| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Published online before print March 10, 2006
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus
1Correspondence: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, 2194 Graves Hall, 333 West 10th Ave., Columbus, OH 43210. E-mail: Sanders.302{at}osu.edu
 |
ABSTRACT |
|---|
Key Words: adrenergic receptor • sympathetic nervous system • norepinephrine • CD4+ T cell • Th1 cell • Th2 cell
|
INTRODUCTION |
|---|
Often, however, discrepancies arise between data obtained in vitro versus data obtained in vivo with regard to the magnitude of the immune response obtained. Classically, in vitro studies have been designed using a reductionist approach, which is helpful when working out mechanisms by which immune cell activity is autoregulated but ignores the multitude of factors exogenous to the immune system itself, which might play a functional role in regulating the level of immune cell activity attained. Such exogenous factors are absent from a culture dish but are released in vivo by nonimmune organ systems to establish the microenvironment in which the immune cells reside and function. With the current emphasis by the National Institutes of Health for a "bench-to-bedside" approach to research, a major challenge has been to take in vitro-generated, immune data and apply the findings to a clinical situation. This means taking data from an autoregulatory system in vitro to one in which multiple regulatory systems are in place that affect cellular activity in most every organ system of the host. Therefore, we need to understand if these nonimmune, cell-derived factors play a role in regulating the level of immunity and if so, the mechanisms by which this regulation occurs and its clinical relevance.
Accumulating evidence over the past few decades has documented that the brain communicates with the periphery via two different pathways, each of which releases factors that function to regulate the magnitude of an innate or adaptive immune response [1 2 3 4 5 ]. The first pathway involves activation of the hypothalamic-pituitary-adrenal axis (HPA) and the release of corticotropin-releasing hormone (CRH) from the hypothalamus, which stimulates the expression and release of adrenocorticotropic (ACTH) from the pituitary, inducing the secretion of corticosteroids from the adrenal cortex. All of the HPA hormones have been reported to affect immune cell activity directly (reviewed in ref. [6 ]). The second pathway involves activation of the sympathetic nervous system (SNS) and the release of the catecholamine norepinephrine, neuropeptide Y, and endogenous opioids such as the enkephalins/endorphins, as well as adenosine and adenosine 5'-triphosphate, which all affect immune cell activity directly (reviewed in ref. [4 ]). In addition, other neuropeptides such as calcitonin gene-related peptide, somatostatin, vasoactive intestinal peptide (VIP), and Substance P are released by other nerve fibers within lymphoid tissue, also to affect immune cell activity (reviewed in refs. [5 , 7 ]). Although each of these molecules likely plays a role in regulating the course of an immune response in vivo, the timing of their release in relation to each other and in relation to the state of immune cell activation, the absence or presence of receptors to bind the molecules, and the immune cell function being regulated by the molecule may each determine the final immune effect that will be expressed. The present review will focus on one aspect of this complex regulatory system, which is external to the immune system itself, namely, the ability of the sympathetic neurotransmitter norepinephrine alone to regulate CD4+ T cell and B cell activity specifically.
The peripheral nervous system is comprised of efferent nerves, which are responsible for transmitting signals from the brain to various organ systems throughout the body. In this way, the brain maintains homeostasis by regulating the level of both somatic functions, such as muscle movement, and autonomic functions, such as heart rate, vascular tone, gastrointestinal motility, and respiratory rate. The autonomic part of the nervous system is further divided into the SNS and parasympathetic nervous system, which secrete the neurotransmitters norepinephrine and acetylcholine, respectively, bound by specific receptors expressed on almost every cell in the body. The SNS is often referred to as the system that precipitates a "fight-or-flight" response, which is an evolutionarily conserved mechanism in vertebrates that functions solely to maintain homeostasis. For example, when a human is fiercely assaulted or experiences the stress associated with an examination or public speaking, the SNS is activated to induce a change in heart rate, respiratory rate, vascular tone, and gastrointestinal motility to increase the likelihood of host survival from the assault or stressful experience. In parallel, it has been proposed that a bacterial or viral insult to the host also activates the SNS to induce a change in immune cell activity to increase the likelihood of host survival.
