The effects of catecholamines on the immune system in particularly the effects they have on T-helper lymphocytes
The immune system is a vast and versatile collection of cells within the human body. These cells prevent the spread of infections, viruses and bacteria throughout the entire body and help in maintaining a healthy lifestyle. The immune system can be affected in many ways with a variety of substances up or down regulating its ability to function correctly. Catecholamines which are found in varying quantities are one such substance.
Catecholamines are commonly known as the “flight or fright” hormone and are chemical compounds derived from the amino acid tyrosine (Elenkov et al, 2000) and act as hormones and neurotransmitters. Catecholamine is a collective name for the three main molecules known as adrenaline, noradrenaline and dopamine. The stimulation of the central nervous system results in the direct activation of its two major outflow systems which subsequently regulate the release of catecholamines and cortisol. These 2 systems, the hypothalamic-pituitary-adrenal axis (HPA-axis) and the sympathetic nervous system (SNS) (Smith, 2003), can activate one another and are often triggered by circulating cytokines within the blood. The more important of the two systems, SNS, regulates catecholamines and excitation causes the release of the two most important compounds adrenaline from the adrenal medulla and noradrenaline from the sympathetic nerve terminals. This produces an elevated arterial plasma concentration of both hormones which is thought to occur in a linear fashion with the duration and intensity of exercise performed (Pedersen and Hoffman-Goetz, 2000).
Catecholamines released due to the excitation of the SNS affect lymphocytes, monocytes, macrophages and granulocytes each to a varying degree. These changes in immune cells subsequently cause a change in cellular trafficking, proliferation, antibody production and cytokine secretion and activity (Padgett and Glaser, 2003). When released adrenaline and noradrenaline circulate within the blood and express their effects on immune species which express adrenergic receptors on their surface (Pedersen and Hoffman-Goetz, 2000). These receptors are known as α- and β- receptors. The majority of immune cells (T and B lymphocytes, NK cells, macrophages and neutrophils) which are vital to immune function express β2-adrenergic receptors on their surface. Without the presence of the receptor many immune cells would not be able to instigate an immune reaction and therefore during times of heightened adrenaline and noradrenaline immune function would not be as effective.
Adrenaline and noradrenaline are known to have either direct or indirect effects on the redistribution of immune cells during exercise and stress. They indirectly cause mobilisation of immune cells by causing demargination of lymphocytes from the vascular endothelium. This effect is brought about by the release of noradrenaline from the SNS which causes an increase in heart rate and blood pressure which consequently causes an increase in shear stress through the blood vessel (Blannin, 2006). When adrenaline is released from the adrenal medulla it acts directly on the immune cells themselves. Adrenaline binds to the β2-adrengenic receptors on many lymphocytes subclasses and directly leads to alteration in its cellular function (Blannin, 2006).
It was previously thought that catecholamines had immunosuppressive effects and during physical or psychological stress the increase in these substances blunted the body's ability to combat infection. Previous literature from the 1970s and 1980s (Calcagni and Elenkov, 2006) has provided evidence that catecholamines cause lymphocytopenia, inhibit lymphocyte cytotoxicity and decrease the secretion of certain cytokines. However more recent literature contradicts this, stating that catecholamine could influence the immune system in a positive way (Padgett and Glaser, 2003). Variations in the concentration of circulating adrenaline and noradrenaline may appear to play a vital role in the re-distribution of circulating lymphocytes. Increases in both hormones can occur rapidly and could cause an increase in leukocytosis via demargination of lymphocytes from the vascular endothelial wall (Bishop, 2006). It is also thought that adrenaline and noradrenaline may mediate the acquired immune system though the process of selectively inhibiting T helper 1 lymphocytes (TH1) and potentiating T helper 2 lymphocytes (Th2) which would subsequently affect their cytokine production (Smith 2003). Alterations of the acquired immune system in this way would lead to an anti-inflammatory response within the body (Calcagni & Elenkov, 2006) seeming beneficial to health.
