URC

Psychoneuroimmunology: An Analysis of HIV/AIDS and Cancer

Seth R. Batten
Margaret Upchurch*
Transylvania University


Abstract

Psychoneuroimmunology (PNI) is the study of how psychological factors such as stress and depression can affect the immune system through the nervous system. This review examines PNI in relation to HIV/AIDS and cancer. It discusses the possible mechanisms through which these diseases are affected by stress and depression as well as known PNI treatments. It concludes by discussing limitations of the research as well as where PNI may go in the future. 

Introduction

The brain is a powerful organ and it essentially controls all functions in the body. Considering this, it is not outlandish to think that factors that affect the brain, whether they are social, physical, or biological, could affect the rest of the body. Furthermore, these factors could affect one’s brain in such a way that they weaken the immune system, thus making one susceptible to disease or worsening an already existing disease. This is the basis for psychoneuroimmunology.

Psychoneuroimmunology (PNI) is the scientific field of study that investigates the interactions among the nervous system, the endocrine system, and the immune system and how these systems influence one another (Kaplin & Bartner, 2005). The emphasis of PNI is on developing an understanding of how the immune system is influenced by both sociobehavioral and physiological factors (McCain, Gray, Walter, & Robbins, 2005). Work in this area has evolved to focus on three types of interactions between the central nervous system (CNS) and the immune system: CNS modulation of immunity, immune modulation of CNS, and bidirectional modulation of CNS and immunity (Kaplin & Bartner, 2005). PNI can be used to understand how pathogens may weaken the immune system to cause psychological ailments such as stress and depression and how psychological ailments can weaken the immune system to potentiate or attenuate disease. It is easier to understand these interactions when they are thought of through a paradigm.

The PNI paradigm consists of three major components: the psychological component, neurological component, and immunological component (McCain et al., 2005). Under these major components are cofactors, which are defined as factors that have the potential to predispose an individual to certain stress, coping, and health patterns (McCain et al., 2005). Cofactors include gender, age, nutrition, severity of one’s illness, adherence to treatment regimens, and side effects of treatments.

This paradigm is applied by taking all of the major components and cofactors and adding them together to assess an individual's overall health. In using this model to assess patients, one must understand that the intervention (treatment) affects the psychological component. This component is then assumed to affect the neurological component (anatomically and physiologically), which then signals the immunological component. In other words, the treatment for an immunological problem is through the psyche because in certain instances that is believed to control the effectiveness of the immune system. Through this paradigm, it becomes easy to see that a psychological problem such as stress or depression could affect immune system function, thus resulting in disease reduction or worsening of an already present disease. In order to better understand PNI, a basic knowledge of what stress and depression are, as well as what effects they have on the anatomy and physiology of the brain, is needed.

Stress, Depression, and Physiology

Stress as defined physiologically is the state in which the sympathetic-adrenal-medullary (SAM) and the hypothalamic-pituitary-adrenal (HPA) axes are co-activated, causing a disruption of homeostasis in the body (Reiche, Morimoto, & Nunes, 2005). Under normal conditions, the cross-talk between the nervous and immune systems contributes to the physiological balance among various organs in the body (Amati et al., 2006). However, when stress is present it can cause a series of pathological conditions.

Acute, short-term stressors have been shown in vitro to suppress the activation of lymphocytes in response to mitogen stimulation and to suppress natural killer cell cytokines (Kaplin & Bartner, 2005). This can be interpreted as an immune response that could make one more susceptible to illness. Furthermore, when the brain is stressed the hippocampus, amygdala, and prefrontal cortex are vulnerable because all three regions are targets of stress hormones (Fava & Kendler, 2000). Specifically, the HPA and SAM axes are activated because the paraventricular nucleus (PVN) of the hypothalamus processes neurosensory signals, which cause the release of hormones by the pituitary gland. These hormones in turn trigger the release of glucocorticoids from the adrenal cortex. Glucocorticoids stimulate the sympathetic nervous system (SNS), which releases norepinephrine throughout the body. This in turn activates the PVN. This system works as a positive feedback loop, so as long as there is stress, hormone release continues. This creates problems for the immune system because glucocorticoids trigger hormones that have immunosuppressive effects.