Accumulating evidence suggests that activated immune cells secrete cytokines that influence central nervous system (CNS) activity and that pathways back to the periphery are activated to regulate the level of immune cell activity and the magnitude of an immune response. In this review, we will summarize and discuss the evidence that the antigen-activated immune system induces activation of the SNS; sympathetic nerve fibers penetrate the parenchyma of primary and secondary lymphoid organs; norepinephrine is released from these sympathetic nerve terminals after antigenic challenge; immune cells express a specific receptor that binds norepinephrine; and stimulation of this receptor by norepinephrine regulates the level of immune cell functional activity. Such evidence suggests that norepinephrine stimulates the ß2 adrenergic receptor (ß2AR) during the course of an immune response to play a role in disease prevention but also may play a role in disease development and progression if a disruption occurs in any part of the bidirectional communication pathway.
|
FINDINGS THAT INDICATED AN ASSOCIATION EXISTED AMONG THE BRAIN, BEHAVIOR, AND IMMUNITY |
|---|
However, for this association to occur, a mechanism would need to exist by which the brain perceived the peripheral environment, created a behavioral response, and sent a message back to the periphery to affect immunity. Such a mechanism remained unknown, although it was proposed that the effector mechanism involved one or both of two pathways used by the brain to communicate with the periphery. One pathway involved activation of the HPA, and the other involved activation of the SNS (Fig. 1 ). Activation of the HPA causes the secretion of a cascade of mediators, such as CRH and ACTH, which have been described above, culminating in the secretion of corticosteroids from the adrenal cortex. In contrast, activation of the SNS involves the release of the neurotransmitter norepinephrine from nerve terminals in the close vicinity of cells within most organ systems. Thus, mechanisms were indeed in place by which the brain could communicate with the periphery. However, the question remained as to whether these pathways from the brain, which could be activated by an environment that promoted stress and fatigue, could also be activated by antigen. The question also remained as to whether the biological mediators released by the HPA and SNS could affect the ability of cells of the immune system to function optimally.
|
|
MECHANISMS INVOLVED IN MEDIATING THE BIDIRECTIONAL COMMUNICATION |
|---|
 TOPABSTRACTINTRODUCTIONFINDINGS THAT INDICATED AN... MECHANISMS INVOLVED IN MEDIATING... EVIDENCE FOR AR EXPRESSION...REGULATION OF CD4+T CELL...REGULATION OF B CELL-MEDIATED...CONCLUSIONREFERENCES |
|---|
The parenchyma of primary and secondary lymphoid organs were found to be innervated with sympathetic nerve fibers within the bone marrow, thymus, splenic white pulp, and lymph nodes [27 28 29 ]. In addition, nerve endings were found to terminate in the parenchyma of secondary lymphoid tissues (Fig. 2 ), primarily within the areas adjacent to CD4+ T cells, as well as in the vicinity of macrophages and B cells within the marginal sinus [30 , 31 ]. The level of norepinephrine released at a nerve terminal was found to reach a local concentration of 1 x 10–5 to 5 x 10–4 M [32 ]. This high concentration of norepinephrine dissipated quickly as norepinephrine was taken back into the nerve terminal or degraded by enzymes, explaining why immune cells needed to be located within the direct vicinity of a nerve terminal to be affected by norepinephrine and why such high concentrations were required in vitro to exert an effect on immune cell activity. Thus, a mechanism was now in place by which a messenger from the brain, norepinephrine, was released into the lymphoid organ microenvironment in which immune cells were responding to antigen.
|
|
EVIDENCE FOR AR EXPRESSION ON CD4+ T CELLS AND B CELLS |
|---|
or ß subtype. Adrenergic-binding sites expressed on immune cells are saturable, of a high affinity, and almost exclusively of the ß2AR subtype, as determined using radioligand-binding analysis (reviewed extensively in refs. [17
, 39
]). In contrast, AR expression on immune cells appears to be limited to specific innate immune cell subsets and is primarily of the 1AR subtype [40
]. To mediate the neurotransmitter message to the cell interior, stimulation of the ß2AR on an immune cell induces an increase in the intracellular level of cAMP, which activates PKA. As has been discussed above, messages are also being sent to the cell by other molecules being released at the same time as norepinephrine from the sympathetic nerve terminal, e.g., neuropeptide Y and adenosine. In addition, other nerves are releasing various neuropeptides, such as VIP. Although most immune cells express receptors for all of these regulatory molecules, the relevance of two or more receptors being stimulated at the same time on an immune cell activated in vitro or in vivo remains unknown. However, as we accumulate more data in vitro about when the neuroreceptors are expressed in relation to the state of immune cell activation, we will be better prepared to interpret the in vivo data as it is generated. This situation is similar to an immune reaction taking place in vivo in which multiple cytokines and inflammatory mediators impinge on cell activity, some at the same time and some after the appropriate receptors are expressed. Without the in vitro data to indicate the ability of one cytokine or mediator to stimulate a receptor and affect a given immune cell activity, interpretation of the in vivo data would likely be impossible. We think that the same possibility is applicable to the study of the role played by neurotransmitters and neuropeptides in regulating immune activity. As more data accumulate about the effect exerted by each individual neurotransmitter and neuropeptide on immune cell activity, we will be better prepared to address questions concerning their regulatory role in vivo. It is important to note that the molecules released by the nervous system do not activate or impart any new activity to an immune cell but instead, regulate the magnitude of the activity induced by the immune system itself.
