathetic innervation to brown fat. Brown fat cells can produce a unique peptide called uncoupling protein 1 (UCP1), whose expression is mediated by activation of beta-1 and beta-3 adrenergic receptors by norepinephrine.21 UCP1 permeabilizes the mitochondrial inner membrane to protons, which uncouples the respiratory chain and oxidative phosphorylation system from mitochondrial metabolism. This results in the generation of heat rather than ATP as a byproduct of mitochondrial activity. Brown adipocytes can increase their metabolic rate 10-fold from baseline and are able to produce about 3 nW of heat per cell, which is about 300 w/kg of tissue,21 or the heat equivalent of three 100 watt light bulbs burning continuously.

Mechanism of Heat Generation by Brown Fat. Brown Fat Cells Can Produce a Unique Peptide Called Uncoupling Protein 1 (UCP1), Whose Expression Is Mediated by Activation of Beta-1 and Beta-3 Adrenergic Receptors by Norepinephrine. UCP1 Permeabilizes the Mitochondrial Inner Membrane to Protons, Which Uncouples the Respiratory Chain and Oxidative Phosphorylation System from Mitochondrial Metabolism. This Results in the Generation of Heat Rather than Atp as a Byproduct of Mitochondrial Activity. A Note from the Editors: All Illustrations in This Article Have Been Created by George I. Viamontes, MD, PhD, for Specific Use in This Issue of Psychiatric Annals.

Figure 15. Mechanism of Heat Generation by Brown Fat. Brown Fat Cells Can Produce a Unique Peptide Called Uncoupling Protein 1 (UCP1), Whose Expression Is Mediated by Activation of Beta-1 and Beta-3 Adrenergic Receptors by Norepinephrine. UCP1 Permeabilizes the Mitochondrial Inner Membrane to Protons, Which Uncouples the Respiratory Chain and Oxidative Phosphorylation System from Mitochondrial Metabolism. This Results in the Generation of Heat Rather than Atp as a Byproduct of Mitochondrial Activity. A Note from the Editors: All Illustrations in This Article Have Been Created by George I. Viamontes, MD, PhD, for Specific Use in This Issue of Psychiatric Annals.

As the discussion above illustrates, sickness responses are usually complex and are induced by multiple mechanisms. However, there is a common, unifying theme in that they represent genetically programmed reactions to detected immune responses that are coordinated by the brain.

Cytokines and Depression

Cytokine-induced sickness behavior bears many similarities to the symptomatology that characterizes major depressive disorder (MDD). In animal models, inflammatory cytokines can cause lasting symptoms, such as decreased drinking of sweet liquids, which do not resolve even after inflammation has abated. Under certain circumstances, these symptoms can be diminished by antidepressant treatment.7 In humans, IFN-alpha is used for the treatment of several disorders, including hepatitis C, malignant melanoma, multiple sclerosis, and chronic myelogenous leukemia. Other inflammatory cytokines that have been used in cancer therapy, although less frequently, include IL-1, IL-2, and TNF-alpha. Administration of these substances frequently causes symptoms to emerge that are similar to those of MDD.

Treatment with IFN-alpha, for example, causes diagnosable MDD in 30% to 50% of treated individuals, in a dose-dependent manner.6 Some of these symptoms are responsive to antidepressant treatment. Possible mechanisms for the induction of depressive symptoms by cytokines may include a fall in plasma tryptophan levels (with concomitant decrease in serotonin because tryptophan is a necessary serotonin precursor) that is frequently observed in conditions of chronic immune system hyperactivity. This has been linked to activation of one of the major enzymes that metabolize tryptophan, called indoleamine 2,3 dioxygenase (IDO).7 Activation of IDO also generates metabolites that affect N-methyl-D-aspartate (NMDA) neurotransmission.7 Other possible mechanisms that may link chronic immune responses to depression may include enhanced serotonin turnover and the chronic production of corticotropin releasing factor (CRF) and vasopressin, which are known to induce symptoms of depression.7

Functional imaging of individuals with cytokine-induced depression have demonstrated decreased metabolism in the dorsal prefrontal cortex and increased metabolism in the basal ganglia and cerebellum.7 Increased metabolism in the left putamen and nucleus accumbens was significantly correlated with anergia and fatigue.7 These regions normally function in the coordination of motivated behaviors and movements. Patients treated with IFN-alpha also demonstrated increased activation of the anterior cingulate cortex during the performance of tasks that required a high level of visuospatial attention, and cingulate activity was specifically connected to error detection.7 Involvement of the cingulate may reflect recruitment of limbic and autonomic regions, with a higher degree of emotional reactivity in the performance of demanding tasks.

