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Sunday, September 8, 2024

Gastroesophageal reflux disease

From Wikipedia, the free encyclopedia
 
Gastroesophageal reflux disease
Other namesBritish: Gastro-oesophageal reflux disease (GORD); gastric reflux disease, acid reflux disease, reflux, gastroesophageal reflux
X-ray showing radiocontrast from the stomach (white material below diaphragm) entering the esophagus (three vertical collections of white material in the mid-line of the chest) due to severe reflux
Pronunciation
SpecialtyGastroenterology
SymptomsTaste of acid, heartburn, bad breath, chest pain, breathing problems
ComplicationsEsophagitis, esophageal strictures, Barrett's esophagus
DurationLong term
CausesInadequate closure of the lower esophageal sphincter
Risk factorsObesity, pregnancy, smoking, hiatal hernia, taking certain medicines
Diagnostic methodGastroscopy, upper GI series, esophageal pH monitoring, esophageal manometry
Differential diagnosisPeptic ulcer disease, esophageal cancer, esophageal spasm, angina
TreatmentLifestyle changes, medications, surgery
MedicationAntacids, H2 receptor blockers, proton pump inhibitors, prokinetics
Frequency~15% (North American and European populations)

Gastroesophageal reflux disease (GERD) or gastro-oesophageal reflux disease (GORD) is a chronic upper gastrointestinal disease in which stomach content persistently and regularly flows up into the esophagus, resulting in symptoms and/or complications. Symptoms include dental corrosion, dysphagia, heartburn, odynophagia, regurgitation, non-cardiac chest pain, extraesophageal symptoms such as chronic cough, hoarseness, reflux-induced laryngitis, or asthma. In the long term, and when not treated, complications such as esophagitis, esophageal stricture, and Barrett's esophagus may arise.

Risk factors include obesity, pregnancy, smoking, hiatal hernia, and taking certain medications. Medications that may cause or worsen the disease include benzodiazepines, calcium channel blockers, tricyclic antidepressants, NSAIDs, and certain asthma medicines. Acid reflux is due to poor closure of the lower esophageal sphincter, which is at the junction between the stomach and the esophagus. Diagnosis among those who do not improve with simpler measures may involve gastroscopy, upper GI series, esophageal pH monitoring, or esophageal manometry.

Treatment options include lifestyle changes, medications, and sometimes surgery for those who do not improve with the first two measures. Lifestyle changes include not lying down for three hours after eating, lying down on the left side, raising the pillow or bedhead height, losing weight, and stopping smoking. Foods that may precipitate GERD symptoms include coffee, alcohol, chocolate, fatty foods, acidic foods, and spicy foods. Medications include antacids, H2 receptor blockers, proton pump inhibitors, and prokinetics.

In the Western world, between 10 and 20% of the population is affected by GERD. It is highly prevalent in North America with 18% to 28% of the population suffering from the condition. Occasional gastroesophageal reflux without troublesome symptoms or complications is even more common. The classic symptoms of GERD were first described in 1925, when Friedenwald and Feldman commented on heartburn and its possible relationship to a hiatal hernia. In 1934 gastroenterologist Asher Winkelstein described reflux and attributed the symptoms to stomach acid.

Signs and symptoms

Adults

The most common symptoms of GERD in adults are an acidic taste in the mouth, regurgitation, and heartburn. Less common symptoms include pain with swallowing/sore throat, increased salivation (also known as water brash), nausea, chest pain, coughing, and globus sensation. The acid reflux can induce asthma attack symptoms like shortness of breath, cough, and wheezing in those with underlying asthma.

GERD sometimes causes injury to the esophagus. These injuries may include one or more of the following:

  • Reflux esophagitis – inflammation of esophageal epithelium which can cause ulcers near the junction of the stomach and esophagus
  • Esophageal strictures – the persistent narrowing of the esophagus caused by reflux-induced inflammation
  • Barrett's esophagus – intestinal metaplasia (changes of the epithelial cells from squamous to intestinal columnar epithelium) of the distal esophagus
  • Esophageal adenocarcinoma – a form of cancer

GERD sometimes causes injury of the larynx (LPR). Other complications can include aspiration pneumonia.

Children and babies

GERD may be difficult to detect in infants and children since they cannot describe what they are feeling and indicators must be observed. Symptoms may vary from typical adult symptoms. GERD in children may cause repeated vomiting, effortless spitting up, coughing, and other respiratory problems, such as wheezing. Inconsolable crying, refusing food, crying for food and then pulling off the bottle or breast only to cry for it again, failure to gain adequate weight, bad breath, and burping are also common. Children may have one symptom or many; no single symptom is universal in all children with GERD.

