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January 2005

Stress Reduction as a Means to Enhance Oral Immunity in HIV- infected Individuals

Kenneth D. Phillips University of Tennessee - Knoxville, [email protected]

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Recommended Citation Hand, G. A., Phillips, K. D., *Dudgeon, W. D., & Skelton, W. D. (2005). Stress reduction as a means to enhance oral immunity in HIV-infected individuals. Journal of the Association of Nurses in AIDS Care, 16(5), 58-63.

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Stress Reduction as a Means to Enhance Oral Immunity in HIV-Infected Individuals

Gregory A. Hand PhD, MPH Kenneth D. Phillips, PhD Wesley D. Dudgeon William D. Skelton, DAc

Key words: perceived stress, , IgA, cortisol, HIV-infected individuals and are associated with state anxiety, depression acute as well as chronic conditions. It seems that stress can have a detrimental effect on oral as well as The primary diseases that currently plague the in- general health. Oral immunity and health becomes an dustrialized world are those resulting from cumula- important area of study with regard to the HIV- tive damage over many years, such as cerebrovascu- infected population, because these individuals are lar diseases, heart disease, and cancer. These diseases disproportionately affected with opportunistic oral would have been unrecognizable to past generations and esophageal infections. of Americans, who dealt with acute conditions re- lated primarily to infectious diseases and malnutri- tion. Diseases of the late 20th and early 21st century Psychoneuroimmunology Theory are brought on by decades of wear-and-tear, poor lifestyle choices, and a condition commonly referred Psychoneuroimmunology theory proposes that the to as “stress.” In fact, the programmed physiological reduction of perceived stress (rather than reduction of response to our everyday stressors, the stress re- the stressors themselves) and increased immunity are sponse, has allowed animals to survive extreme and interrelated. This proposition is based on extensive dangerous acute conditions. However, overwhelming evidence that there are multidirectional communica- evidence during the past few decades indicates that tion pathways among the neural, endocrine, and im- chronic activation of this biological stress response to mune systems. For example, immune cells have re- nonlife-threatening situations such as traffic jams and ceptors that are specific to catecholamines released work pressures affects physiological systems like during sympathetic nervous system (SNS) activation immunity and is believed to cause or exacerbate and other receptors that are specific to corticosteroids many contemporary physical and psychological ail- (primarily cortisol) released by the limbic-hypotha- ments. The study of the relationship among the neu- ral, endocrine, and immune systems, called psycho- Gregory A. Hand PhD, MPH, is an Associate Professor at neuroimmunology, is an important piece in the Arnold School of Public Health, University of South understanding and treating the effects of stress (Ader Carolina. Kenneth D. Phillips, PhD, is an Associate Pro- & Cohen, 1993; Solomon, 1969). Understanding this fessor at the College of Nursing, University of South Carolina. Wesley D. Dudgeon is a doctoral candidate at relationship is especially relevant for the immuno- the Arnold School of Public Health, University of South compromised population infected with HIV. Stress- Carolina. William D. Skelton DAc, is a certified acupunc- related conditions are prominent clinical problems in turist at The Acupuncture Clinic in Columbia, SC.