B cells were found to express the ß2AR at a level twice as high as CD4+ T cells (reviewed extensively in refs. [17 , 39 ]). As subsets of CD4+ T cells were identified, i.e, naive, Th1, and Th2 cells, it became important to determine if each subset expressed the ß2AR to a similar level. As radioligand-binding analysis required that a large number of cells be used, it was difficult to perform the analysis on a purified population of naive CD4+ T cells. Thus, reverse transcriptase-polymerase chain reaction analysis was used to show that murine naive CD4+ T cells expressed mRNA for the ß2AR [41 ] and that exposure to a ß2AR agonist induced a functional change in naive T cell activity [41 , 42 ].
Radioligand-binding analysis was used to show that clones of murine Th1 cells expressed the ß2AR and accumulated cAMP upon exposure to a ß2AR agonist but that clones of Th2 cells did not [43 ]. The latter finding was suggested earlier from studies using different CD4+ T cell lines, which had not been characterized as Th1 or Th2. These cell lines were found to differentially accumulate cAMP in response to a ß2AR agonist, although all cell lines accumulated cAMP in response to other ligands such as histamine or prostaglandin E2(PGE2) [44 , 45 ]. This finding suggested that these cell lines differentially expressed the ß2AR and that their failure to accumulate cAMP following exposure to a ß2AR agonist was not a result of a lack of the biochemical machinery needed to generate it. The level of ß2AR expression on primary Th1 and Th2 cells generated from a naive CD4+ T cell precursor remains unknown, although preliminary data appear to confirm similar findings to those found with clones (V. M. Sanders et al., unpublished results). When CD4+ T cell subsets were activated, the level of ß2AR expression increased [46 47 48 49 50 ] or decreased [47 , 51 ] but remained undetectable on murine Th2 cells [49 ]. The mechanism responsible for mediating the differential expression of the ß2AR by these two effector cell subsets remains unknown, although new findings indicate that epigenetic mechanisms may be involved (V. M. Sanders et al., unpublished results). The finding of differential ß2AR expression by Th1 and Th2 cells has been difficult to confirm using human cells, as human CD4+ T cells do not polarize their cytokine profiles as clearly as mouse cells under Th1- and Th2-polarizing conditions [52 53 54 ]. Nonetheless, reports have confirmed [55 ] or refuted [56 , 57 ] the idea of differential ß2AR expression by human Th1 and Th2 cells.
Taken together, the data indicate that naive CD4+ cells, Th1 cells, and B cells express the ß2AR subtype and that although murine Th2 cells appear not to express a detectable level of the ß2AR, the jury is still out as to whether this holds true for human Th2 cells. Thus, the presence of a functional ß2AR on immune T and B cells confirms that these cells express the ear to hear the norepinephrine message delivered from the brain (Fig. 2) .
