Case 49

Published on 18/02/2015 by admin

Filed under Allergy and Immunology

Last modified 22/04/2025

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CASE 49

LG is an 18-year-old girl in your practice with a history of seasonal allergies and, she says, multiple “bad responses” to many medications with rashes, wheezing, and general malaise. She has a known allergy to animal dander, including cats and dogs as well as rabbits (she had had one as a pet as a young child but was forced to give it up).

A patient in your practice, knowing your love for your German Shepherd dog who recently died, has purchased for you a gift of a porcelain statue of a full-sized shepherd that you have accorded a “pride of place” in the corner of your office. LG comes to visit for a routine physical and Papanicolaou test, but within a minute of being in the room develops severe signs of respiratory distress, relieved only by aggressive albuterol (Ventolin) inhalation in the adjacent examining room. She says it was “brought on” by the dog statue. Is this possible? Why?

QUESTIONS FOR GROUP DISCUSSION

1. What is classical conditioning? How is it induced experimentally?
2. At present, how can you eliminate the conditioned part of a response in humans?
3. In general terms, describe the experimental protocol and results of the guinea pig study regarding abrupt and not abrupt isolation stress on histamine release to a conditioned stimulus. How would you extrapolate that to human experiences?
4. Consider ischemic conditioning (see Case 43) and how you might extrapolate this to the results of question 3 and childhood experiences in general?
5. Describe the conditioning studies using epinephrine, a neutral sherbet, and NK cell activity. On the basis of this study, what activity of NK cells would you predict in acute stress responses?
6. Provide a rationale for the selection of IL-2 and IFNγ as dependent measures in the conditioned studies using cyclosporine. How could the results of this study be used to design studies to offset drug toxicity?
7. Explain why it is oversimplistic to suggest that inhibition of the hypothalamic-pituitary-adrenal (HPA) axis is the only explanation for conditioned immunosuppression.
8. Describe conditioning studies that indicate that β-adrenergic receptor activity is not required for the establishment of conditioned morphine-induced changes in immune status.
9. Describe conditioning studies that support the concept that endogenous opioid activity is involved in conditioned-stimulus–induced alterations of immune function.
10. What immune responses does blockade of glutamate release and/or uptake block?

RECOMMENDED APPROACH

Implications/Analysis of Family History

Although there is evidence for genetic associations for susceptibility to allergies, evidence for genetic susceptibility for conditioning in humans is lacking. However, studies with wild-type mice and laboratory mice lacking dopamine receptor D4 (D4R) have shown that mice lacking D4R showed heightened avoidance to classical fear conditioning. Future research may identify susceptibility genes in humans.

Implications/Analysis of Clinical History

Classical conditioning is deemed to have occurred when a particular stimulus (conditioned stimulus) evokes a similar response to that generated by an unconditioned stimulus, following pairing of these two stimuli. The number of pairings required to effect a conditioned response seems, in part, to depend on the strength of the emotional response at the time of the pairing.

In the absence of more information, we are unable to determine if LG’s respiratory distress in the presence of the porcelain dog statue was due to a single emotional pairing (e.g., attacked by a dog when she was an infant and has no conscious memory of that experience) or whether this is the result of multiple pairings of another nature.

Implications/Analysis of Laboratory Studies

Whereas laboratory studies and/or allergen skin testing can identify the allergens to which this child is responding, these tests cannot possibly identify the objects that serve as conditioned stimuli.

Additional Laboratory Tests

Laboratory tests are not available to measure responses to conditional stimuli; however, psychological assessment should be considered.

DIAGNOSIS

The evidence to date (see later) is quite consistent with the clinical observation that this girl has a “conditioned” allergic response to animal dander, which can be elicited by visual cues alone.

THERAPY

The treatment at this stage would be of two kinds. You can continue to treat symptoms, and, as here, give this patient β-agonist therapy (and/or epinephrine) as appropriate during exacerbations. Alternatively, you could attempt to eliminate at least the conditioned part of this response, using behavioral therapy (extinction).

CONDITIONING OF VARIOUS IMMUNE PHENOMENA

Although there have been a number of studies concerning classical conditioning of a variety of immune phenomena in animals over the past several years, there are limited controlled experimental studies on conditioned immune responses in humans.

Conditioned Immune Phenomena: Guinea Pigs

Studies in the animal literature have attempted to model evidence for conditioned “allergic-type” responses. Learned histamine release has been one such model. In a classical conditioning procedure in which an immunologic challenge was paired with the presentation of an odor, guinea pigs subsequently showed a plasma histamine increase when presented with the odor alone.

