Allergy Papers: Study of Initial Response and Reversion Rates of Subjects Treated with the Allergy Technique
Section 5 – The Allergic Response
What is an allergic response? An allergic response occurs when a person’s immune system makes a type of antibody called IgE which recognizes a specific allergen. The tail (Fc portion) of the IgE antibody binds to IgE receptors on the surface of mast cells many of which coat the mucosal linings of the respiratory system, skin, and gut. The head of the IgE (Fab portion) recognizes specific allergens. Allergens bind to several adjacent IgE molecules causing cross-linking of the IgE receptors (Figure 1). This triggers the mast cell to degranulate releasing a number of mediators including histamine, proteases, prostaglandins, and chemotactic factors which cause allergic symptoms11-13.
Several studies in humans suggest that allergic reactions can occur in the absence of allergen or physical irritant14,15. These results suggest that neural stimuli such as sensory events (conditional stimuli) may become associated with allergens such that subsequent exposure to the conditional stimuli elicits an allergic response.
Animal studies support the idea that an allergy is a learned response. In a Pavlovian conditioning experiment, rats in the control group were exposed to an audiovisual cue (conditional stimulus) while rats in the experimental group were exposed to an audiovisual cue with an injection of an allergen (unconditional stimulus) which causes mast cell degranulation16. The control animals when re-exposed to the cue did not experience mast cell degranulation. The experimental animals re-exposed to the audiovisual cue alone experienced the same level of mast cell degranulation (conditioned response) as animals re-exposed to the audiovisual cue plus allergen. Conditional secretion of histamine was also reported for guinea pigs exposed to a specific odor with simultaneous injection of allergen17.
How does the central nervous system regulate an allergic response? Nerve cells communicate chemically at specialized junctions (synapses) using chemicals known as neurotransmitters. The presynaptic cell releases neurotransmitters which migrate across a synaptic cleft to bind to specific receptors on the postsynaptic cell causing it to transmit an electrical impulse. A cytokine is a chemical which is released by an immune cell and which binds to specific receptors on other immune cells causing them to respond in some way. Recently, however, neurotransmitter receptors have been found on cells of the immune system, and cytokine receptors have been found on cells of the central nervous system indicating direct communication between the nervous system and the immune system18.
Other mast cell surface receptors in addition to IgE receptors trigger or inhibit mast cell degranulation. Interestingly, some of these mast cell receptors are neurotransmitter receptors (Figure 1). In vivo and in vitro studies indicate that allergic reactions can be triggered by neuropeptides such as substance P19-22, adrenocorticotropic hormone (ACTH)23, and opiate peptides such as dynorphin and beta-endorphin 24-26. Stress activates the release of ACTH and endogenous opioid systems27 (of which beta endorphin and dynorphin are members), neuropeptides known to stimulate mast cell degranulation. As in the case of Pavlovian conditioning, it is possible that a significant emotional reaction acting as a conditional stimulus causes the release of stress neuropeptides which act as the unconditional stimulus resulting in a learned allergic (conditioned) response.
In contrast, other neuropeptides can inhibit mast cell degranulation even in the presence of IgE and allergen. In a study by Jankovic and Maric, rats were sensitized with an allergen28. Some of the rats were concomitantly treated with 10 injections of the opioid peptides, met-enkephalin or leu-enkephalin. The rats were then given a sufficiently large dose of allergen to induce anaphylactic shock. The mortality rate of untreated rats was 70%, rats treated with 10 doses of leu-enkephalin for 5 consecutive days or 1 dose of met-enkephalin just 1/2 hour prior to challenge was 50%. Rats treated with 10 doses of met-enkephalin was 0%. Other neuropeptides can down regulate mast cell degranulation independently of IgE mediated pathways. For example, neurotensin inhibits mast cell degranulation triggered by substance P but not by IgE receptors, probably by interacting with the same receptor as substance P20.
Consistent with the finding of neurotransmitter receptors on mast cells is the finding that mast cells are directly innervated by sensory and sympathetic peripheral nerves in virtually all tissues of the body29,30. Not surprisingly, sensory neurons contain many neuropeptides including opioid peptides, substance P, and calcitonin gene related peptide (which inhibits mast cell degranulation)30. The idea that allergic reactions can be directly mediated by the central nervous system is further supported by the work of Amir and van Ree who demonstrated that intracerebroventricular (i.c.v.) injection of gamma-endorphin significantly improved survival in anaphylactic shock in mice31. Furthermore, i.c.v. injection of beta-endorphin exacerbated anaphylactic shock, an effect which could be reversed by DT gamma-endorphin.