Research Database –
International Updates

Immune Function

Issue 89

FERGUSON and CASSADAY, School of Psychology, University of Nottingham, Nottingham NG7 2RD, UK, eamonn.ferguson@nottingham.ac.uk, give theoretical accounts of Gulf War Syndrome from environmental toxins to psychoneuroimmunology and neurodegeneration.
Abstract: This review (123 references) deals with evidence that suggests it is often more parsimonious to explain non-specific illness as single symptom clusters than as a set of separate illnesses, even though a wide variety of symptoms can be included ranging from behavioural to cognitive to physiological. The superordinate syndrome, for instance Gulf War Syndrome GWS, could have its biological basis in the activity of pro-inflammatory cytokines, in particular interleukin-1 (IL-1), that give rise to what is known as the ‘sickness response’. It is further argued that the persistence of non-specific illnesses may be in part due to a bio-associative mechanism. In the case of GWS, physiological challenges could have produced a non-specific sickness response that became associated with smells (e.g., petrol) coincidentally experienced in the Persian Gulf. Later on, these same smells could act as associative triggers to maintain the conditioned sickness response. Such associative mechanisms could be mediated through the hypothalamus and limbic system via vagal innervation and would provide an explanation for the persistence of a set of symptoms that should normally be self-limiting and short-lived.
Evidence is also presented that the symptom pattern produced by the
pro-inflammatory cytokines reflects a shift in immune system functioning towards a T-helper-1 profile. This position contrasts with other immunological accounts of GWS that suggest that the immune system demonstrates a shift towards a T-helper-2 (allergy) profile. Evidence pertaining to those two contrasting positions is reviewed.
Ferguson E, Cassaday HJ. Theoretical accounts of Gulf War Syndrome: from environmental toxins to psychoneuroimmunology and neurodegeneration. Behavioural neurology 13 (3-4): 133-147, 2001-2002.

Issue 39

MARUCHA and colleagues, Periodontology, College of Dentistry, The Ohio State University, Columbus USA. Marucha.1@osu.edu write that wound healing impairment is a well-recognised constellation of conditions altering immune function, which include diabetes, jaundice and advanced age. There is also increasing evidence that psychological stress adversely affects immune function. The authors conducted a study to address the effects of a commonplace stressor upon wound healing.
Methods: 2 punch biopsy wounds were placed on the hard palate of 11 dental students. The first wound was performed during the summer vacation, whereas the second was place on the other side 3 days prior to the first major term examination. Hence, each student served as their own control. The healing was assessed using daily photographs and a foaming response to hydrogen peroxide.
Results: During the examinations, the students took an average of 3 days longer to completely health the 3.5mm wound, i.e. 40% longer to heal the small, standardised wound. Interleukin 1beta (IL-1beta) messenger RNA (mRNA) production declined by 68% during the examination period, which provided evidence of a possible immunological mechanism. The differences were reliable in that not one student healed as rapidly or produced as much IL-1beta mRNA during examinations as during vacation.
Conclusions: The results of this study suggest that examination stress can exert significant influence upon wound healing.
Marucha PT, Kiecolt-GlaserJK and Favagehi M Mucosal wound healing is impaired by examination stress. Psychosom Med 60(3): 362-5 May-June 1998.

BROSSCHOT and colleagues, Department of Clinical Psychology, University of Amsterdam, The Netherlands. KPBROSSCHOT@MACMAIL.PSY.UVA.NL write that although stressor uncontrollability has been demonstrated to suppress immune responses in animals and people, results are inconsistent. The authors reanalysed results from their previous study regarding stress-related immune deviation in order to establish whether perceived uncontrollability of an acute stressor is a co-determinant in the observed immunological changes.
Methods: The authors assessed 3 kinds of cognitive reactions to an acute interpersonal stressor: 1) motivation; 2) uncontrollability; and 3) guiltiness. The stress-induced changes in several types of immune cells in peripheral blood and the proliferative responses of lymphocytes to antigens and mitogens were monitored.
Results: Compared with the control subjects and with those people who perceived high control over the experimental stress situation, those subjects perceiving low control showed a stressor-induced decrease in T helper cell numbers. Conversely, those subjects who perceived high control demonstrated an increase in the number of B cells, compared to the other two groups. The effects of perceived uncontrollability could not be accounted for by mood changes, but were related to previously experienced life stress.
Conclusions: Perceived uncontrollability of an acute stressor may have immuno-modulating effects over and above those of the stressor per se.
Brosschot JF et al. Experimental stress and immunological reactivity: a closer look at perceived uncontrollability. Psychosom Med 60(3): 359-61. May-Jun 1998.