Abrupt versus Nonabrupt Isolation Stress on Histamine Release

A guinea pig model investigated the effect of (abrupt and nonabrupt isolation, or relief from isolation) stress on classically conditioned histamine release, using ovalbumin as an unconditioned stimulus and dimethylsulfide (sulfur smelling) as a conditioned stimulus. Plasma histamine levels were monitored to assess responses.

The study consisted of two separate phases, with phase I serving as the conditioning phase and phase II as the test phase. Of the four groups in the study, two groups remained paired or single for both phases of the study. The remaining groups were either single for the first phase, then paired for the second, or vice versa.

Plasma histamine levels increased from baseline in response to the conditioned stimulus in all animals except for the animals that were paired in phase I and single in phase II. Although animals that were single in phase I and paired in phase II had histamine levels higher than the control group, the histamine level was still lower than that of guinea pigs, which were isolated or paired during both phases. Thus, a change of social relations, particularly isolation during the presentation of the conditioned stimulus, could produce a conditioned suppressive effect on immediate (asthmatic) responses.

CONDITIONED IMMUNE PHENOMENA: HUMAN STUDIES

Conditioned Increase in NK Cell Activity

Most of the published literature deals with studies exploring conditioning of NK cell activity in volunteer subjects. As an example, in one such study, subjects were exposed to a conditioning procedure in which a neutral sherbet was repeatedly paired with a subcutaneous injection of 0.2 mg epinephrine. After epinephrine administration an increase of NK cell activity could be observed (unconditioned response). On the conditioning test day the conditioned group showed increased NK cell activity after re-exposure of the sherbet combined with saline injection. No increase was found in control groups who previously received the sherbet in combination with saline (saline control) or with epinephrine in an unpaired manner (unpaired control). This study certainly supports the previously documented animal literature.

Conditioned Increase in Cytokine Secretion

In a further follow-up to the NK cell investigations (see earlier), healthy subjects in a double-blind, placebo-controlled study were conditioned in four sessions over 3 consecutive days, receiving the immunosuppressive drug cyclosporine as an unconditioned stimulus paired with a distinctively flavored drink each 12 hours. In the next week, re-exposure to the conditioned stimulus (drink), but now paired with placebo capsules (instead of cyclosporine), induced a suppression of immune functions, as analyzed by IL-2 and IFNγ mRNA expression, intracellular cytokine production, and in vitro release of IL-2 and IFNγ, as well as lymphocyte proliferation.

Whereas these data are consistent with the hypothesis that immunosuppression can be behaviorally conditioned in humans, it is important to note that at least one other group failed to replicate these data. Similarly, other workers reported a failure to condition allergic-type immune responses in human skin.

CONDITIONING OF IMMUNE RESPONSES: POSSIBLE MECHANISMS

Analysis of the biologic mechanism(s) implicated in classical conditioning of immune responses have taken several routes, depending on whether the cellular or biochemical aspects of the alterations in immunity are being studied.

Alterations in Cells, Receptors, and/or Environment in Conditioning

Several groups, using animal models, have reported changes in the cells/cellular receptors (and/or cellular environment) of conditioned animals that might contribute to changes in immune responses in this fashion. Included in such changes are alterations in the release of chemoattractants in conditioned mice, which might contribute to differences in cell migration. Indeed, data have confirmed that CNS control of cell migration is likely a fundamentally important mechanism for integration of the CNS/immune system axis, and there is evidence that a significant change in T cell population dynamics (resulting from altered cell migration) might underlie conditioned immunosuppression.

Alterations in Neuroendocrine Responses in Conditioning

Stressors (both physical and psychological) can influence antigen-specific as well as nonspecific reactions. Conditioning and stressful stimulation can alter the development and/or progression of a number of immunologically mediated pathophysiologic processes.

These behaviorally induced neural and endocrine responses alter various immune parameters, which interact with the concurrent immunologic events on which they are superimposed, and vice versa. Analyzing the causative interactions contributing to conditioned immunomodulation thus becomes very complicated, particularly since the neural or neuroendocrine pathways involved in the behavioral alteration of immune responses are largely known.

As discussed in more depth below, there is evidence that both conditioning and stressor-induced effects may result from the action of adrenocortical steroids, opioids, and catecholamines, among others, and all have been implicated in the mediation of some immunologic effects observed under some experimental conditions. An inability to generalize from one experimental study to another may reflect the fact that different conditioning and stressful environmental circumstances induce different constellations of neuroendocrine responses composing the milieu within which ongoing immune reactivity and the response to immunologic signals occur.