T lymphocytes are particularly important within the immune system as they are required for the thymus dependent humoral response within the body (Noelle and Snow, 1992) and are part of acquired immunity. T lymphocytes mature within the thymus and assist other white blood cells such as B lymphocytes and NK cells in immunological processes (Zinkernagel et al, 1978). They are recognised by the presence of CD4 on their cell surface and are frequently referred to as CD4+ cells; they also express special receptors on their cell surface known as T cell receptors (TCR). T lymphocytes are split into cytotoxic T cells (Smith, 2003) and T helper (TH) cells (Wahle et al, 2006) of which both are part of cell-mediated immunity. TH cells have further been split into two distinct functional subsets (O'Leary, 1990) which are particularly important in establishing and maximizing the capabilities of the immune system. Literature concludes (Smith, 2003; Elenkov et al, 2000) that both subsets originate from a naïve CD4+ TH0 cell and when activated by cytokines, either interleukin (IL) -12 or IL-4, differentiate into TH1 and TH2 cells respectively (see figure 1.). TH1 lymphocytes are predominately involved in functions of innate cell-mediated immunity (Padgett and Glaser, 2003) with the response of this cell being caused by the release of cytokines IL-2 and interferon (IFN) -γ. TH2 lymphocytes on the other hand are involved in the humoral (antibody-mediated) immunity with the response of this cell being caused by the release of cytokines IL-4, IL-5 and IL-10 (Noelle and Snow, 1992).
TH1 and TH2 lymphocytes are thought to be involved in counter-regulation, that is when the body is responding to stress or trauma there is a tip in the favour of one of the subsets (Smith, 2003). Therefore when one pathway is activated the other is potentially inhibited, this being possibly due to the conflicting effects of the TH1 lymphocytes causing pro-inflammatory cytokine production and the TH2 lymphocyte causing anti-inflammatory cytokine production (Calcagni and Elenkov, 2006). The cytokines within the blood often serve as a marker to allow the up-regulation of the different TH subsets to be determined (Smith, 2003).
TH lymphocytes are involved in the process of antigen recognition through their TCRs which recognise specific peptide-MHC complexes presented on antigen presenting cells (APCs), of which most are B cells (Takahama, 2006). When TH2 lymphocytes attach to the MCH-II complexes they cause activation of B cells (Noelle and Snow, 1992). This subsequently allows the B lymphocytes to grow, differentiate and proliferate into soluble factors, antibodies, which are able to protect against infection. Catecholamines released via the activation of the SNS or which are infused by injection to mimic the effects of exercise have been seen as having robust effects on CD4+ TH lymphocytes; mainly producing lymphocyte proliferation (Moynihan and Santiago, 2007). It is also thought that acute elevation of these catecholamines can affect the migration of lymphocytes, enabling them to leave the lymphoid organs and enter the circulation (Carlson et al, 1996).
Elenkov et al (2000) suggest that the main effect of catecholamines on the TH subsets is the control of the varying cytokines that they release or that cause activation of them. IL-12 production from macrophages and other APCs is thought to have the most influential effect on TH1 activity, causing a considerable increase in its activity. It was proposed by Elenkov et al (2000) that the release of IL-12 is inhibited by adrenaline and noradrenaline through the binding of these hormones to β-adrenergic receptors on the APCs. This provides strong evidence for the shift of TH1 towards TH2 activity. In keeping with this is a study by Koff et al (1986) who previously suggested that catecholamines can also suppress the release of IL-1 another powerful pro-inflammatory cytokine released from macrophages and the endothelium. This again inferred the down regulation of TH1 activity within the blood.
An earlier paper by Elenkov et al (1996) provides more supportive evidence for the down regulation of TH1 activity. They state that catecholamines, while suppressing the release of pro-inflammatory cytokines favour the release of anti-inflammatory cytokines, consequently up-regulating TH2 activity. Also providing evidence that IL-10 an abundant and potent anti-inflammatory cytokine is released by APCs and TH2 lymphocytes and that this release is augmented by noradrenaline and adrenaline. However it is also stated that another cytokine, IL-6, which is thought to be regulated by catecholamines, can cause increased expression of both TH1 and TH2 activity. This provides evidence against the well observed counter-balance theory of TH1 and TH2 activity and therefore contradicts the majority of literature. Elenkov et al (1996) do however suggest that the effects of IL-6 are predominantly anti-inflammatory rather than inflammatory, perhaps indicating that in fact there is a shift towards TH2 activity.
Catecholamines exert their effects through binding to β-adrenergic receptors on a cell surface. Therefore the number of receptors a cell expresses could determine the degree to which the cell can react to the catecholamine. Mohede et al (1996) have provided research that suggests that β-adrenergic receptors are mainly expressed on TH1 lymphocytes and this could therefore explain the effect we see of the mainly TH1 activity being inhibited. Consequently it could be presumed that the effects of adrenaline and noradrenaline cannot directly affect TH2 activity as these cells express lower quantities of the β-adrenergic receptors. Elenkov et al (2000) state that when lymphocytes are exposed to noradrenaline which stimulates its effect though β-adrenergic receptors there is an increase in antibody production. This may be due to noradrenaline causing an enhanced frequency of B cells to differentiate into antibody secreting cells. This enhanced release of antibodies further supports the reality that catecholamines, via the β-adrenergic receptors, selectively inhibit cellular immunity and improve humoral immunity.
