What comes to your mind when you think of histamine? I bet you think about runny nose, itchy skin or other symptoms of allergies. While histamine plays a key role in allergic and inflammatory reactions, it is also very important for your brain and your entire body.
I.Histamine-Introduction
II.Histamine Receptors
III. The Link Between Histamine, Allergies (H1Rs) and MS
IV. Physiological Effects of Histamine (Allergies, Inflammation, Gastric Acid Secretion, Regulation of the Immune Response, Its Role in The Nervous System, Histamine & Hormones and Metabolism, Histamine & Stress)
Do You Want To Know How to Improve Histamine Levels Naturally With Diet, Supplements and More? – Read Here : Part I and Part II
I.Histamine-Introduction
Histamine is an important neurotransmitter and a signaling molecule in the gut, the skin, and the immune system. It formed from the amino acid histidine.
It is found in almost all bodily tissues secreted by various cells (i.e mast cells, basophils, histamine producing neurons, gastric enterochromaffin-like cells, histaminergic neurons, platelets, dendritic cells, T cells and some microbes).
Histamine producing neurons are located in the hypothalamus and send their axons all over the central nervous system. They are active only when you are awake, as they promote arousal, wakefulness and attention [1].
II.Histamine Receptors
Histamine receptors are proteins found in various parts of the body, and there are four of them : H1, H2, H3, H4. The receptor that the histamine will react with is dependent upon where the histamine is released in the body. It ‘s important to understand these receptors, because some drugs that target histamine receptors show benefits for managing MS. For details about the use of these drugs for MS treatment read this article.
H1 receptors (H1Rs): are key receptors for modulating your internal clock. When histamine reacts with H1Rs in your brain, it changes the brain chemistry, making you feel more awake and alert. They also control your appetite, thirst and body temperature (antihistamine H1 drugs work the opposite of H1R will cause drowsiness and increased appetite). In other body’s tissues, stimulating H1Rs will lead to skin rashes, constriction of the bronchi, motion sickness and widening of the blood vessels which cause redness of the skin. These symptoms are seen in seasonal allergies because H1Rs are overstimulated. H1Rs are also found in the immune system cells like T cells, B Cells and dendritic cells.
H2 receptors (H2Rs): H2Rs are found in the stomach lining. Histamine action of H2Rs stimulates the release of the gastric acid. Antihistamine H2 drugs decrease the secretion of the gastric acid, thus used in acid reflux and peptic ulcers). You should know that H2Rs can also be found in the heart, uterus and the smooth muscles of the blood vessels, as well as in immune system cells like neutrophils, B cells, T cells and dendritic cells. When reacting with H2Rs, histamine can also inhibit the production of certain antibodies and cytokines (cytokines are molecules that aid cell to cell communication in immune responses, being involved in inflammation, infections and autoimmune reactions).
H3 receptors (H3Rs): H3Rs are found in the nervous system. They are called auto-receptors because regulate (actually inhibit) the production of histamine. The more H3Rs are triggered by histamine, the less histamine will be produced in the body. H3Rs play an important role in neurotransmission are also involved in sleep awake cycle and inflammation.
H4 receptors (H4Rs): H4Rs are found in the thymus, digestive tract and bone marrow. They regulate the immune system response, the levels of white blood cell release from bone marrow and play a role in inflammation [1].
III. The Link Between Histamine, Allergies (H1Rs) and MS
Histamine and its receptors are involved in the development of multiple sclerosis. Histamine increases the permeability of blood brain barrier, thus promoting chronic inflammation of the nervous system. The levels of histamine in CSF (cerebrospinal fluid) is significantly elevated (as much as 60% higher) in individuals with MS (RRMS and Progressive MS) compared with healthy controls. It also appears that histamine levels also increase with age [2].
More recently, a 2015 study found that that people with MS who have food allergies have a more active disease than those without allergies [3].
While it is mostly known as being a promoter of inflammation, it appears that sometimes can be anti-inflammatory [4],[5].
It seems like a paradox- how histamine can be both pro- and anti-inflammatory ? The most simple answer would be this: The effects of histamine on the brain, immune cells and other cells in the body can vary greatly (sometimes having opposite effect). For example, stimulating H1Rs can have the same effect but also the opposite effect with a stimulated H2R depending on the circumstances (i.e. the time and context of receptor activation)[1].
For now, I’d like to keep things simple and focus on the fact that MS is associated with histamine excess(particularly H1Rs). Histamine (from both neurons and mast cells) alter the function of the blood vessels, the blood brain barrier and how the immune system function. Abnormal levels of histamine are neurotoxic, causing brain degeneration and neuron death.
On the other hand, lowering histamine with antihistamine drugs and supplements can help improve the symptoms, and even repair the myelin sheet.
Technical: MS and animal model of MS (EAE) are generally considered Th1/Th17-mediated autoimmune diseases However, more recent research suggest that Th2-driven “allergic” conditions may take part to the development of CNS autoimmunity. Among those, mast cells ( the key effectors cells in IgE-mediated immediate hypersensitivity reactions) seemed to be involved in the development of MS and EAE [6].
Back in the mid 1940s, scientists found that allergic reactions are associated with MS relapses, and removing the allergen lead to periods of remission. The most severe symptoms were correlated with molds and fungi, and less severe symptoms with pollen and other chemicals[7].
