Here is some information from a clinical session with Dr. Sam Yanuck, leading immunologist in the U.S.
I wanted to share the info here for those who are interested in this topic and Immunology. He shared this information with us and the research to back it up as well in an educational session. it is a heavy topic but I wanted to pass it along to those here to perhaps help you better understand the biology behind histamine imbalances. If you scroll to the bottom, you will find the research articles Dr. Sam Yanuck was referring to and the important areas highlighted.
We all know people who have some combination of factors from this list: mast cell / histamine issues, GI or respiratory dysfunction, chronic bladder pain, itching, migraine, and lymphedema. This post discusses the neurogenic inflammation mechanism that connects them all and talks about what to do about this.
Lots of patients deal with issues related to histamine. It drives allergic symptoms, food reactions, mold reactions, contributes to brain fog, increases pain, and promotes a whole host of other mischief. Some patients make too much histamine. Some patients can’t clear it out of their systems efficiently. Some patients have both overproduction and slow clearance. For all these patients, neurogenic inflammation is a key factor.
I’ve talked before about how Th2 dominance tends to yield high histamine. And I’ve talked about the fact that there are so many ways to become Th2 dominant, including high stress chemistry, age, pesticide and mold burdens that are so common, and especially dysfunction of hollow spaces like intestines, sinuses, lungs, vaginal tract, and bladder. Any combination of those factors will increase histamine burden and drive the inflammatory process. Now we want to talk about the neurogenic inflammation that the histamine is driving and how that cascades into other forms of dysfunction in these people with histamine issues.
What the research says…
The factors above are connected through the mechanism of neurogenic inflammation (NI). In NI, mast cell degranulation leads to the release of histamine. Histamine stimulates sensory nerves to release CGRP, substance P (SP), and VIP, which drive mast cell degranulation (loop). These substances also drive pain and inflammation. CGRP is a known driver of both migraine and lymphedema, so you’ll often see people whose clusters of symptoms include leg swelling when they’re in a histamine-mediated flare. VIP drives the activity of innate lymphoid cells type 2 (ILC2), a cell of the Th2 response system, to release the cytokines IL-5 (driving mast cell activation) and IL-13 (with similar Th2-promoting effects as IL-4). In addition, mast cells have receptors for histamine, so histamine is itself a driver of mast cell histamine release (loop). The GI tract is a known generator of both CGRP and mast cell degranulation-mediated histamine release, so you can see why it’s so useful to clean up the GI tract in these individuals. Beyond just the GI tract, it’s important to understand the far-reaching implications for other symptoms and what to do to address the pattern.
Application…
Taken together, these studies suggest that patients with any combination of mast cell disorders, histamine intolerance, Th2 dominance, interstitial cystitis, migraine, lymphedema, itching, dysbiosis, respiratory issues, and related disorders should be assessed with an understanding of neurogenic inflammation in mind. Finding a practitioner who can navigate this is essential to finding lasting remission. In particular, the goal is to inhibit the neurogenic loop, by breaking it from the histamine end. The following considerations may apply:
There are two goals in lowering histamine: 1) make less, and 2) clear it from the system faster.
► Making less histamine involves two parts:
- Inhibit mast cells from releasing histamine. This is best done with luteolin, quercetin, rutin, or other similar substances.
- Break down the mtDNA’s that mast cells also release. This is done with bromelain. mtDNA’s are highly inflammatory. When mast cells degranulate, they release histamine and other substances, including mitochondrial DNA fragments (mtDNA’s). The mtDNA’s inflame the epithelial lining of the sinuses, bronchi, bladder, or GI tract, causing the epithelial cells to make TSLP, IL-33, and IL-25. The TSLP and IL-33 drive more mast cell degranulation, completing the loop. This loop activation between mast cell mtDNA release and epithelial inflammation keeps the histamine release going and keeps the person entrenched in the problem. Degrading the mtDNA’s is a key step in addressing the problem, so the bromelain is an important part of the plan.
► Clearing histamine from the system is done by two enzymes, diamine oxidase (DAO) and aldehyde dehydrogenase (ALDH). DAO gets lots of focus from clinicians, but I’ve measured DAO on a very large number of people and been surprised at how infrequently it’s low. The key is the ALDH. The cofactors for ALDH are molybdenum, B2, B3, and iron. Of these cofactors, the key is the molybdenum. If the patient needs iron, you’ll know that from your basic workup.
And ALDH also gets rid of aldehydes. Aldehydes are in perfumes; they’re released from new carpets and building materials, and molds release aldehydes. And, patients who are sensitive to perfumes, molds, building materials, etc. are often the same patients who have trouble with histamine. So, supporting ALDH plays a crucial role in all facets of these cases.
The Research
The role of histamine in neurogenic inflammation
Rosa AC, Fantozzi R.
Br J Pharmacol. 2013 Sep;170(1):38-45.