|
REGULATION OF CD4+T CELL-MEDIATED IMMUNITY BY NOREPINEPHRINE AND ß2AR STIMULATION |
|---|
B activation via a mechanism that involved the stabilization of its inhibitor protein, IB, providing a possible molecular mechanism by which IL-2 production and receptor expression were decreased [64
]. In recent years, a few studies have focused on using purified populations of naive CD4+ T cells and effector Th1 and Th2 cells to determine if norepinephrine (NE) affected each CD4+ T cell subset similarly (Fig. 3 ). When a purified population of naive CD4+ T cells was activated and exposed to norepinephrine, IL-2 secretion was decreased in comparison with unexposed cells, and this decrease was prevented only when a ß2AR antagonist was added to the culture [41 , 42 ]. Taken together, these results suggested that norepinephrine and ß2AR stimulation affected the ability of naive CD4+ T cells to produce the cytokine that would allow for the activated cells to expand in number. However, the decrease in IL-2 was usually no greater than 50% of the control level, suggesting that a level of IL-2 might remain, which would be sufficient to expand a population of activated T cells. Nonetheless, as a result of this possibility, exogenous IL-2 was added to cultures in the following studies, which addressed whether naive T cell differentiation into a Th1 or Th2 cell was affected by norepinephrine and ß2AR stimulation.
|
per cell upon reactivation when norepinephrine was present in the naive CD4+ T cell culture [41
]. It is important that the effect induced on the amount of IFN- produced by the resulting Th1 cells occurred without a change in the number of Th1 cells that developed and was a result of norepinephrine stimulation of the ß2AR on the naive T cell. It was found that the presence of IL-12 was essential for the ß2AR-induced, enhancing effect to occur, suggesting that the IL-12R and ß2AR signaling pathways in a naive T cell may interact with each other to mediate the enhancing effect. If an antigen-presenting cell (APC) and peptide antigen were used to activate the naive T cell, norepinephrine and ß2AR stimulation had no effect on the level of IL-12 secreted by the APC [41
], a finding that has been refuted using a different mode of APC activation [65
66
67
68
69
]. Thus, a naive CD4+ T cell that is activated in a Th1-polarizing microenvironment appears to respond to norepinephrine and ß2AR stimulation by increasing the level of IFN- secreted by the Th1 cells that develop (Fig. 3)
.
To determine if the generation of an optimal Th1-mediated response in vivo required the presence of norepinephrine, mice were examined, which were genetically deficient for the enzyme dopamine ß-hydroxylase, which is required for the synthesis of norepinephrine. These norepinephrine-deficient mice were more susceptible to the Th1-promoting pathogens Listeria monocytogenes or Mycobacterium tuberculosis and produced significantly less IFN-, suggesting that norepinephrine participated normally in the generation of an optimal, protective Th1 cell-mediated, immune response in vivo [70
]. Whether T cell activity was affected directly by norepinephrine and/or indirectly via an effect of norepinephrine on the level of IL-12 produced by APC or the ability of the APC to migrate to the lymph node [71
, 72
] remains unknown but likely involved a combination of all three possibilities. As far as the effect on naive CD4+ T cell activity is concerned, the in vitro findings suggested that norepinephrine exerts an effect during naive T cell differentiation, which increases the amount of IFN- secreted by the Th1 cells that develop.
For murine Th1 cells, an increase in the intracellular concentration of cAMP was found to decrease the level of IL-2 [73
74
75
] and IFN- [75
] produced. Likewise, exposure of Th1 cells to norepinephrine or a ß2AR-selective agonist decreased the level of IL-2 and IFN- produced [43
] but only when the ß2AR was stimulated before TCR activation. When the ß2AR was stimulated on a Th1 cell, at the time of or after cell activation, there was no effect or a small increase induced in the level of IFN- produced [49
]. Thus, the effect of norepinephrine and ß2AR stimulation on Th1 cells appeared to be dependent on the time of ß2AR stimulation in relation to the time of cell activation (Fig. 3)
. Future mechanistic studies will need to determine if an association exists between the magnitude of the different effector responses elicited and the biochemical and molecular activities affected by cAMP during the different stages of cell activation. For example, a cAMP increase after early ß2AR stimulation may affect the threshold for TCR activation [76
] or NF-B dissociation from IB [64
], and later, ß2AR stimulation may affect the level of transcription factor expression and/or binding to regulatory regions of DNA.
