Allergy symptoms made worse by altered neuromodulation

Allergy symptoms are worsened by neuronal dysregulation that increases nervous system excitability. This causes increased symptoms to be produced by the same degree of stimulus  in affected individuals as detailed in a fascinating and clinically important paper recently published in the Journal of Allergy and Clinical Immunology. Here the authors are commented on acute hypersensitivity (IgE mediated) allergy:

"Allergy is the consequence of an IgE-driven overreaction of the immune system to what would otherwise be a relatively innocuous stimulus. Clinically, allergy is characterized by symptoms that, by in large, are secondary to an altered nervous system. The panoply of neuronal symptoms depends on the organ in which the reaction occurs but can include itchy and red eyes; rhinorrhea, nasal congestion, and sneezing; urge to cough, dyspnea, airway mucus secretion, and episodic reflex bronchospasm; dysphagia, altered gastrointestinal motility, and discomfort; and cutaneous itching and flare responses. These events are either in toto or in part secondary to changes in neuronal activity. Therefore allergy can be characterized as an immune-neuronal disorder."

Sparse recognition of this has resulted in lack of attention to therapies that regulate neuronal excitability. They comment on the preponderance of antiinflammatory and antihistamine medications in the standard pharmacopoeia:

"...one might argue that the immune-driven inflammation associated with allergic reactions might in some cases be trivial unless transduced into the neurogenic symptoms of suffering (eg, itch, cough, bronchospasm, motility disturbance, pain, sneeze, skin conditions). Yet although the anti-inflammatory pipeline in allergy therapeutics is teeming with activity, the antineuromodulatory pipeline is largely empty. This might be due to the less than appropriate attention given to the neuronal aspect of this immune-neuronal disorder."

The authors remind readers that nociceptors  (the small-diameter, unmyelinated, slowly conducting nerve C-fibers that also act as sensory nerves in visceral organs) are the nerves most prone to stimulation by an allergic reaction. Commenting on nociceptors they state:

"The signals (action potentials) arising from these primary afferent nerves are integrated in the CNS, where the ultimate consequence can be either conscious perception (eg, pain, cramping, itch, dyspnea, or urge to cough or sneeze) or a subconscious activation of preganglionic autonomic neurons, thereby initiating sympathetic, parasympathetic, and enteric reflexes. In the skin nociceptor activation leads to itching and pain. In the respiratory tract activation of nociceptors leads to sneezing, coughing, dyspnea, and reflex bronchospasm and secretions. In the gut nociceptor activation can lead to secretion, diarrhea, gastric discomfort, and visceral pain. In other words activation of these nerves leads to strong sensations and/or reflexes aimed at avoidance of the stimulus. As we discuss in more detail below, nociceptors are the subtype of afferent nerve most susceptible to stimulation secondary to an acute allergic reaction."

Regarding the role of the autonomic nervous system in allergy and mast cell activity (mast cells release histamine):

"......action potentials conduct along the preganglionic axon that ultimately form synapses with neurons in the autonomic ganglia. It should be kept in mind that these ganglia are not simple relay stations but sites where filtering and integration of the CNS input occurs. This might be relevant in allergy because mast cells are commonly associated with sympathetic, parasympathetic, and enteric ganglia (as we will discuss further below). In the gut, in particular, there is also autonomous efferent control that is independent of the CNS neural processing. In this case a sensory nerve that detects a stimulus in the local environment can transmit this information directly to nearby efferent enteric neurons through local afferent-efferent synapses. This is referred to as a local ‘‘peripheral reflex.’’

And neurogenic inflammation also occurs on a local tissue level:

"n some organs neuropeptide-containing afferent C-fibers can directly regulate organ function independently of either the CNS or efferent autonomic or enteric neurons through local ‘‘axon reflexes.’’...The released peptides can lead to edema, vasodilation, smooth muscle contractions and relaxations, and immune cell recruitment and activation. The overall consequence of axon reflexes is often referred to as ‘‘neurogenic inflammation.’’

And mast cells, the effectors of histamine release, localize in the neuronal environment:

"...anatomic investigations, especially when evaluating whole mounts of tissue, often reveal a spectacular display of mast cells residing along afferent, autonomic, and enteric nerve branches. These images leave little doubt that many, if not most, nerve fibers in tissues are within the sphere of influence of mediators released from mast cells." 

Most importantly, due to plasticity a lowered threshold to stimuli for neuroexcitability can persist, sometimes for even years after the initial stimulus:

"The allergic response comprises changes at all 3 levels of the neural arc: sensory nerve function, CNS integration, and autonomic/enteric neuroeffector cell function. These changes can be subdivided into acute changes (overt activation of nerves that lasts only as long as the stimulus is present), longer-lasting changes in neuroexcitability that can outlast the stimulus by hours or days, and the even more persistent phenotypic changes that can last for weeks and perhaps, when one considers the idea of developmental ‘‘critical periods,’’ for years."