Catecholamines are commonly known as stress hormones and therefore are regularly released during physical and psychological stress (O'Leary, 1990). Therefore when under a stressful situation our immune function can change depending on the level of circulating adrenaline or noradrenaline within the system. The length of the exercise or psychological stress could play a key role in the level of reaction seen. It is also thought that the number of β-adrenergic receptors that are expressed on the lymphocyte population, in particular the TH subsets, could determine the degree to which catecholamines can mobilise these immune cells (Pedersen and Hoffman-Goetz, 2000).
Much research has been carried out to evaluate the level of stress and circulating catecholamines within the population with regards to immune function. A study by Kiecolt-Glaser et al (1987) found that family members looking after relatives with Alzheimer's disease, and who were therefore under chronic stress, had a lower percentage of total T lymphocytes and in particular in TH cells. This was in keeping with Arnetz et al (1987) who established that prolonged stress due to unemployment was a factor in reduced phytohemagglutinin lymphocyte response in women. These studies would therefore suggest that stress causes down regulation of TH cells in general, not specifically the TH1 subset. These results are not in keeping with the literature. During these periods of prolonged stress we would assume to see severe heightened levels of adrenaline and noradrenaline within the blood and would therefore expect to see the up regulation of TH2 activity. With this not being the case and both TH subsets being suppressed it would suggest that catecholamines though realised in stress may only be prevalent in acute rather than prolonged physical or psychological stress and their affect may be attenuated rather than augmented in this situation.
In support of this idea is data on acute physical stress, which appears to have contradictory findings compared to those for chronic stress. Bishop (2006) summaries that acute exercise causes a biphasic response in the number of circulating lymphocytes found within the blood. Numerous studies have stated that during exercise lymphocytosis takes place, leading to an increased number of lymphocytes. However during the recovery period, numbers drastically reduce with a decline being particularly evident for T lymphocytes and to lesser extent B lymphocytes. This biphasic response is thought to be highly dependent upon catecholamines which become elevated during exercise but decrease post exercise, when the body is no longer under stress. Increases have been shown to cause a redistribution of blood flow which bring about shear stress on endothelial cells and result in the demargination of lymphocytes. Declines in catecholamines have the opposite effect allowing lymphocytes to remargination to endothelial walls. Therefore the decline in lymphocytes due to remargination, in particular T lymphocytes, post exercise might explain the body's increased susceptibility to infection.
Landman et al (1984) found through the use of acute physical and psychological stress that changes in leukocyte concentration were paramount. Physical stress caused an elevation in lymphocyte subtypes, in particular increasing suppressor T cells compared to TH cells. In line with the increase of lymphocytes during the physical stress task there was a parallel increase in both adrenaline and noradrenaline shown through an increased activation of α- and β-adrenergic receptors. With the most pronounced changes in the immune system being seen in B and T cells it could be concluded that the cellular changes seen may be attributed to the direct action of adrenaline upon the β-adrenergic receptors which are of high density on theses lymphoid cells, this would be in line with much of the previously referenced literature.
It is hard to ascertain whether the effects seen in both chronic and acute stress, whether physical or psychological, are beneficial or harmful to heath. The outcomes of both stress types have shown a decline in T lymphocyte production, in particular TH cell activity, but these have occurred at different time points depending on the type and length of the stress. However, both will lead to a period of susceptability to both viral and bacterial type infections in an individual. One particular condition which is seen during immunosuppression, especially during the recovery period, is known as upper respiratory tract infection (URTI) (Smith, 2003). This period leads to bacteria gaining a foothold within the immune system and poses the risk of severe infection. This immunosuppression period in athletes is often known as the ‘open window' and explains how the immune system becomes compromised in athletes (Smith, 2003).
On the other hand exercise could lead to enhanced immunity. An increase in circulating leukocytes in relation to physical stress, whether acute or prolonged, could explain the body's ability to up-regulate the immune system. This may be due to immune cells having enhanced immune surveillance of tissues around the body. During exercise increased demargination of immune cells from endothelial walls increases the numbers within the body. This then allows more cells to migrate into the tissues and look for infection, therefore increasing the body's resistance to external pathogens. Results from a study by Karacabey et al (2005) have also shown that antibodies within the blood and saliva increase during periods of regular exercise. Increases in salivary antibodies, salivary IgA, could be a mechanism which prevents an athlete's susceptibility to URTI.
Data on the effects of exercise and psychological stress are mixed and it would seem that the intensity and duration as well as the nature of the stress play a particular part in how the immune system is affected. Further research is needed to give a solid answer on this topic of concern.
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