JOURNAL OF THE ASSOCIATION OF NURSES IN AIDS CARE, Vol. 16, No. 5, September/October 2005, 58-63 doi:10.1016/j.jana.2005.07.006 Copyright © 2005 Association of Nurses in AIDS Care Hand et al. / Stress and Oral Disease 59 lamic-pituitary-adrenal axis (LHPA) (Borboni et al., ral drug efficacy. These conditions are categorized as 1989; De Souza, Webster, Grigoriadis, & Tracey, (a) oral fungal infections including oropharyngeal 1989). These two pathways, the SNS and LHPA candidiasis (OPC), the most common infection of the axes, are the primary drivers for the stress response , (b) bacterial infections such as necrotizing and have a profound inhibitory effect on immune ulcerative and necrotizing ulcerative peri- function. Activation of these pathways coincides dontitis (HIV peridontitis), (c) oral viral infections with reduced proliferation of lymphocytes during such as and Epstein-Barr , and administration of immunostimulatory phytohemag- (d) oral malignancies such as Kaposi’s sarcoma. glutinen and concanavalin-A, reduced natural killer OPC is the most common oral manifestation of cell number and activity, reduced number and per- HIV infection, a significant indicator of CD4ϩ num- centage of circulating B and T lymphocytes, and bers, a marker for seroconversion illness, and a first reduced levels of a number of immunoglobulins. clinical sign of immunosuppression during the pro- A number of studies support that there is negative gression of HIV to AIDS (Langlais & Miller, 1998; impact of personal and environmental stressors on Reichert, Gelderblow, Becker, & Kuntz, 1987). A general health and immune function in HIV-infected number of oral conditions suggest HIV infection in individuals (Hillhouse & Adler, 1991; Maier, nondiagnosed subjects. These conditions include Watkins, & Fleshner, 1994; O’Leary, 1990). Per- OPC, hairy , Kaposi’s sarcoma, and ul- sonal stressors that are typically identified include the cerative gingivitis. HIV infection itself, commonly identified markers of Oral viral infection figures prominently in acute the disease including CD4ϩ cell count and HIV- and chronic oral disease with AIDS. Herpes simplex RNA viral load, and stage of HIV disease with as- infections usually appear on the as herpes sociated symptoms. In addition to these personal labialis or in the mouth on keratinized epithelium. stressors, there are environmental stressors that im- Unlike patients with normal immune function, HIV- pact the HIV-infected individual that usually are infected individuals may have herpetic lesions on identified as an increased number of hassles of daily mucosal surfaces such as the tongue (Langlais & living and social issues associated with HIV infec- Miller, 1998; Reichert et al., 1987). Recurrent viral tion. These interactions hold importance for the HIV- infections are more frequent, more persistent, and infected individual dealing with opportunistic oral more severe with HIV immunosuppression. Hairy infections and other oral diseases. Theoretically, a leukoplakia on the lateral tongue, specific to HIV- reduction in stress should enhance oral immune func- infected people, is associated with Epstein-Barr virus tion and reduce stress-related oral symptoms of HIV and immunosuppression (Langlais & Miller; infection. Based on this general psychoneuroimmu- Reichert et al.). nology model, the authors of this report and other Lastly, Kaposi’s sarcoma is the most common investigators have hypothesized that various types of cancer associated with HIV infection, presenting as stress reduction techniques will reduce the chronic painful tumors usually found on the hard (Lan- activation of the stress response, reduce the stress- glais & Miller, 1998; Reichert et al., 1987). induced progression of HIV-associated oral immuno- Although immune suppression is associated with suppression, and reduce common oral manifestations each of these HIV-related oral conditions, altered of compromised immune function in HIV-positive oral immunity can be divided into changes in the individuals. specific immune system (activation of lymphocytes in response to contact with particular antigens) or Oral Disease Associated With HIV Infection innate immune system (general protective mecha- nisms). The physiological mechanisms are quite dif- Several oral conditions are associated with disease ferent for these two immune systems, but both can be state and are used in staging systems for the diagno- suppressed by HIV infection. These impairments of sis of progression of HIV infection. Further, oral immunity at the can contribute to sus- conditions are often used as inclusion criteria and ceptibility to opportunistic infectious processes. A therapeutic endpoints in clinical trials of antiretrovi- number of studies have reported significant changes 60 JANAC Vol. 16, No. 5, September/October 2005 to specific immunity as it affects oral surfaces. HIV through activation of the LHPA axis, and activation infection commonly alters oral epithelial cell func- of the SNS, may increase viral replication and lead to tion and can impair mucosal CD4ϩ T-cell activity. A HIV disease progression. The overall effect of these result of this impairment is a reduced cytokine se- changes is a reduction in the robustness of immune cretion during infection. For example, one of the best system communication and a decrease in the number described HIV-associated changes in oral immunity and activity level of immune cells. is a decrease in salivary immunoglobulin A (IgA) The stress-induced inhibition of immune reactivity levels (Muller, Froland, Hvatum, Radl, & to viral challenge has been reported in animal and Brandtzaeg, 1991). Although most studies report a human studies (Mcewen et al., 1997). Normally, reduction in salivary IgA levels in HIV-infected in- infection with an active influenza strain or inactive dividuals, IgA levels rise in serum samples—a seem- virus will elicit an immune response as measured by ing dichotomy that has yet to be explained. levels of antibodies found in the blood or secreted Reductions in innate oral immunity seem to result fluids. However, stress-induced increases in cortisol primarily from reductions in saliva secretion (Chal- can suppress the immune system response to viral lacombe & Sweet, 2002). Reduced fluid-producing challenge. For example, Glaser, Pearl, KiecoltGlaser, function is a common pathology as- and Malarkey, (1994) showed that administration of sociated with HIV infection and is reported in 6% to the hepatitis B vaccine produces a greater antibody 10% of HIV-infected individuals in the United production in medical students who perceive a better States. Further, mouth dryness because of reduced social support network and less overall stress. In saliva production () is a common clinical addition to a stress-induced decrease in the immune complaint of HIV infection. Because salivary secre- response to viral challenge, the reduced immune tion is the vehicle for many nonspecific immune function manifests itself in a reduced capacity to factors, reduced saliva production may explain the inhibit reactivation of latent viruses during times of reported net reductions in many of the innate factors stress. A common example is the recurrence of that protect the oral mucosal surfaces. Xerostomia blisters and other outbreaks in individuals dealing often results from a seen only with stressful situations (Jemmott & Magloire, with HIV infection identified as diffuse infiltrative 1988). Several studies examining the effects of stress lymphocytosis syndrome. This syndrome is charac- on medical students indicate an increased outbreak of terized by enlargement, CD8 lympho- herpes and high levels of antibody to Epstein-Barr cytosis, and lymphocytic interstitial pneumonitis. virus during examination periods (Malarkey, Pearl, Diffuse infiltrative lymphocytosis syndrome is most Demers, KiecoltGlaser, & Glaser, 1995; Glaser et al., prevalent in the United States among HIV-infected 1994). These same responses to stress have been African American men, a population that generally observed in men going through divorce proceedings. has a high level of emotional stress. Specific to stress-related immune responses in the mouth, several studies have demonstrated a pro- Stress as a Mediator of Disease Symptomatology nounced immunosuppressive effect with corticoste- roid administration. Steroid therapy has been shown The oral immunosuppression observed in HIV- repeatedly to predispose individuals to OPC and high infected individuals is representative of a general oral yeast levels (Schechtman, Archard, & Cox, deteriorating host immunity. One likely mechanism 1986; Odds & Webster, 1988). for the decreased immune function is a stress-in- HIV infection is associated with psychological duced increase in the activity of the LHPA axis. This and social stresses. Changes in medical status or enhanced activity results in increased serum cortisol personal and work relationships can trigger psycho- levels. A number of studies indicate that stress-in- logical distress. Psychosocial factors such as life duced neuroendocrine activation facilitates the stressors, social support, and coping styles have been switch from Th1 cytokine production to Th2 cyto- associated with reduced immune system measures, kine production, which is an important step in the increased physical symptoms, and accelerated HIV pathogenesis of HIV disease. Therefore, stress disease progression to AIDS (Leserman, 2000). For Hand et al. / Stress and Oral Disease 61 example, Leserman et al. (2000) and Evans et al. oral dryness and in the resultant reduction in immune (1997) demonstrated that stressful life events for function. HIV-infected individuals are associated with greater reductions in killer lymphocytes and faster progres- Stress Management and Immune Function sion to AIDS. Further, a longitudinal cohort study found that low CD4ϩ cell counts were related to Whereas it seems that the industrialized world is high self-reported life stressors and poor coping destined biologically to suffer from stress and its styles (Goodkin, Blaney, & Feaster, 1993). In a study associated problems, there is good news in that we of HIV-infected men (Caumartin, Joseph, & have the capacity to control our responses to stress. Gillespie, 1993), a longer survival time was associ- Remember, it is the perceived stress rather than the ated with greater social participation. It has been stressor itself that controls our physiological stress hypothesized that elevated cortisol levels mediate the response. It is generally accepted that managing effects of stress on the immune system and hasten stress levels is an important aspect in the treatment of disease progression. Membrenon, Irony, & Dere HIV. A number of studies have shown beneficial (1987) showed an increased basal cortisol level in physiological and psychological effects of stress individuals hospitalized with HIV compared with management therapy in HIV disease (Auberbach, non-HIV patients. Recently, it has been demonstrated Oleson, & Soloman, 1992; Eller, 1999b; LaPerriere that cortisol works in synergy with