Case 51

Published on 18/02/2015 by admin

Filed under Allergy and Immunology

Last modified 22/04/2025

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CASE 51

KL is a 20-year-old first-year medical student who is visiting you for the fifth time in 4 months, with evidence of a viral-type respiratory infection. He has previously been a healthy individual, has all his vaccinations up to date, and has not traveled out of the country. He admits to finding his course study load “tiring and difficult” and has had to stay up at night on at least one occasion each week over the last month to prepare for tests. His roommate is well. His weight is stable. He is currently afebrile, with a dry cough. You order routine blood work and a chest radiograph, with all results returning as normal. What is the potential pathophysiology of this problem? What might you do about it?

QUESTIONS FOR GROUP DISCUSSION

1. Many animal studies, designed with a goal of defining the effect of stress on immune responses, used adrenalectomy as a variable to analyze behaviorally induced changes in immunity. Provide a rationale for this approach.
2. Sleep deprivation in rodent models has led to both increased levels of corticosterone and significant changes in immune responses. How would you explain the fact that there is little evidence to suggest a correlation between immune dysfunction and altered serum corticosterone levels in these animals?
3. How would you rationalize the fact that cortisol levels are increased in both acute stress and chronic stress yet many reports indicate that acute stress enhances the immune system but that chronic stress is immunosuppressive.
4. In human studies, low levels of endotoxin lead to increased levels of cytokines (interleukin [IL]-1, IL-6, and tumor necrosis factor [TNF]). IL-1 and TNF are proinflammatory cytokines. Review the inflammatory process and discuss the role of these cytokines in the recruitment of cells to sites of infection or trauma.
5. In human studies (see question 4), low levels of endotoxin also lead to increased levels of cortisol. How would you explain the fact that cortisol, which has been shown to be an anti-inflammatory agent, does not abrogate the inflammatory effect of IL-1 and TNF?
6. Evidence has now accumulated for stress-associated changes in chemokine/cytokine levels, which may underlie some of these observed changes in cell migration. What cytokines are required for increased transmigration? Which chemokines are required to recruit monocytes and neutrophils into tissues?
7. A number of studies conducted on asymptomatic HIV-positive subjects before and after notification of HIV-1 antibody status measured immune system function in patients that were or were not involved in regular aerobic exercise or group, cognitive, or behavioral modification. Those who participated in interventions had lower or minimal decreases in immunologic parameters compared with controls. Describe a model that would explain this phenomenon.

RECOMMENDED APPROACH

Implications/Analysis of Family History

Although we are not provided with any family history, responses to sleep deprivation and stress may have a genetic component. Sleep deprivation is associated with increased levels of cortisol, a stress hormone, which correlate with alterations in immune function, as well as with depression. Recent studies with twins have shown a 62% heritability with respect to the levels of cortisol in stressed individuals.

Cortisol is secreted from the adrenal gland in response to adrenocorticotropic hormone (ACTH), which is released from the anterior pituitary in response to corticotropin-releasing factor (CRF) secreted by the hypothalamus.

Implications/Analysis of Clinical History

KL’s clinical history indicates that he has had five viral-type respiratory infections in the past 4 months. Effective immune responses to viral infections require the activation of cell-mediated immunity, particularly NK cells, CD4+ T cells, and CD8+ T cells. The fact that KL has had so many viral infections suggests that these cells are not functioning at optimal levels.

Implications/Analysis of Laboratory Investigation

KL’s blood work is normal as is his chest radiograph, suggesting that he does not have a major immunologic deficiency disorder. However, the fact that he is having so many viral infections does suggest that T cell and NK cell function is not optimal.

Additional Laboratory Tests

A relatively straight method to assess T cell function is an assay that measures T cell proliferation in response to mitogen stimulation. KL’s T cell proliferative response in this assay was diminished relative to controls, as was the test to measure NK cell cytotoxicity.

DIAGNOSIS

KL was diagnosed with chronic stress.

THERAPY

Daily exercise or other approaches to relaxation (e.g., reading, listening to music, relaxation tapes) are recommended. In some cases, medication may be required.

EFFECT OF STRESS ON IMMUNE RESPONSES

Whereas the early field of investigations into behavior and immunity was replete with studies examining “stress,” both psychological and/or physical, and its implication for immunosuppression, it rapidly became apparent that not all of the observations made in this area were easily subsumed under an umbrella of stress-induced effects. As noted in another case, in animal studies in particular, adrenalectomy, which would prevent release of cortisol, did not eliminate behaviorally induced changes in immunity and the changes did not follow the circadian rhythmicity of corticosteroid production. Furthermore, both acute and chronic stress lead to increases in cortisol, but acute stress is often reported as enhancing immune function whereas chronic stress is immunosuppressive.

This has great relevance to the large literature on behavior and susceptibility to infectious disease in the human population, which has been presumed to represent the ultimate “stress-related change.” Once again, however, animal studies, as well as human studies, do not support such a simple model but rather imply more subtle changes in other neurohormonal/neurotransmitter-mediated immune changes.