Alterations in the Hypothalamus-Pituitary-Adrenal Axis in Conditioning

Several studies using a serum corticosterone time course to examine possible involvement of glucocorticoids in conditioned immunosuppression detected no significant differences in serum corticosterone levels between nonconditioned controls and any conditioned group at any time point. These results support the hypothesis that conditioned immunosuppression is not linked to a rise in glucocorticoid levels. Further support for refuting the role of the HPA axis in conditioning comes from an animal model of conditioned immunosuppression, in which adrenalectomy failed to abort the conditioned suppression seen.

In another study, recombinant IL-1β, which is capable of stimulating the HPA axis to secrete corticosterone (an immunosuppressant), was paired with environmental cues in either a taste aversion or odor conditioning procedure. Animals receiving paired delivery of cues and IL-1 showed corticosterone production on re-exposure to cues, although no evidence was seen for altered CNS concentrations of IL-1 in conditioned animals, which might have reflected a peripheral effect (of IL-1 increases), subsequently eliciting a conditioned CNS response.

Sympathetic Nervous System and/or β-Adrenergic System in Conditioning

Evidence implicating the sympathetic nervous system in conditioning of immune responses also comes from animal studies. Rats receiving subtherapeutic cyclosporine rejected heart allografts at the same time as non–cyclosporine-treated rats. However, a behavioral conditioning regimen (using saccharin and cyclosporine) added to the subtherapeutic cyclosporine protocol produced a significant prolongation of graft survival. Additional data implicated altered production of interleukin-2 and IFNγ in these effects.

Peripheral β-Adrenergic Receptor Activity in Conditioning

Yet another animal study explored the involvement of peripheral β-adrenergic receptor activity in the establishment and expression of conditioned morphine-induced alterations of immune status. Animals received two conditioning sessions during which a subcutaneous injection of morphine sulfate was paired with exposure to a distinctive environment. On the test day, rats were re-exposed to the conditioned stimulus before sacrifice. As a variable, saline or nadolol was administered either before the training sessions or before the test session (nadolol [Nandol] is a β-adrenergic receptor inverse agonist).

Administration of nadolol before training did not affect the development of conditioned alterations of immune status. However, nadolol administration before testing completely attenuated the expression of a subset of the conditioned morphine-induced changes in immune status. Thus, although peripheral β-adrenergic receptor activity is not required for the establishment of conditioned morphine-induced alterations of immune status, it is involved in the expression of at least a subset of those responses. Other studies have suggested a role for central noradrenergic and dopaminergic systems in regulating the conditioned recall of NK cell responses.

Opioids/Opioid Receptors in Conditioning

Studies evaluating the effect of administration of the opiate receptor antagonists naltrexone and N-methylnaltrexone on the immunomodulatory effect of a conditioned stimulus that had been paired with electric footshock have been performed in animals. Naltrexone attenuated the conditioned stimulus–induced suppression of the in vitro proliferative response of splenic lymphocytes to several mitogens (concanavalin A, lipopolysaccharide, and a combination of ionomycin and phorbol myristate acetate) in a dose-dependent fashion. Naltrexone also attenuated the conditioned stimulus–induced reduction in NK cell activity. In contrast, the quaternary form of naltrexone, N-methylnaltrexone, failed to attenuate the conditioned stimulus–induced immunomodulatory effects. These data support the concept that endogenous opioid activity is involved in conditioned stimulus–induced alterations of immune function. Furthermore, the failure of N-methylnaltrexone to attenuate the conditioned stimulus–induced immunomodulatory effect suggests that the opioid receptors involved are located in the CNS.

GABA Signaling in Conditioning

The roles of glutamate and γ-aminobutyric acid (GABA) in recall of the conditioned NK cell response have also been examined. These results suggest that glutamate, but not GABA, was required for recall of the conditioned NK cell response. NMDA but not the kainate/AMPA receptors were suggested to be involved in the response. The levels of glutamate that were released, and/or taken up, also appeared to be critical, given the evidence that blockade of glutamate release and/or uptake abolished the conditioned NK cell response.

Altered Chemokine and/or Cytokines Production in Conditioning

While chemokines function primarily to regulate cell trafficking, it is now clear that their function is considerably more complex than this. They are of importance in HIV infection, in cell activation, in autoimmune diseases and neoplasia, and even in atherosclerosis. The potential role of altered chemokine synthesis in classical conditioning remains unknown.

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