Case 6: The Case of a Life Size Labrador Dog

Case 6: The Case of a Life Size Labrador Dog

 

 

LG is an 18 y/o girl in your practice with history of seasonal allergies and poor response to many medications with rashes, wheezing and general malaise. She has known allergy to animal dander including cats and dogs as well as rabits (she had one as a pet but was forced to give it up).  You have a porcelain statue of a Labrador dog. When LG arrives to your office for a routine examination developed signs of acute distress relieved only by beta2 agonists. She says it was “brought on” by the dog statue.

Summary

This particular case involves classical “Pavlovian” conditioning relative to learned immune responses. In this case, the patient presents to the doctor with a past history of various allergies to pet dander with poor response to allergen medication. Upon arrival, the patient developed an immune response when seeing a statute of a dog. Thus, the patient has acquired classical Pavlonian conditioning to her specific allergen.

There is evidence that immune processes are involved in behavior and neural plasticity (Fig. 1). Learning, memory and synaptic plasticity involve neural activation of hippocampal circuits. Consolidation of long term memory requires limbic activation, which in turn stimulates the hypothalamus-pituitary-axis and the sympathetic nervous system to release hormones that stimulates target organs to send afferent signals that activates memory.

 

 “The exposure to a specific antigen and its categorization as an allergen (memory) might be centrally associated with a specific environment (the statue) or food”. ⁴ Hence, the connection between the learned immune response and neurological pathways that it stimulates exist. The pathway is not exactly understood but includes parasympathetic stimulation of the vagus nerve which in turn releases acetylcholine into pulmonary tissue, causing broncoconstriction and mucus secretion. This is a classical example of a type 1 hypersensitivity reaction. 

Specifically, in the mechanism of this reaction, there is an initial process of sensitization. The girl had already experienced the exposure to the allergen, which is the reaction from the dog. This sensitization involves activation of the humoral pathway, CD4+ Th2, which stimulates B-cells production of IgE antibody. IgE binds with high affinity to Fc receptors in mast cells and basophils. During a second exposure to the same allergen, the antigen binds to the IgE present in the surface of the mast cells and by cross linking they activate the degranulation of the mast cells. During the immediate phase, histamine, and during the late phase, leukotrienes, cytokines and prostaglandins, are liberated resulting in smooth muscle contraction of the airways, vasodilation and an increase in vascular permeability.

There are two main steps involved in the classical conditioning, the “acquisition” and “evocation” phase. Figure 2 shows an experiment that clearly demonstrates that the central nervous system (CNS) acquire neural afferent sensorial stimulus, such as taste or vision, and it is associated and stored as any other event. During the evocation phase, when the organism is re-exposed to the stimulus via efferent neural and/or humoral pathways, the stored information induces an immunologic response. ⁴ It has been determined that both the insular cortex and central nucleus of the amygdala are involved in the “acquisition” of the enhancement of the antibody response to lysozyme, whereas the “evocation” process is mediated only by the insular cortex. ⁴ This suggests that the learning processes taking place in the CNS are directly related to the immune responses. This would explain why the visual stimulus activated the limbic system resulting in the allergic reaction. In conclusion, the immune system plays an important role in the process of learning, modulation of memory and neural plasticity.



 

Case Questions

Is this possible? Why?

Yes, it is now recognized that the nervous system and immune system speak a common biochemical language and communicate via a complete bidirectional circuit involving shared ligands such as neurotransmitters, neuroendocrine hormones, cytokines and the respective receptors. The Immune system functions as a sixth sense for the CNS that acts reciprocally. ² The CNS can influence the immune response and the immune system can, in turn provide signals to the CNS. Therefore the patient upon seeing the porcelain dog will activate certain areas of the brain and thus stimulate the immune system accordingly.

 

Is this a case of “Pavlovian” conditioning?

 

Yes, the scenario is to repeatedly pair administration of an immune-regulatory compound as an unconditioned stimulus, the allergic reaction of the patient, with an external event which is the conditioned stimulus. In Pavlov case the ringing of the bell, but in our patient the sight of a dog or cat. The crux of this paradigm depends on repeated stimulus followed by a subsequent reaction. In our case the patient has had a lifelong history of hypersensitivity towards cats and dog, giving ample time for such a conditioned response to occur, just as Pavlov had described in famous experiments.

 

What type of neuro-immune interactions can explain the events observed in this case?

 

The chemical signals and receptors used by the immune system and the CNS have been shown to be present in both systems. The hypothalamus promotes the release of several hormones from the pituitary gland, and has been shown to be influenced by cytokines INF- Alpha and IL-1. Conversely, Lymphocytes carry mRNA for neuropeptides, which reflects the bidirectional communication between these two systems. Either system can influence one another. The immune system regulates a primary response to an antigen, eventually this regulation will be controlled by the CNS and the immune system. The brain has an inherent tendency to avoid potentially harmful stimuli therefore, visual stimuli of the dog could be relayed to the hypothalamus and influence the release of hormones, or stimulate the autonomic control centers of the brain to, ultimately influencing an immunological reaction. An anxiety attack triggered by the dog causes the brain to release a host of chemical messengers that

 

Which neurological structures are involved in this type of response?

 

The neurological structures involved are many but include the nucleus of the solitary tract, parabrachial nucleus, lateral thalamus, amygdala, insular cortex and visual association cortex. The vagus nerve is an important route for messages being sent by neurotransmitter from the CNS thus bypassing hormonal messengers.

 

 

 

 

 

 

Clinical Applications

Multiple Sclerosis

It has been found that treatment of a flavored solution administered along with an immunosuppressive drug induces taste/immune associative learning. The treatment must be given 4 times or more. Re-exposure of the drink without the drug results in inhibition of cytokines, IL-2 and IFN gamma, causing a suppression of the immune system by the classical conditioning theory.

Cancer

Assessment of T cell was conducted on 20 cancer patients at hospitals and patients at their homes prior to chemotherapy. From blood samples, patients at hospitals had a lower amount of T cells compared with the patients that were at their homes or neutral environment. In response to reminders of chemotherapy patients developed nausea, anxiety and fatigue. These type of patients also evoke these symptoms when were shown images of chemotherapy. Therefore, the results concluded that the conditioned effects from the different settings provoked the symptoms and suppressed the immune system of cancer patients. Healthcare professionals can benefit from this knowledge by considering the effects of classical conditioning into therapies. In fact, this type of investigation has also been replicated in ovarian patients and pediatric patients generating similar response.

References

 

1.     R. Yirmiya, I. Goshen / Brain, Behavior, and Immunity.2011; 25: 181–213.

2.     Blalock JE, The immune system as the sixth
Sense. J Intern Med 2005; 257: 126–138.

3.     T. Wirth et al. / Brain, Behavior, and Immunity.2011;25: 1444–1451.

4.     M. Schedlowski, G. Pacheco-López / Brain, Behavior, and Immunity.2010; 24: 176–185

5.     D. Lysle, J. Cunnick, AND K. Maslonek. Pharmacological Manipulation of Immune Alterations Induced by an Aversive Conditioned Stimulus: Evidence for Beta-Adrenergic Receptor-Mediated Pavlovian Conditioning Process. Behavioral Neuroscience.1991; 105: No. 3, 443-449.