And this can recruit the involvement of other types of nerves:

"In general terms, overt activation of C-fiber leads to sensations and reflexes consistent with the organ sensing a danger stimulus and responding in a manner that attempts to reduce the exposure of this stimulus. As discussed above, depending on the tissue, activation of nociceptors can ultimately lead to urge to cough or sneeze, reflex bronchospasm, secretions, itch, neurogenic inflammatory responses that contribute to wheal-and-flare reactions, visceral discomfort, and changes in gastrointestinal and bladder motility. Furthermore, if the sensory nerve has been made hyperexcitable by allergic mediators, then subthreshold stimuli and even nonnoxious routine stimuli might evoke these nociceptor- associated reflexes...Interestingly, after allergen challenge, large-diameter myelinated A-fiber nonnociceptor neurons that normally do not express these potent neuropeptides begin to synthesize and transport the peptides to their central and peripheral terminals. In other words, there is a ‘‘phenotypic switch’’ in the neuropeptide innervation of the allergically inflamed tissue...These allergen–sensory nerve interactions can be acute and short lived but can also persist long after the initial allergic response." 

And this lowered threshold of response to stimuli also occurs centrally:

"...peptides and transmitter releases from the central terminals of the afferent nerves can be set in motion events that lead to increases in the synaptic efficacy of the CNS neurons, a process often referred to as ‘‘central sensitization.’’ When the CNS neurons become sensitized, the consequence of a given amount of afferent input can be enhanced and even qualitatively changed."

This can cause a person to cough or sneeze, feel pain, have to urinate, or experience different types of gastrointestinal distress with what would normally be a tolerated stimulus. Regarding the GI tract :

"When mast cells situated close to the autonomic ganglia are stimulated, this leads to substantial increases in ‘‘synaptic efficacy.’’ That is to say that the postganglionic output increases relative to a given preganglionic input. These ganglia are the first sites of peripheral integration of efferent information arising from the CNS. Therefore changes in synaptic efficacy at these sites can exert powerful modulation of the CNS control over organ function. In addition, changes in activity of the neuron within the enteric ganglia can also alter the characteristics of the autonomous functioning of the gastrointestinal tract."

Occurring in the bronchi:

"After allergen activation of nearby mast cells, the synaptic efficacy is enhanced and the filtering capacity of the ganglion is lost."

Of course this phenomenon takes place in the sympathetic nerve fibers as well:

"Within minutes of allergen-induced activation of mast cells in the superior cervical ganglion or celiac ganglion, there is a pronounced increase in the synaptic efficacy, often leading to a doubling of the postganglionic output. The potentiation of synaptic efficacy by mast cell activation is not a short-lived event. As with the increase in excitability of afferent nerve terminals, allergen-induced synaptic potentiation can persist for many hours after acute activation of the mast cells....In susceptible subjects this may be heightened to the extent that serious symptoms occur (eg, severe bronchospasm, mucus secretion, gastrointestinal cramping and pain, diarrhea, and dysregulation of motility)."

The authors also discuss a 'critical period' early in life during which neuronal circuits can be conditioned to lowered sensitivity and heightened responses:

"It has long been known that inflammation of the colons of laboratory animals leads to a neuronal hypersensitivity and an exaggerated and abnormal reflex physiology of the gut (somewhat analogous to the airway hyperreactivity of asthma)...Allergic (or infectious) inflammation in critical periods therefore raises the possibility that the inflammatory response might leave behind a nervous system that is subtly altered many years later, such that a mild inflammatory insult could lead to overly exaggerated responses."

The authors conclude:

"Among the constellation of symptoms that characterize the allergic reaction, many, if not most, are secondary to changes in the nervous system..In this sense allergy is an immune-neuronal disorder...Activation of mast cells and the consequent eosinophilic TH2-driven inflammation can lead to profound alterations in the function of afferent neurons, neurons within the CNS, and neurons in sympathetic, parasympathetic, and enteric ganglia. These alterations comprise acute overt activation of nerves, long-lasting increases in their excitability, and even longer- lasting phenotypic changes in the nervous system...More than the fact that those with allergy produce neuroactive mediators at sites of allergic inflammation, it would appear that the nervous system itself is altered in allergic disease. Whether because of events occurring during critical periods in neuronal development or simply because of persistent nerve activation, the nervous system is rendered hyperactive in many patients with allergic disease." 

Key point: The longer immune-neuronal symptoms are permitted to occur without ameliorating underlying causes, the harder they are to treat as persistent nerve activation results in nervous system changes becoming more entrenched.Clinical note: The practical implication is that interventions that treat the altered neuromodulation (including various sensory-based peripheral stimuli that activate centrally such as acupuncture, neuroregulatory chiropractic, Pain Neutralization Technique) should be part of a comprehensive treatment plan, certainly for the more severe or persistent cases of allergy.

"It can be anticipated that as our understanding of these basic mechanisms continues to evolve, new therapeutic strategies that target the nervous system will continue to emerge that, by working synergistically with anti-inflammatory strategies, will serve to quell the suffering of those with the immune-neuronal disorder we refer to as allergy."