Summary

The sickness response is a genetically programmed, adaptive reaction that parallels the activity of the immune system. Its implementation relies on the production of cytokines by immune system cells as they attack pathogens and the detection of these cytokines within the brain. Three main cytokines are believed to mediate sickness responses: IL-1, IL-6, and TNF-alpha. All three cytokines are pyrogenic, or fever-producing. IL-1 and TNF-alpha can cause a gamut of sickness-related symptoms and behaviors, which can include any combination of fever, malaise, fatigue, anhedonia, amplification of pain, sleep disturbances, suppression of appetite and libido, weight loss, dysphoria, social withdrawal, concentration deficits, and cognitive impairment. IL-6 does not seem to cause sickness responses other than fever; however, it appears to amplify the amounts of IL-1 and TNF-alpha within the hippocampus and the intensity of hippocampus-based memory deficits.

Cytokines and other indicators of immune responses are believed to cross the blood-brain barrier to reach the brain through one of four methods:

  1. Active transport across the blood-brain barrier into the brain;

  2. Detection by peripheral sensory nerves with subsequent brain signaling through NST activation;

  3. Detection of bacterial and viral antigens by toll-like receptors on migroglia within the circum-ventricular organs, which have attenuated blood-brain barriers. This leads to the production of cytokines that are believed to diffuse into the brain; and

  4. Activation of IL-1 receptors on brain endothelial cells and perivascular macrophages. This leads to the production of prostaglandin E2, which can mediate febrile responses and possibly other elements of sickness reactions.

Cytokines are able to cause depressive symptoms. In a significant number of cases, chronic exposure to high cytokine levels, as occurs in chronic inflammatory states, can evolve into a full-fledged major depressive disorder. This has been observed in many patients who are receiving exogenous interferon for the treatment of a chronic viral infection or multiple sclerosis.

Although limited sickness responses can serve a number of adaptive functions, chronic or very intense sickness responses can be highly maladaptive. Understanding the mechanisms by which immune reactions trigger sickness responses can be an important asset in managing these conditions, in patient communication, and in discussions with primary care or specialty physicians who are providing medical care for a psychiatric patient.

References

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  2. Schiepers OJG, Wichers MC, Maes M. Cytokines and major depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2005;29:201–217. doi:10.1016/j.pnpbp.2004.11.003 [CrossRef]
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  13. Sparkman NL, Buchanan JB, Heyen JR, Chen J, Beverly JL, Johnson RW. Interleukin-6 facilitates lipopolysaccharide-induced disruption in working memory and expression of other proinflammatory cytokines in hippocampal neuronal cell layers. J Neuro-sci. 2006;26(42):10709–10716.
  14. Koutcherov Y, Huang X-F, Halliday G, Paxinos G. Organization of human brain stem nuclei. In: Paxinos G, Mai JK, eds. The Human Nervous System. 2nd ed. New York, NY: Elsevier Academic Press; 2004:267–320.
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  16. Nieuwenhuys R, Voogd J, Van Huijzen C. The Human Central Nervous System. 4th ed. New York, NY: Springer-Verlag; 2008.
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CME Educational Objectives

  1. Define the major behavioral components of the sickness response that accompany most medical conditions.

  2. Review how the brain and immune system communicate via cytokines and cytokine receptors.

  3. Explain how internally produced or exogenously administered cytokines can precipitate symptoms of major depressive disorder.

Authors

Claudia T. Viamontes, MD, PhD, is Regional Medical Director, MHNet Behavioral Health, St. Louis, Missouri.

Dr. Viamontes has disclosed no relevant financial relationship.

A note from the editors: All illustrations in this article have been created by George I. Viamontes, MD, PhD, for specific use in this issue of Psychiatric Annals.

Copyright C. Viamontes 2009; copyright is transferred to the publisher; used with permission.

Address correspondence to: Claudia T. Viamontes, MD, PhD, .viamontes@sbcglobal.net

10.3928/00485718-20091124-04

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