The prooxidant state and psychologic stress. (Correspondence).

We have read with interest the work by Lesgards et al. (1) on the effect of different lifestyle factors on their test system, which measures the resistance of red blood cells to an oxidative challenge. Their study showed that psychologic stress is a major factor influencing antioxidant status. This finding encouraged us to share our experiences of a earlier study that resulted in similar conclusions using an enzyme, 5'-ectonucleotidase (NT), located on the external surface of lymphocytes (2,3). NT is significant because it has a role in lymphocyte maturation; newborns with persistently low activities have multiple infections, whereas with normalization of NT, their infections resolved (4). We previously showed that NT activities decreased, by then-unknown mechanism(s), as the course of HIV (human immunodeficiency virus) infection progressed (5). Later, we carried out this study in psychologically stressed patients to see if stress itself could lower the activity of this enzyme and thereby contribute to the immune deficiency reported for stressed/ depressed patients (6). In one aspect of this study, honors students in psychology were monitored at different times of the year when their stress levels were low (after holidays) and high (exams/thesis writing). These students were psychologically assessed for stress using the Profile of Mood Score (POMS). The POMS scores were significantly correlated with NT, which was significantly lower (30%) at high stress periods and normalized when the stress resolved (after holidays), indicating the reversibility of the effect of stress on NT.

In another group of chronically stressed/ depressed patients, NT values were also found to be very low; however, in a subgroup of these patients taking vitamins A, C, and E and coenzyme Q10, the NT values were equivalent to those of an unstressed healthy population (2). Subsequent in vitro studies showed that NT was inhibited within 5 min after exposure to superoxide anions and that this effect could be reversed either by ascorbate added to the in vitro system at physiologic levels present in serum (100 [micro]M) or by oral administration of the same antioxidant mix to volunteers for about 6 weeks (3,7). Measurement of tissue ascorbate also showed that this metabolite, like NT, decreased significantly at high-stress periods and resolved when the stress dissipated. Our earlier findings of low NT in HIV-positive patients further confirmed our oxidant mechanism when these patients were later shown to have a high prooxidant state (8).

Besides stress, we also studied another prooxidant state--diabetes--and showed that with poor management of this condition, as measured by hemoglobin A1C (HbA1C), NT decreased significantly (7). That is, NT correlated negatively and significantly with HbA1C. These studies, taken together, confirmed that NT is a good indicator of a high prooxidant state, whether through HIV infection, psychologic stress, or diabetes.

In summary, psychologic stress gives rise to a prooxidant state that is reflected by low NT and increased red blood cell sensitivity to oxidative insult. Why stress should cause a prooxidant state is not known. We hypothesize that stress by increasing cortisol favors the development of an innate immune response (2,3). In normal circumstances the innate response would abate as the adaptive immune system takes over. However, with chronic stress the high prooxidant nature of the innate response persists, because of chronically elevated cortisol, and NT and probably other important extracellular proteins of lymphocytes are inhibited, resulting in an attenuated adaptive immune response and subsequent immunodeficiency. That an innate or proinflammatory process persists in stressed patients is evidenced by persistent increased blood concentrations of acute phase, proteins seen in these patients (9,10).

Ainsley H. Chalmers
Flinders University of South Australia
Bedford Park, South Australia
E-mail: [e-mail]

Jane S. Blake-Mortimer
University of Adelaide
Adelaide, South Australia

Anthony H. Winefield
University of South Australia
Adelaide, South Australia

REFERENCES AND NOTES

(1.) Lesgards J-F, Durand P, Lassarre M, Stocker P, Lesgards G, Lanteaume A, Prost M, Lehucher-Michel M-P. Assessment of lifestyle effects on the overall antioxidant capacity of healthy subjects. Environ Health Perspect 110:479-486 (2002).

(2.) Blake-Mortimer JS, Winefield AH, Chalmers AH. The relationship between 5'-ectonucleotidase and psychological stress. Int J Stress Manage 3:189-207 (1996).

(3.) Blake-Mortimer JS, Winefield AH, Chalmers AH. Evidence for free radical-mediated reduction of lymphocytic 5'-ectonucleotidase during stress. Int J Stress Manage 5:57-75 (1998).

(4.) Bastian JF, Ruedi JM, MacPherson GA, Golembsky HE, O'Connor RD, Thompson LF. Lymphocyte ecto-5'-nucleotidase activity in infancy: increasing activity in peripheral blood B cells precedes their ability to synthesize IgG in vitro. J Immunol 132:1767-1772 (1984).

(5.) Chalmers AH, Hare C, Wooley G, Frazier IH. Lymphocyte ectoenzyme activity compared in healthy persons and patients seropositive to or at high risk of HIV infection. Immunol Cell Biol 68:81-85 (1990).

(6.) Cohen S, Miller GE, Rabin BS. Psychological stress and antibody response to immunization: a critical review of the human literature. Psychosom Med 63:7-18 (2001).

(7.) Chalmers AH, Blake-Mortimer JS, Winefield AH. Lymphocytic 5'-ectonucleotidase, an indicator of oxidative stress in humans. Redox Report 5:89-91 (2000).

(8.) Allard JP, Aghdassi E, Chau J, Salit I, Walmsley S. Oxidative stress and plasma antioxidant micronutrients in humans with HIV infection. Am J Clin Nutr. 67:143-147 (1998).

(9.) Maes M. A review on the acute phase response in major depression. Rev Neurosci 4:407-416 (1993).

(10.) Joyce PR, Hawes CR, Mulder RT, Sellman JD, Wilson DA, Boswell OR. Elevated levels of acute phase plasma proteins in major depression. Biol Psychiatry 32:1035-1041 (1992).