Analysis of T cells from human patients and animal models of RA showed a bias toward a Th1-like cell phenotype with a higher frequency of IFN--secreting CD4+ T cells [77
, 78
]. Given this association between RA and the level of Th1 cell immunity, four other findings suggested that an association might exist among SNS activity, ß2AR stimulation of naive T and/or Th1 cells, and the development and/or progression of RA. First, an increase in disease activity among RA patients was associated with an increase in the level of stress experienced by these patients [79
, 80
], suggesting that a stress-induced increase in norepinephrine release might exacerbate naive and/or Th1 cell activity. Second, single nucleotide polymorphisms have been found to be associated with the ß2AR expressed by cells of RA patients [81
], suggesting that a change in the ß2AR structure on a naive T and/or Th1 cell may heighten the level of cell responsiveness to norepinephrine. Third, administration of a ß2AR antagonist [82
] or a ß2AR agonist [83
] prior to or during the development of arthritis inhibits or exacerbates disease pathology, suggesting that if norepinephrine stimulates the ß2AR on a naive T and/or Th1 cell, this might play a role to change the level of IFN- produced. As with the in vitro findings, the latter in vivo effects were found to depend on the time when norepinephrine was released during the course of the disease; i.e., early exposure may have increased naive T cell differentiation into Th1 cells, which secreted increased IFN-, as opposed to late exposure, which may have increased the level of IFN- produced by preactivated T cells [84
]. Fourth, ß2AR stimulation on human peripheral blood mononuclear cells from RA patients induced a higher level of intracellular cAMP accumulation when compared with ß2AR stimulation on cells from healthy individuals [85
]. The increase in cAMP in RA cells occurred independently of a change in the level of ß2AR expression but was associated with a 50% decrease in the level of expression and activity of the G-protein-related kinase 2 (GRK2) [85
], an enzyme that phosphorylates the ß2AR to promote desensitization [86
, 87
]. This finding suggested that a lower level of GRK2 in RA cells might allow for a higher level of cAMP to be generated intracellularly following exposure to a ß2AR agonist, as the receptor would not be desensitized. Although the specific immune cell type associated with this change in GRK2 was not determined, cells from rodents with adjuvant-induced arthritis, which expressed less GRK2, were identified as CD4+ T cells specifically [88
]. Collectively, these four findings suggested that the increased responsiveness of cells from RA patients or animals to ß2AR stimulation following norepinephrine exposure might exacerbate the IFN- response and promote conditions for RA development and progression. Therefore, norepinephrine, which normally participates in a CD4+ T cell response to maintain homeostasis by enhancing the baseline immune cell-regulated IFN- response, may cross over into disease development when the regulatory mechanisms controlling SNS or ß2AR activity are changed.
The role played by norepinephrine in regulating a Th2 cell-mediated response is less clear. An increase in cAMP was found to have no effect, inhibit, or enhance the level of IL-4 and IL-5 produced by Th2 cells (reviewed extensively in refs. [17 , 39 ]). However, it appeared that norepinephrine had no effect on Th2 cell activity, likely, as the Th2 cell does not appear to express the ß2AR [43 ]. Furthermore, when mice were depleted of norepinephrine and immunized with KLH, splenic cells produced significantly higher levels of IL-4 following reactivation in vitro when compared with cells isolated from norepinephrine-intact controls [89 ], suggesting that norepinephrine played a role in the development of a Th2 response as opposed to effector cell development. Alternatively, this effect on Th2 cell function might be mediated indirectly by a direct effect of ß2AR stimulation on macrophages or DC. Support for this latter possibility comes from a report about mice receiving a thermal burn injury. These mice had an elevated level of plasma norepinephrine, which was associated with increased chemokine production by macrophages that shifted the effector cell profile to a predominant Th2-like response [90 , 91 ]. Using such a mechanism, norepinephrine may have increased susceptibility to infection after a thermal burn injury by increasing the accumulation of anti-inflammatory Th2 cells at the site of injury, as opposed to the accumulation of inflammatory Th1 cells, as has been described previously [92 ].
The release of IFN- by Th1 cells is critical for maintaining our resistance to infectious organisms, as well as for controlling our susceptibility/resistance to autoimmune disease development and progression. If the level of IFN- produced by a Th1 cell is affected by norepinephrine stimulation of the ß2AR on a naive T cell or an effector T cell itself, then the mechanism responsible for this effect needs to be understood. It will be informative to test whether ß2AR stimulation on naive CD4+ T cells isolated from healthy individuals induces the generation of Th1 cells, which secrete more IFN-, thus mimicking the finding using naive T cells isolated from mice [41
]. Much remains unknown about the mechanism by which norepinephrine and ß2AR stimulation affect CD4+ T cell immunity and more importantly, how dysregulation of this homeostatic mechanism for immune regulation may contribute to the development and progression of T cell-mediated diseases. An understanding of these regulatory mechanisms may lead to the design of novel clinical strategies to prevent the development/progression of Th1 cell-mediated autoimmune diseases or improve vaccination protocols aimed at promoting Th1 cell immunity.