BENSCHOP and colleagues, The National Jewish Medical and Research Center, Denver, Colorado, USA performed a meta-analysis in order to describe the relationships between cardiovascular and natural killer (NK) cell number changes and acute psychological stress in women.
Methods: Data from 8 studies were analysed. A total of 128 healthy women, 85 aged 18-45 years and 43 aged 49-87 years were subjected to a speech stressor (N = 80) or a mental effort stressor (N = 48), either mental arithmetic or the Stroop test. Correlations between NK cell number changes, systolic (SBP) and diastolic (DBP) blood pressure and heart rate (HR) were computed. Meta-analysis programmes studied correlations across studies and examined whether correlations changed with stressors or age.
Results: In all the studies there were significant increases over the baseline observed for each variable. Across the studies, the mean weighted r between changes in HR, DBP and SBP was medium (rw = 0.25) to large (rw = 0.64). There was a medium to large average correlation between HR and NK changes (rw = 0.37), whereas average correlations of NK cell number changes with blood pressure changes were small to medium (rw < or = 0.23). The correlations between NK cell number changes and cardiovascular variables were homogeneous across the studies; however, mutual correlations between cardiovascular variables were heterogeneous. One moderator variable became visible: correlations between HR and DBP reactions were larger in studies with older than younger subjects.
Conclusions: Changes in NK cell and HR responses induced by acute stress in women are regulated to a certain extent by the same mechanisms. Neither the stressor nor age appear to be very important in considering the correlations between NK cell and cardiovascular changes. This meta-analysis integrates data, which can be used as reference material for future studies, regarding NK cell and cardiovascular responses in women.
Benschop RJ et al Cardiovascular and immune responses to acute psychological stress in young and old women: a meta-analysis. Psychosom Med 60(3): 290-6 May-Jun 1998.

RAVINDRAN and colleagues, Department of Psychiatry, University of Ottawa, Ontario Canada write that there have been inconsistent results reported regarding circulating lymphocyte subsets in depression. The authors assessed lymphocyte subsets in order to establish whether immune alterations observed in depression might be related to neurovegetative symptoms.
Methods: Lymphocyte subsets were assessed in major depressive and dysthymic patients exhibiting either typical or atypical features, the latter characterised by mood reactivity and reversed neurovegetative features. Blood was collected from major depressive, atypical depressive, typical dysthymic or atypical dysthymic patients and from nondepressed controls. Circulating lymphocyte subsets (CD3, CD4, CD8, CD19, CD16/CD56) were determined using flow cytometry. Lymphocyte subsets were also determined following a 12-week course of antidepressants in a subset of patients.
Results: Circulating natural killer (NK) cells were elevated in depressive illness and varied as a function of depressive subtype and sex. In males, NK cells were elevated to a greater extent in typical than in atypical depression and more so in major depressive than in dysthymic patients. Circulating NK cells were lower in women than in males and only in the typical major depressive patients did NK cells exceed those of the controls. Following successful pharmacotherapy, normalisation of NK cells occurred. T and B cell populations did not differ between the depressive subtypes and controls.
Conclusions: Depression may be associated with an elevated level of circulating NK cells. The neurovegetative features associated with depression, especially altered eating may contribute to elevated NK cells; however, the depressive affect itself also contributed in this respect. The relative contributions of these factors vary between male and females.
Ravindran AV et al. Circulating lymphocyte subsets in major depression and dysthymia with typical or atypical features. Psychosom Med 60(3): 283-9 May-Jun 1998.

BENNETT and colleagues, School of Psychiatry, University of New South Wales, Sydney Australia explored the longitudinal relationships between physical and psychological symptoms and immune factors following acute infectious illness.
Methods: The authors report preliminary data from a prospective investigation of patients with proven infectious illnesses due to Epstein-Barr virus (EBV), Ross River virus (RRV) or Q fever. Patients were assessed within 4 weeks of onset of symptoms and reviewed 2 and 4 weeks later. Physical illness data were collected at interview; psychological and somatic symptom profiles were assessed using standardised self-report questionnaires. Cell-mediated immune (CMI) function was measured using delayed-type hypersensitivity (DTH) skin responses.
Results: 30 patients (17 with EBV, 5 with RRV and 8 with Q fever) were included in this analysis. The most common symptoms during the acute phase were profound fatigue and malaise. Classical depressive and anxiety symptoms were not prominent. Initially, 46% of cases had no DTH skin response, which indicated impaired cellular immunity. Over the 4-week period, there was a marked improvement in the somatic and psychological symptoms, although fatigue remained a prominent feature in 63% of patients. Reduction in reported fatigue was correlated with improvement in DTH skin response and with improvement in General Health Questionnaire (GHQ) scores.
Conclusions: Acute infectious illnesses are accompanied by a range of nonspecific somatic and psychological symptoms, especially fatigue and malaise rather than anxiety and depression. Although improvement in several symptoms occurs rapidly, fatigue often remains prominently even at 4 weeks. The resolution of fatigue is associated with improvement in cell-mediated immunity.
Bennett BK et al. The relationship between fatigue, psychological and immunological variables in acute infectious illness. Aust NZJ Psychiatry 32(2): 180-6 Apr 1998.

Comments: The above research studies demonstrate the incredibly advanced progress underway in elucidating the complicated biochemical, neurological and immunological changes associated with stress.

Issue 37

DUDDUKURI and colleagues, Department of Biochemistry, Andhra University, Visakhapatnam, Andhra Pradesh, India studied the immunomodulatory activity of honey.
Methods: The authors investigated the induction of murine humoral antibody responses against various allergens using passive cutaneous anaphylaxis and Ouchterlony double immunodiffusion techniques.
Results: Ovalbumin (OVA)-specific IgE antibody responses with varying doses were completely suppressed by a number of sources of commercial honeys. Honey also suppressed the induction of OVA-specific humoral antibody responses in a number of strains of mice.
Conclusions: These results confirm the immunosuppressive activity of honey and suggest its possible application to health conditions requiring immunosuppression.
Duddukuri GR et al. Immunosuppressive effect of honey on the induction of allergen-specific humoral antibody response in mice. Int Arch Allergy Immunol 114(4): 385-8. Dec 1997.