Abstract
The term ‘neurogenic inflammation’ has been adopted to describe the local release of inflammatory mediators, such as substance P and calcitonin gene-related peptide, from neurons. Once released, these neuropeptides induce the release of histamine from adjacent mast cells. In turn, histamine evokes the release of substance P and calcitonin gene-related peptide; thus, a bidirectional link between histamine and neuropeptides in neurogenic inflammation is established. The aim of this review is to summarize the most recent findings on the role of histamine in neurogenic inflammation, with particular regard to nociceptive pain, as well as neurogenic inflammation in the skin, airways and bladder.
Neuro-immune interactions in allergic diseases: novel targets for therapeutics
Voisin T, Bouvier A, Chiu IM.
Int Immunol. 2017 Jun 1;29(6):247-261.
Abstract
Recent studies have highlighted an emerging role for neuro-immune interactions in mediating allergic diseases. Allergies are caused by an overactive immune response to a foreign antigen. The peripheral sensory and autonomic nervous system densely innervates mucosal barrier tissues including the skin, respiratory tract and gastrointestinal (GI) tract that are exposed to allergens. It is increasingly clear that neurons actively communicate with and regulate the function of mast cells, dendritic cells, eosinophils, Th2 cells and type 2 innate lymphoid cells in allergic inflammation. Several mechanisms of cross-talk between the two systems have been uncovered, with potential anatomical specificity. Immune cells release inflammatory mediators including histamine, cytokines or neurotrophins that directly activate sensory neurons to mediate itch in the skin, cough/sneezing and bronchoconstriction in the respiratory tract and motility in the GI tract. Upon activation, these peripheral neurons release neurotransmitters and neuropeptides that directly act on immune cells to modulate their function. Somatosensory and visceral afferent neurons release neuropeptides including calcitonin gene-related peptide, substance P and vasoactive intestinal peptide, which can act on type 2 immune cells to drive allergic inflammation. Autonomic neurons release neurotransmitters including acetylcholine and noradrenaline that signal to both innate and adaptive immune cells. Neuro-immune signaling may play a central role in the physiopathology of allergic diseases including atopic dermatitis, asthma and food allergies. Therefore, getting a better understanding of these cellular and molecular neuro-immune interactions could lead to novel therapeutic approaches to treat allergic diseases.
And from the same paper…
[referring to the release of neuropeptides from sensory neurons…] “…These neuropeptides then act on the vasculature and immune system to produce vasodilatation, plasma extravasation, edema, and immune cell recruitment and activation.”
Again from the same paper…
“VIP binds its receptor VCAP2 on ILC2, inducing the release of IL-5 and IL-13 to drive the type 2 immunity.”
CGRP and its receptors provide new insights into migraine pathophysiology.
Ho, T. W. et al.
Nat. Rev. Neurol. 6, 573–582 (2010).
SY: This study suggests that migraine circuitry is strongly upregulated in the presence of elevated CGRP levels.
Abstract
Over the past 300 years, the migraine field has been dominated by two main theories-the vascular theory and the central neuronal theory. The success of vasoconstrictors such as ergotamine and the triptans in treating acute migraine bolstered the vascular theory, but evidence is now emerging that vasodilatation is neither necessary nor sufficient to induce a migraine attack. Attention is now turning to the core migraine circuits in the brain, which include the trigeminal ganglia, trigeminal nucleus, medullary modulatory regions, pons, periaqueductal gray matter, hypothalamus and thalamus. Migraine triggers are likely to reflect a disturbance in overall balance of the circuits involved in the modulation of sensory activity, particularly those with relevance to the head. In this Review, we consider the evidence pointing towards a neuronal mechanism in migraine development, highlighting the role of calcitonin gene-related peptide (CGRP), which is found in small to medium-sized neurons in the trigeminal ganglion. CGRP is released during migraine attacks and can trigger migraine in patients, and CGRP receptor antagonists can abort migraine. We also examine whether other drugs, such as triptans, might exert their antimigraine effects via their actions on the neuronal circuit as opposed to the intracranial vasculature.
These studies show that CGRP is elevated in response to intestinal infection and in the presence of immunological reactions to food antigens…
The small intestine plays an important role in upregulating CGRP during sepsis.
Zhou M, Arthur AJ, Ba ZF, Chaudry IH, Wang P.
Am J Physiol Regulatory Integrative Comp Physiol 280: R382–R388, 2001.
SY: In this study, researchers found that plasma CGRP levels went up 177% (a nearly three-fold increase) at the peak, ten hours after the induction of intestinal sepsis, and that the source of the CGRP elevation was the small intestine.