Stress is not the only factor that can stimulate the brain in this way. Depression also has similar effects. Depression is a complex disease and is not thoroughly understood, but it is related to a decrease of serotonin in the brain. It may also be related to an atrophic hippocampus and prefrontal cortex as well as a biphasic change in structure of the amygdala (Reiche et al., 2005).

Immune system cells may be influenced by neurotransmitters because they contain receptors for both neurotransmitters and neurohormones. In light of this, a decrease in serotonin levels due to depression could cause the immune system to be altered. Specifically, depression could be associated with the activation of some aspects of cellular immunity, resulting in the hypersecretion of pro-inflammatory cytokines and the hyperactivity of the HPA axis (Reiche et al., 2005). This could cause immunological problems, and it has also been thought to aid in the pathology of depression. Depression could also weaken the immune system though the same mechanism as stress.

Overall, a number of studies have demonstrated that the release of glucocorticoids, cytokines, and other chemicals during chronic stress and depression suppresses many cells in the immune system. These cells include natural killer cells (NK), cytotoxic T-lymphocytes, tissue macrophages, dendritic cells, and Th1 lymphocytes. If these cells are damaged it becomes easier to contract a disease. Along with this, if one already has a disease it could get worse because of a weakened immune system. These mechanisms have been highly studied in HIV and cancer because these diseases already weaken the immune system. Therefore, if an HIV or cancer patient becomes stressed or depressed, life span could be reduced. If these effects could be controlled, the patient's quality of life and life span could be greatly increased.

PNI and HIV/AIDS

HIV is a disease characterized by depletion of the host's immune system, specifically lymphocytes, CD4+, and T-helper cells, thus making the individual vulnerable to a variety of infections. When an infection develops, the patient is said to have AIDS (Stern, 1994). The course of HIV infection appears to be influenced by a complex interaction between biological and psychosocial factors (Persson, Östergren, Hanson, Lindgren & Naucler, 2002). Therefore, PNI studies play a large part in understanding the proliferation of HIV.

Stress and HIV/AIDS

Stress can have many effects on the anatomy and physiology of the brain, and as one could imagine, having HIV could cause stress. The anticipation of HIV antibody test results; the emergence of the first symptom of the disease; changes in occupational plans, lifestyle behaviors and relationships; and the burdens, costs, and responsibilities of complex medication regimens are all highly stressful (Antoni, 2003). Stress could dysregulate endocrine and immunologic processes underlying HIV disease (Antoni & Schneiderman, 1998), reactivating other latent viral infections and thereby activating immune cells infected with HIV. Also, stress could reduce NK cells and T-lymphocyte cytotoxicity. Evans et al. (1995) reported significant relationships between severe stress levels and reduced numbers of CD8+ and/or CD57+ cytotoxic T lymphocytes as well as NK cells.

The increase in cortisol could also exacerbate the disease because of its effect on cytokines. Stress lessens the amount of interferon-γ, which disinhibits the virus. Along with this, increased levels of interleukin-10 due to stress inhibit the anti-HIV response of many immune system cells, thus permitting the proliferation of HIV.   

As discussed earlier, stressors affect the HPA and SAM axes, which stimulate the SNS. Heightened SNS activity may facilitate HIV replication as well as diminish the effectiveness of HIV antiretroviral therapy (Cole, Kemeny, Naliboff, Fahey & Zach, 2001). Specifically, HIV+ men with signs of heightened autonomic nervous system activity show less HIV plasma viral load suppression and poorer CD4+ T cell recovery on highly active antiretroviral therapy. In sum, stress can affect the immune system, and this can have detrimental effects for someone who has HIV because it allows the disease to replicate and it inhibits the effects of some treatments. Depression works through a similar mechanism and it can also have an effect on HIV.