gp120 (a mem- et al., 1990). Stress management has been shown to brane protein that allows binding of the virus with decrease HIV-related symptoms, increase vigor and CD4ϩ lymphocytes) and leads to apoptosis of hardiness, and increase CD4ϩ cell number (Auber- CD4ϩ lymphocytes, thus contributing to the immu- bach et al., 1992; Eller, 1999a; Eller, 1999b). Antoni nosuppression associated with HIV infection (Nair, et al. (2002) have shown repeatedly the effectiveness Mahajan, Hou, Sweet, & Schwartz, 2000). of cognitive behavioral stress management tech- Although not studied extensively, there is some niques in improving outcomes in HIV-infected indi- information available concerning the effect of stress viduals (Ironson et al., 1990; LaPerriere et al.; Antoni and mood on saliva secretion and oral dryness. It has et al.). For example, these investigators showed re- been estimated that 29% of HIV-infected individuals duced self-reported depressed affect and anxiety in receiving medical care in the United States have conjunction with reduced salivary and urinary corti- reported subjective oral dryness (Younai et al., sol and increases in natural killer cell and CD4ϩ cell 2001). As discussed earlier, salivary secretion plays a number. Further, the reduction in salivary cortisol significant role in oral mucosa immunity. Experienc- correlated with the number of relaxation sessions ing a stressful life change or taking prescribed med- during the study. ications that mimic SNS activation significantly re- A stress reduction technique that is growing in duces salivary flow and increases subjective oral popularity and is of interest to the authors is acu- dryness (Bergdahl, Bergdahl, & Johansson, 1997; puncture. A number of studies indicate that acupunc- Locker, 1993). In addition, studies suggest that xe- ture can enhance immune function or reduce the rostomia resulting from prescribed medications may immunosuppression associated with trauma, stress, result in part from psychological factors (Locker, and infection. Recent studies of acupuncture in 1993). It seems that affect such as depression or asthma patients showed increased levels of CD3ϩ/ anxiety can also reduce salivary flow and increase CD4ϩ cells, decreased interleukin 6 and interleukin subjective oral dryness (Bergdahl et al., 1997; 10, increased in vitro lymphocyte proliferation rate, Mathew, Weinman, & Claghorn, 1979). One study and enhanced immunoglobulin levels, compared examining oral dryness in clinically depressed indi- with controls (Joos, Schott, Zou, Daniel, & Martin, viduals showed an increase in saliva production fol- 2000). Berman and Lundberg (2002) showed that a lowing electroconvulsive therapy (Bolwig, 1972). So 9-month regimen of acupuncture reduced plasma it is fairly clear that stress and affect can play a cortisol levels in prison psychiatric patients. In addi- significant role in saliva production and subjective tion, the patients reported increased perceived auton- 62 JANAC Vol. 16, No. 5, September/October 2005 omy, improved inner harmony, and increased Auberbach, J. E., Oleson, T. D., & Soloman, G. F. (1992). A calmness. behavioral medicine intervention as an adjunctive treatment A number of studies suggest that acupuncture can for HIV related illness. Psychology and Health, 6, 334. Bergdahl, M., Bergdahl, J., & Johansson, I. (1997). Depressive regulate oral immunological functions and relieve symptoms in individuals with idiopathic subjective dry oral symptoms that are common with HIV infection. mouth. Journal of Oral Pathology & Medicine, 26, 448-450. Blom et al. (1992) reported that 12 weeks of acu- Berman, A. H. & Lundberg, U. (2002). Auricular acupuncture in puncture on subjects with severe xerostomia in- prison psychiatric units: A pilot study. Acta Psychiatrica creased salivary flow rates as compared with con- Scandinavica, 106, 152-157. Blom, M., Davidson, I., & Angmarmansson, B. (1992). The trols. Further, acupuncture has been shown to effect of acupuncture on salivary flow rates in patients with enhance salivary and gingival fluid immunoglobulin xerostomia. Oral Surgery Medicine Oral Pathology Oral levels in healthy individuals (Yang, Ng, Zeng, & Radiology and Endodontics, 73, 293-298. Kwok, 1989), and reduce salivary IgA in patients Bolwig, T. G. (1972). Salivation in affective disorders. Psycho- with allergic asthma (Yang, Chen, Zhao, & Wang, logical Medicine, 2, 232-238. 1995). These studies are supported by results from Borboni, P., Di Cola, G., Sesti, G., Marini, M. A., Del Porto, P., Saveria, M. et al. (1989). Beta-endorphin receptors on cul- the authors’ laboratory that indicate a regimen of tured and freshly isolated lymphocytes from normal subjects. stress-reduction acupuncture in HIV-infected indi- Biochemical and Biophysical Research Communications, viduals reduces perceived stress levels, increases sal- 163, 642-648. ivary IgA levels, reduces salivary cortisol levels, and Caumartin, S. M., Joseph, J. G., & Gillespie, B. (1993, June). The reduces the number and size of HIV-related fungal relationship between social participation and AIDS survival in the Chicago MACS/CCS cohort. Paper presented at the and bacterial mouth infections. IXth International AIDS Conference, Berlin, Germany. In summary, it is well established that personal Challacombe, S. J. & Sweet, S. P. (2002). Oral mucosal immu- and environmental stressors can take a serious toll on nity and HIV infection: Current status. Oral Diseases, 8, the health of HIV-infected individuals. 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