Abstract
Although studies have indicated that calcitonin gene-related peptide (CGRP), a potent vasodilatory peptide, is upregulated after endotoxic shock, it remains controversial whether this peptide increases during sepsis and, if so, whether the gut is a significant source of CGRP under such conditions. To study this, polymicrobial sepsis was induced by cecal ligation and puncture (CLP) followed by fluid resuscitation. Plasma levels of CGRP were measured at 2, 5, and 10 h after CLP (i.e., early, hyperdynamic sepsis) and at 20 h after CLP (late, hypodynamic sepsis). The results indicate that plasma CGRP did not increase at 2–5 h but increased by 177% at 10 h after CLP (P < 0.05). At 20 h after the onset of sepsis, however, the elevated plasma CGRP returned to the sham level. To determine the source of the increased plasma CGRP, the liver, spleen, small intestine, lungs, and heart were harvested, and tissue CGRP was assayed at 10 h after CLP in additional animals. Only the small intestine showed a significant increase in tissue levels of CGRP (by 129%, P < 0.05). Determination of portal vs. systemic levels of CGRP indicates that portal CGRP was 65.7 +/- 22.7% higher than the systemic level at 10 h after CLP, whereas portal CGRP in sham-operated rats was only 4.9 +/- 2.1% higher. Immunohistochemistry examination revealed that CGRP-positive stainings increased in the intestinal tissue but not in the liver at 10 h after the onset of sepsis. The distribution of CGRP stainings was associated with intestinal nerve fibers. These results, taken together, demonstrate that upregulation of CGRP occurs transiently during the progression of sepsis (at the late phase of the hyperdynamic sepsis), and the gut appears to be a major source of such an increase in circulating levels of this peptide.
Enhancement of CGRP sensory afferent innervation in the gut during the development of food allergy in an experimental murine model.
Lee J, Yamamoto T, Hayashi S, Kuramoto H, Kadowaki M.
Biochem Biophys Res Commun. 2013 Jan 18;430(3):895-900.
SY: In this study, researchers again found that CGRP levels were upregulated in plasma, not just in enteric nervous system neurons, reflecting a systemic elevation.
Abstract
Recent advances in neuroscience and immunology have revealed a bidirectional interaction between the nervous and immune systems. Therefore, the gastrointestinal tract may be modulated by neuro-immune interactions, but little information about this interaction is available. Intrinsic and extrinsic primary afferent neurons play an important role in this interaction because of their abilities to sense, process and transmit various information in the intestinal microenvironment. Calcitonin gene-related peptide (CGRP) is exclusively contained in intrinsic and extrinsic primary afferent neurons in the mouse intestine. Therefore, we investigated CGRP-immunoreactive nerve fibers in the colonic mucosa of mice induced to develop food allergy. CGRP-immunoreactive nerve fibers were specifically increased with the development of food allergy, and the fibers were juxtaposed to mucosal mast cells in the colonic mucosa of food allergy mice. Denervation of the extrinsic afferent neurons using neonatal capsaicin treatment did not affect the development of food allergy or the density and distribution of CGRP-immunoreactive nerve fibers in the colonic mucosa of food allergy mice. Furthermore, the mRNA and plasma level of CGRP was increased in food allergy mice. These results suggest that the activation of intrinsic primary afferent neurons in the intestine contributes to the development and pathology of food allergy.
The following paper is noteworthy, suggesting the CGRP may play an important role in the formation of new lymph vessels. One can imagine that the same substance that drives leakage from lymph vessels in lymphedema might compensate by driving formation of new vessels to handle an increased load. The immune system is always hedging its bets. As usual, dysregulation of the system, either by excess or deficiency, can be problematic. In the following mouse study, complete absence of CGRP was shown to create dysfunction. An animal study involving CGRP null mice may not have key application to humans. Nonetheless, it’s worth showing here. It’s also interesting to see that the authors associate CGRP with a drive toward M2 macrophage polarization.
Endogenous Calcitonin Gene-Related Peptide Deficiency Exacerbates Postoperative Lymphedema by Suppressing Lymphatic Capillary Formation and M2 Macrophage Accumulation
Matsui S, Tanaka M, Kamiyoshi A, et al.
Am J Pathol. 2019 Dec;189(12):2487-2502.
Abstract
Lymphedema is a chronic condition caused by disruption of lymphatic vessels, which often occurs after invasive surgery. Calcitonin gene-related peptide (CGRP) is a 37-amino acid peptide produced by alternative splicing of the primary transcript of the calcitonin/CGRP gene (Calca). CGRP was initially identified as a neuropeptide released primarily from sensory nerves and involved in regulating pathophysiological nociceptive pain. However, recent studies have shown CGRP is also released from a variety of other cells and possesses multiple functions. In this study, CGRP knockout (-/-) mice were used to show the actions of endogenous CGRP in postoperative lymphedema. After generating a mouse postoperative tail lymphedema model, the edema was observed to be more severe in CGRP-/- mice than in wild-type mice. Numbers of lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1)-positive lymphatic capillaries were decreased and lymphatic capillary formation-related factors were down-regulated in CGRP-/- mice. In addition, accumulation of M2 but not M1 macrophages was selectively reduced in the edematous tissue of CGRP-/- mice. Selective depletion of M2 macrophages decreased lymphatic capillary formation and worsened lymphedema in wild-type mice but not CGRP-/- mice, where numbers of M2 macrophages were already diminished. These findings suggest that endogenous CGRP acts to ameliorate postoperative lymphedema by enhancing lymphatic capillary formation and that M2 macrophages play critical roles. CGRP may be a useful therapeutic target for the treatment of postoperative lymphedema.