Newer studies found that histamine levels are high and the levels of DAO (an enzyme that breaks down histamine) are low in individuals with RRMS compared with control (healthy) subjects [8],
It appears that the production of H1Rs is higher in people with multiple sclerosis [9]. Although the link between MS and allergies is not accepted by everyone [10],[11],[12], I think it’s worth exploring this topic.
Technical : TH1 vs TH2 dominance debate. Some studies still suggest that TH2 dominant conditions like allergies would offer some protection against TH1 dominant conditions like MS [13]. I think everyone should be aware that 1). MS can be TH1 or TH2 dominant and 2) Other TH cells can also be out of balance in MS and other autoimmune diseases- this would include TH17, TH9 and TH22 and T follicular helper (Tfh) cells [14],[15], [16] . Talking about Th1 and Th 2 dominance, you should know that drugs like Copaxone and newer drugs stimulate TH2 response, while Interferon beta promotes TH1/TH17 response [17].
I suspect that future studies will find even more types of immune cells involved in the development and progression of MS. I’d rather focus on improving Tregs ( in charge of suppressing potentially dangerous activities of Th cells and preventing autoimmune diseases). More research is needed on Tregs as well [18].
IV. Physiological Effects of Histamine:
Histamine plays a key role in allergic and inflammatory reactions and antihistamine H1 are use for treating allergies and asthma (they also work for MS, details in this article)
Secretion of gastric acid is also stimulated by histamine, and the antihistamine H2R are used to treat peptic ulcer diseases
Technical: The vagus nerve regulates histamine mobilization from enterochromaffin-like cells of the stomach by controlling their sensitivity to gastrin; and histamine (H2R) controls gastric acid secretion by activating the proton pump in parietal cells [19].
Regulation of the Immune Response
Histamine can bind to receptors expressed on various immune cells including B and T lymphocytes, influencing the development and activation of the immune cells [20].
The Role of Histamine in the Nervous System
As a neurotransmitter, histamine modulates important functions of the brain including cognition, food consumption and wakefulness. Histamine plays a key role in attention and vigilance [21].
Histamine producing neurons can regulate and be regulated by other neurotransmitters, particularly acetylcholine, dopamine, norepinephrine and serotonin.
Technical : For example, activation of brain H3 receptors decrease the release of acetylcholine, dopamine, norepinephrine and certain peptides where histamine could also cause the opposite effect(increase the activity of some neurotransmitters) through H1 and/or H2 receptors. Dopamine D2 receptors and some serotonin receptors can raise the release of histamine from neurons, where other transmitters will decrease the release of histamine.
Histamine modulates neuronal activity (through H3R) of the autonomic nervous system (which include parasympathetic nervous system involved in “rest and digest” and the sympathetic nervous system, involved in “flight or fight” reactions.
Through H1R, H2R receptors, histamine stimulates the neurons from cerebellum ( which are involved in motor performance, balance, and coordination)
Histamine (H1R) stimulates hypothalamus, thus having a significant impact on feeding, drinking, and body temperature.
Synaptic plasticity (the ability of brain cells to create new connections) and memory consolidation are strongly influenced by histamine.
Technical: Brain tissues pH switches to more acidic during metabolic challenges (like intense neuronal firing, e.g., during burst activity evoking synaptic plasticity or under pathological conditions like hypoglycemia, ischemia, or epilepsy). Histamine (through H1R) along with orexins can detect changes in tissue pH with consequences for synaptic plasticity, whole brain physiology, and pathophysiology.
Histamine increases blood brain barrier permeability, thus having a great impact on brain autoimmunity and degeneration. Inflammation induced by histamine affects the entire brain, and some of the most affected brain cells are those that produce dopamine.
Histamine, Hormones and Metabolism
Histamine suppresses the appetite and increases thirst (H1 receptors) and influences the control of the body temperature, the metabolism of sugars and fats and the blood pressure.
Histamine producing neurons help regulate various hormones including oxytocin, vasopressin, prolactin, ACTH and ß-endorphin (H1 and H2 receptors involved).
Technical :Histamine is also involved in estrogen-induced LH surges in females (mediated by GnRH) and PRL release induced by suckling. Histamine is mostly inhibitor of GH and TSH but stimulates AVP and oxytocin release. Histamine has a clear circadian rhythm. Melatonin shifts circadian rhythms and resets the internal clock at night, when histamine levels are low. Re: thermoregulation – thermogenic effects of orexins and TRH also rely on central histamine actions.
Stress Significantly Increases Histamine Levels
Stress is a potent activator of histamine producing neurons. In fact, histamine release is a sensitive indicator of stress. Do not consider only the common stress, but also metabolic stressors, like hypoglycemia and dehydration.
Technical: Histamine mediates the stress-induced neuroendocrine hormone raises of ACTH, ß-endorphin, and AVP and controls stress-related activity of serotonin-, norepi-, dopa-, and acetylcholine-containing neurons [23],[24],[25],[26].
7. Histamine has potent and effective painkiller qualities (H2 receptors being involved in the analgesic effects of histamine) [22].
How to Improve Histamine Levels Naturally With Diet, Supplements and More – Read Here : Part I and Part II