|
REGULATION OF B CELL-MEDIATED IMMUNITY BY NOREPINEPHRINE AND ß2AR STIMULATION |
|---|
|
TOPABSTRACTINTRODUCTIONFINDINGS THAT INDICATED AN...MECHANISMS INVOLVED IN MEDIATING...EVIDENCE FOR AR EXPRESSION...REGULATION OF CD4+T CELL...REGULATION OF B CELL-MEDIATED...CONCLUSIONREFERENCES |
|---|
The role played by norepinephrine in regulating the magnitude of a murine antibody response in vivo was suggested from the results of a number of studies conducted in norepinephrine-depleted mice. Initial findings were confusing, showing that a T cell-dependent IgM or IgG response was increased or decreased after norepinephrine depletion (reviewed extensively in refs. [17 , 95 ]). One reason for the disparate results may have been that the drug used for norepinephrine depletion caused an initial burst of norepinephrine to be released, possibly exerting an effect on resident immune cells before a norepinephrine-depleted state was obtained. To address this possibility, severe combined immunodeficient mice were depleted of norepinephrine prior to reconstitution with antigen-specific Th2 cells and B cells and then immunized with the specific antigen [96 ]. A lower serum level of antigen-specific IgM and IgG1 was measured in these mice when compared with norepinephrine-intact, reconstituted mice, an effect that was prevented by the administration of a ß2AR-selective agonist at the time of immunization. This finding indicated that norepinephrine stimulated the ß2AR during the early stages of a Th2 cell-dependent antibody response to allow for an optimal level of IgM and IgG1 to be produced. When secondary immunization of these mice occurred at a later time when norepinephrine levels had returned to baseline, there was a delay in serum levels of antigen-specific IgG1 reaching a control level, suggesting that the early absence of norepinephrine also caused a delay in attainment of an optimal memory response. Although norepinephrine depletion did not alter T and B cell localization in the spleen, follicular expansion and germinal center formation were compromised after primary antigen administration when compared with that in norepinephrine-intact controls. These findings in vivo suggested that norepinephrine participated in regulating the level of a Th2 cell-dependent IgM and IgG1 response by targeting the B cell, as the Th2 cell did not express the ß2AR. Furthermore, the data suggested that norepinephrine was part of the normal antibody response in vivo and that in vitro culture conditions in the absence of norepinephrine would reflect antibody responses involving endogenous immune cell regulation alone (Fig. 4 ).
|
Using a model system of murine B cells stimulated with LPS and IL-4, data showed that PGE2 stimulation, which will increase the intracellular concentration of cAMP, increased the level of germ-line 1 transcription and the number of IgG1-secreting B cells [99
]. In contrast, using a model system of purified, splenic, naive B cells cultured in the presence of CD40 ligand (CD40L)/Sf9 cells and IL-4, data showed that ß2AR stimulation increased the amount of IgG1 produced per B cell, without affecting the number of cells that switched to produce IgG1 or the number of IgG1-secreting cells, when compared with B cells not exposed to ß2AR stimulation [98
, 100
, 101
]. The discrepancy between these two findings with regard to CSR may be a result of the different B cell-activating stimuli used, i.e., LPS and PGE2 versus CD40L and ß2AR. Using CD40L-induced activation, ß2AR stimulation has been reported to induce the enhancing effect on the amount of IgG1 produced by a B cell in two ways. First, the ß2AR directly activated a PKA-dependent signaling pathway [98
], and second, the ß2AR directly up-regulated the expression of an important costimulatory molecule, CD86 [100
, 102
], which when stimulated by an anti-CD86 antibody or CD28-Ig, activated another distinct signaling pathway in the B cell that also regulated the amount of IgG1 produced per cell. Thus, ß2AR stimulation on a B cell uses a direct and indirect mechanism to regulate the level of an IgG1 response, and this has been confirmed using B cells from wild-type and ß2AR-deficient mice.