Depression and HIV/AIDS

Depression has been shown to weaken the immune system, thus causing HIV proliferation. At the onset of HIV-related symptoms individuals may become overwhelmed and socially isolated, and may use poor coping strategies, possibly resulting in increased depression (Antoni, 2003). Men characterized by chronic and severe depression over a two-year period demonstrated a sharper decline in CD4+ cells than nondepressed men who were matched on age and CD4+ levels at baseline (Kemeny et al., 1994). Along with this, men who had lost one or more close friends to AIDS, compared to men who had not, had lower numbers of CD4+ cells and increased expression of activation markers on lymphocytes (Kemeny et al., 1994; Kemeny et al., 1995). In contrast, men who had more contact with their families and who were more socially active had longer half lives of CD4+ lymphocytes compared to those who did not (Persson et al., 2002). This suggests that more withdrawn depressed men have weaker immune systems, thus heightening their chances for HIV proliferation.

 It has also been found that HPA and SAM malfunction may be more likely when an individual is experiencing continual anxiety and depressed affect (Antoni, 2003). This, as described earlier, can also cause immune suppression, which can allow HIV to further develop. It should be noted that some other researchers (Schifitto & McDermott, 1999) found no difference between CD4+ count between depressed and nondepressed HIV+ women. This finding raises the possibility that a gender difference exists in the effects of depression on immune system reactivity in HIV infection, something that merits further investigation. 

PNI and Cancer

We are all susceptible to developing cancer. Changes caused by stress and depression to the HPA and SAM axes and to brain chemistry can increase the likelihood of developing cancer or contribute to the proliferation of existing cancer cells.

Stress and Cancer

Stress can inhibit antitumor cells, like NK cells, from initiating cancer-fighting responses such as apoptosis. Compelling evidence exists for the role of these cells in the immune system in resisting the progression and metastatic spread of tumors once they have developed (Herberman, 2001). Stress can cause release of catecholamines from the adrenal glands, activating β1- and β2-adrenoreceptors, which can cause suppressed NK cell activity and consequently compromised resistance to NK-sensitive metastasis of a tumor (Ben-Eliyahu, Shakhar, Page, Stefanski & Shakhar, 2000). Along with this, stress may also enhance carcinogenesis through hormones, alterations in cellular DNA repair mechanisms, and/or effects on apoptosis (Keicolt-Glaser & Glaser, 1999). Stress has been associated with proliferation of cancer, but even more, so has depression.

Depression and Cancer

 Depression may have an important role in cancer initiation (Brenda et al., 1998). Although, major factors that heighten cancer risk and progression were assessed (Garssen & Goodkin, 1999; Reiche et al., 2004), and the results showed depression is more likely to influence cancer progression as opposed to initiation (Reiche et al., 2005). Most of this was attributed to lower NK cell activity along with the development and accumulation of somatic mutations and genomic instability.

It has also been suggested that reactive oxygen species (ROS) play an important role in cancer. Increasing evidence shows that oxidative DNA damage is one of the crucial steps in ROS-related cancer initiation (Cooke, Evans, Dizdaroglu & Junec, 2003). 8-hydroxydeoxyguanosine (8-OH-dG) was found to be a biomarker for oxidative DNA damage and is associated with mutagenesis. Depressive states in females were associated with 8-OH-dG levels, with a strong positive correlation between the percentage of peripheral neutrophils (phagocytes that migrate to areas of inflammation caused by some cancers) and 8-OH-dG levels (Irie, Asami, Ikeda & Kasai, 2003). This level was shown to be even higher in those with major depressive disorder, suggesting that those with clinical depression are at great risk for cancer initiation.

The increase in inflammatory response induced by depression could be another pathway linked to cancer. Inflammatory cells move into a growing tumor, suggesting that they produce numerous substances that can contribute to tumor growth and survival (Reiche et al., 2005). Macrophage activation in the pro-inflammatory response appears to be especially dangerous because many weapons that these cells release can promote cancer.

Depression can induce activation of the SAM and HPA axes, which can cause changes in the expression of matrix metalloproteinases (MMPs) and tissue inhibitor metalloproteinases (TIMPs). Studies in isolation-stressed mice with colon tumors showed higher mRNA level of MMP-2 and MMP-9 in their tumor and liver tissues than in control mice (Wu et al., 1999). Data exist that implicate the MMP-2 in several developmental processes, including tumorigenesis (John & Tuszynski, 2001). This raises the possibility that activation of SAM and HPA can cause MMPs to engage in pathological processes including tumor progression and metastasis.