Sleep Deprivation (Chronic Stress) and Serum Cortisol/Corticosterone

Note that different stressors, and their longevity, can, as mentioned many times, produce different changes in cortisol levels in humans. Acute stress can produce rapid changes in serum cortisol levels, whereas the effect of sleep deprivation (chronic stress) produces changes in a much slower fashion. In animal models, sleep loss is thought to be more stressful than in humans, and significant alterations in immune responses have been observed after sleep deprivation in mice. Nevertheless, there has been little evidence to suggest a correlation between immune dysfunction and altered serum corticosterone levels in such mice, despite profound alterations in cytokine levels. A similar dichotomy between cytokine changes and cortisol levels has also been reported in humans after exposure to low levels of endotoxin, which increase both cortisol and cytokines (IL-1, TNF, and IL-6).

Role of IL-1 and TNF in Cell Transmigration

There are some studies that can provide insight into the mechanism by which stress can affect immune function. Stress is known to produce profound changes in cellular redistribution/migration. Cell migration from circulation to the tissues occurs, in part, in response to the action of proinflammatory cytokines IL-1 and TNF on the vascular endothelium. IL-1 and TNF trigger biochemical signaling pathways that lead to the expression of adhesion molecules on the vascular endothelium. These adhesion molecules induce cell rolling and margination as a preliminary step to transmigration into the tissues. Recent evidence has now been accumulated for stress-associated changes in cytokine levels (and hence alteration in adhesion molecule expression), which may underlie some of these changes in cell migration.

Effect of Mental Stress and Sleep Deprivation on Cytokine Production

Mental stress has been reported to have an effect in altering cytokine production, including alterations in levels of IL-1, TNF, and IL-1 receptor antagonist (IL-1Ra). IL-1 and TNF are proinflammatory, whereas IL-1Ra competes with IL-1 for the IL-1R binding and so is inhibitory. Similar changes in these cytokines have been reported in medical students after academic stress. In association with the stress of infection there has been reported an association between stress levels and increased IL-6 production, beyond that accorded to infection per se.

Sleep deprivation itself, common among students, is a stressor and a modulator of cytokine/chemokine production, perhaps even independent of its stress-associated effects. There is a great deal of evidence indicating a role for the cytokines TNF and IL-1 in the regulation of normal sleep behavior with an association between sleep disruption, cortisol levels and IL-1 in an elderly human population.

Cytokines in Sleep Physiology

Numerous studies in humans have described interactions between cortisol, sleep deprivation, and cytokine changes, and it has been suggested that the activated hypothalamic-pituitary-adrenal (HPA) axis in humans stimulates arousal, whereas IL-1, IL-6, and TNF are possible mediators of excessive daytime sleepiness. Interferon gamma (IFNγ) may interact with TNF in producing altered sleep physiology, whereas more recent data have suggested a potential role for alterations in selected chemokines (CCL4/MIP-1β, but not CCL5/RANTES) in altered sleep in HIV-infected individuals.

Does Behavior Influence Infectious Disease Progression?

In the human field, research in AIDS has provided some additional insight into the possible influence of behavior on infectious disease. A number of studies conducted on asymptomatic HIV-positive subjects before and after notification of HIV-1 antibody status measured immune system function in patients who were or were not involved in aerobic exercise or group, cognitive, or behavioral modification. Those who participated in interventions had lower or minimal decreases in immunologic parameters compared with controls. One model under investigation theorizes that in the absence of aerobic conditioning or behavioral restructuring, a cascade of events (virologic and/or immunologic) occurs that decreases the individual’s immunologic endocrine and neuropathic functioning. The patient’s overall homeostasis (an interaction of physical and psychosocial factors) is proposed to be a key in preventing the initiation of a downward spiral that culminates in overt presentation of disease.

Effect of Examination Stress on Disease Susceptibility

Interesting and older studies investigated the role of stress on the susceptibility of human populations to infectious disease (influenza in particular). Cohorts of students about to take examinations were found to show enhanced susceptibility to disease, as well as an increased incidence of infection. In other studies, students were shown to have decreases in secretory IgA in saliva during acute examination stress. Again, the actual mechanisms(s) involved remain unknown.

FURTHER READING

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Caspi A, et al. Influence of life stress on depression: Moderation by a polymorphism in the 5-HT gene. Science. 2003;310:291.

Clement Y, Catatayud F, Beizung C. Genetic basis of anxiety-like behaviour: A critical review. Brain Res Bull. 2002;57:57.

Davis CJ, Harding JW, Wright JW. REM sleep deprivation-induced deficits in the latency-to-peak induction and maintenance of long-term potentiation within the CA1 region of the hippocampus. Brain Res. 2003;973:293.

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Hairston IS, et al. Sleep deprivation elevates plasma corticosterone levels in neonatal rats. Neurosci Lett. 2001;315:29.

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