More specifically, the coactivator protein, octamer (Oct) coactivator from B cells (OCA-B), was up-regulated by ß2AR activation of PKA and subsequent phosphorylation of cAMP response element-binding protein (CREB) [101
]. Using chromatin immunoprecipitation, the increase in OCA-B was associated with a higher level of OCA-B binding to the 3'-IgH enhancer region of the IgH locus [101
], suggesting that OCA-B was binding to a transcription factor that activated 3'-IgH enhancer activity directly. In parallel, CD86 stimulation increased the level of expression of the B cell-specific transcription factor Oct-2 in a NF-B- and PKC-dependent manner and was associated with an increase in Oct-2 binding to the 3'-IgH enhancer [101
]. Taken together, these findings suggested that signaling pathways activated in a B cell through stimulation of an immunoreceptor (CD86) and a neuroreceptor (ß2AR) converged to regulate the magnitude of an IgG1 response (Fig. 5
). For a more detailed description of how the study of the ß2AR-induced enhancing effect on the IgG1 response led to the discovery of the signaling pathway activated by CD86 [please refer to the review in ref. 103
].
|
-dependent IgG2a [70
], suggesting that norepinephrine was necessary for the development of Th1 cell immunity and subsequent IgG2a production. Another study reported that stress diminished the IgG2a response and that this diminution appeared to result from a stress-induced depletion of splenic norepinephrine, which was reversed pharmacologically [104
], again suggesting that norepinephrine exerted an enhancing effect on IgG2a production. In addition, mice exposed to a virus at the time of restraint stress had a decreased number of virus-specific IgM-, IgG1-, and IgG2a-secreting cells in all lymphoid organs, except the lymph nodes, where the number of antibody-secreting cells was increased in a ß2AR-dependent manner [105
]. Thus, norepinephrine appears to play a role in regulating the level of an IgG2a response, but the cell type affected (Th1 cell and/or B cell) is less clear than it is for a Th2 cell-dependent IgG1 response.
The recent results with IgG1 suggest strongly that norepinephrine participates in regulating the magnitude of an antibody response via a unique mechanism that does not affect CSR but affects the level of antibody produced by the antibody-secreting cell. Understanding these mechanisms further, particularly the proximal signaling pathway used by CD86 to activate NF-B, will provide a molecular basis for the role of norepinephrine and ß2AR stimulation in regulating the Th2 cell-dependent antibody response, thus providing a defined target for therapeutics and a potential mechanism for increasing the efficacy of vaccination protocols. The findings will also provide a better understanding of the mechanisms by which the release of antigen- and stress-induced norepinephrine affects immune responsiveness in vivo.
|
CONCLUSION |
|---|
We propose that this scenario between in vitro and in vivo findings holds true for every immune response studied. Thus, the magnitude of a normal immune response in vivo may be determined by the level of norepinephrine released after antigen, the level of SNS innervation of lymphoid organs, and/or the level of ß2AR expression on immune cells. In this way, an insult to the host by an antigen will activate immune cells to produce cytokines that communicate with the brain or peripheral nervous system, which in turn, activate the SNS to release norepinphrine to regulate the activity of the immune cells responding to the insult. However, as discussed in this review using the clinical disease, RA, and as discussed elsewhere for stress and depression [106 ], such clinical conditions might precipitate a change in some facet of homeostatic regulation by norepinephrine, which will affect immune cell activity positively or negatively. For example, if the sympathetic neurotransmitter norepinephrine plays a role in modulating immune function, an age-related decline in lymphoid tissue innervation [107 108 109 ] may contribute to the age-associated increase in the incidence of autoimmunity, cancer, and susceptibility to infection [110 111 112 ]. Conversely, if cytokines play a role in modulating nervous system function, then an age-related decline in immune function may contribute to the age-associated increase in behavioral and cognitive dysfunctions [113 ]. Although these possibilities are speculative, they do emphasize the need for a better understanding of the mechanisms by which one system influences the functioning of the other.
Received November 2, 2005; revised January 13, 2006; accepted January 17, 2006.
|
REFERENCES |
|---|
-1 adrenergic receptors in the immune system Brain Behav. Immun. 16,799-807[CrossRef][Medline] production by Th1 cells generated from naive CD4(+) T cells exposed to norepinephrine J. Immunol. 166,232-240 adrenoceptor activation in modulating the murine primary antibody response in vitro J. Pharmacol. Exp. Ther. 232,395-400