PNI Treatments for HIV/AIDS and Cancer

PNI proposes a few different cognitive-behavioral treatments for HIV and cancer. All of these treatments aim to manage stress and depression, because the PNI approach states that if you ease the mind you should help strengthen the immune system.

Many stress management techniques have been proposed for people with HIV. One line of stress management was proposed in order to aid people in better complying with medicinal regimens. This is because HIV+ people who are stressed seem to have poor medication adherence compared to those who are not (O’Cleirigh, Ironson & Smits, 2007; Vanable, Carey, Blair & Littlewood, 2006). These findings suggest that the incorporation of adherence training components in stress management interventions may promote healthier immune systems in these populations. Note, though, that no empirical evidence has been collected at this time to assess the success of these proposed interventions.

Another line of management for HIV treatment includes stress management solely in order to reduce stress, which could reduce the harmful effects it has for HIV patients. McCain et al. (2008) tested several nontraditional treatments for HIV. They focused on relaxation training, chi training, and spiritual growth groups. Their findings suggested that these nontraditional therapies may improve immune function, coping, and quality of life.

A few stress management interventions have been proposed for the treatment of cancer as well. Most of the treatments focused on self-maintenance and leisure activities. These activities were used to build self-esteem and reduce anxiety. Other treatments have taught relaxation and stress management and have resulted in reduced anxiety and distress (Ewer-Smith & Patterson, 2002) and improved quality of life (Cooper, 2002). Overall these treatments were created to reduce stress, therefore reducing the mechanisms that could potentiate cancer. Treatments in this field still have a long way to go, and they are not (and probably never will be) substitutions for medications. They are simply used to aid medication in helping a patient.

Limitations of the Research on PNI, HIV/AIDS, and Cancer

A stressed or depressed brain can cause many anatomical and physiological malfunctions that affect the immune system. This has large implications, especially for persons who have diseases that already weaken their immune system or that can be exacerbated by a weakened immune system. As discussed, HIV and cancer are two major diseases that are affected by a stressed brain. Although much of the research supports the value of the PNI approach, it should be noted that the PNI paradigm as well as the research does have some flaws.  

The PNI paradigm has weak points. Specifically, a lot of its mechanisms remain unclear, especially in more complex diseases such as HIV and cancer. Scientists do have an idea of what stress and depression can do to people with these diseases, but they still are not exactly sure of the specifics beyond those discussed in this paper. Research should be directed toward identifying the factors that mediate the relationship between the brain and the immune system in persons with these diseases.

There are also several issues with the research conducted in this field. The most obvious problem, especially in terms of HIV and cancer, is that these are all quasi-experiments; therefore, direct causation cannot be determined. There are also issues with confounding variables.

When testing the effects of stress treatments or stress itself on participants, it is unethical to take them off of their retroviral or cancer drugs. Therefore, it is hard to tell whether a treatment works or if stress is causing an immunological problem because the drugs could confound these reactions. However, there are some studies that do have medication-free participants (Persson et al., 2002) or participants where a confounding reaction is controlled (Cole et al., 2001; Kemeny et al., 1995).

It is also sometimes hard to tell if psychological factors themselves weaken the immune system. This is because people who are stressed or depressed may engage in behaviors that affect their immune system (e.g., recreational drug use). Therefore, it could be the behaviors of the people and not anatomical and physiological changes of the brain that cause immune system suppression.
Another confounding variable in some studies is whether or not the stressors make the person more susceptible to contracting a disease. This is because stressed and depressed people generally seek out help from others. Therefore, it is hard to tell whether a person is getting sick because the brain is causing the immune system to be weaker or whether exposure to more people has heightened the chance of coming into contact with, and therefore contracting, an illness.

Also, the research may be biased in some regards because of the homogeneity of participants (for example, all the HIV/cancer study participants could have similar traits, but they are not traits of the general HIV/cancer population). This in return makes it hard to generalize to the larger HIV/cancer population.

In spite of all of this, the research is conducted proficiently and the researchers control as many variables as they possibly can. The use of advanced statistical techniques and the development of additional technologies for assessing the biological aspects of the nervous system-immune system relationship should enable PNI to evolve. In turn, this will enable clinicians to better assess their patients' needs and treat their diseases.

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