Of the estimated 4 million babies born in the US each year, up to 35% of them may have difficulties with reflux in the first few months of their lives, known as 'spitting up'. About 90% of infants will outgrow their reflux by their first birthday.

Mouth

Frontal view of severe tooth erosion in GERD
Severe tooth erosion in GERD

Acid reflux into the mouth can cause breakdown of the enamel, especially on the inside surface of the teeth. A dry mouth, acid or burning sensation in the mouth, bad breath and redness of the palate may occur. Less common symptoms of GERD include difficulty in swallowing, water brash, chronic cough, hoarse voice, nausea and vomiting.

Signs of enamel erosion are the appearance of a smooth, silky-glazed, sometimes dull, enamel surface with the absence of perikymata, together with intact enamel along the gum margin. It will be evident in people with restorations as tooth structure typically dissolves much faster than the restorative material, causing it to seem as if it "stands above" the surrounding tooth structure.

Barrett's esophagus

GERD may lead to Barrett's esophagus, a type of intestinal metaplasia, which is in turn a precursor condition for esophageal cancer. The risk of progression from Barrett's to dysplasia is uncertain, but is estimated at 20% of cases. Due to the risk of chronic heartburn progressing to Barrett's, EGD every five years is recommended for people with chronic heartburn, or who take drugs for chronic GERD.

Causes

A comparison of a healthy condition to GERD

A small amount of acid reflux is typical even in healthy people (as with infrequent and minor heartburn), but gastroesophageal reflux becomes gastroesophageal reflux disease when signs and symptoms develop into a recurrent problem. Frequent acid reflux is due to poor closure of the lower esophageal sphincter, which is at the junction between the stomach and the esophagus.

Factors that can contribute to GERD:

  • Hiatal hernia, which increases the likelihood of GERD due to mechanical and motility factors.
  • Obesity: increasing body mass index is associated with more severe GERD. In a large series of 2,000 patients with symptomatic reflux disease, it has been shown that 13% of changes in esophageal acid exposure is attributable to changes in body mass index.

Factors that have been linked with GERD, but not conclusively:

In 1999, a review of existing studies found that, on average, 40% of GERD patients also had H. pylori infection. The eradication of H. pylori can lead to an increase in acid secretion, leading to the question of whether H. pylori-infected GERD patients are any different from non-infected GERD patients. A double-blind study, reported in 2004, found no clinically significant difference between these two types of patients with regard to the subjective or objective measures of disease severity.

Diagnosis

Endoscopic image of peptic stricture, or narrowing of the esophagus near the junction with the stomach: This is a complication of chronic gastroesophageal reflux disease and can be a cause of dysphagia or difficulty swallowing.

The diagnosis of GERD is usually made when typical symptoms are present. Reflux can be present in people without symptoms and the diagnosis requires both symptoms or complications and reflux of stomach content.

Other investigations may include esophagogastroduodenoscopy (EGD). Barium swallow X-rays should not be used for diagnosis. Esophageal manometry is not recommended for use in the diagnosis, being recommended only prior to surgery. Ambulatory esophageal pH monitoring may be useful in those who do not improve after PPIs and is not needed in those in whom Barrett's esophagus is seen. Investigation for H. pylori is not usually needed.

The current gold standard for diagnosis of GERD is esophageal pH monitoring. It is the most objective test to diagnose the reflux disease and allows monitoring GERD patients in their response to medical or surgical treatment. One practice for diagnosis of GERD is a short-term treatment with proton-pump inhibitors, with improvement in symptoms suggesting a positive diagnosis. Short-term treatment with proton-pump inhibitors may help predict abnormal 24-hour pH monitoring results among patients with symptoms suggestive of GERD.

Endoscopy

Endoscopy, the examination of the stomach with a fibre-optic scope, is not routinely needed if the case is typical and responds to treatment. It is recommended when people either do not respond well to treatment or have alarm symptoms, including dysphagia, anemia, blood in the stool (detected chemically), wheezing, weight loss, or voice changes. Some physicians advocate either once-in-a-lifetime or 5- to 10-yearly endoscopy for people with longstanding GERD, to evaluate the possible presence of dysplasia or Barrett's esophagus.

Biopsies performed during gastroscopy may show:

  • Edema and basal hyperplasia (nonspecific inflammatory changes)
  • Lymphocytic inflammation (nonspecific)
  • Neutrophilic inflammation (usually due to reflux or Helicobacter gastritis)
  • Eosinophilic inflammation (usually due to reflux): The presence of intraepithelial eosinophils may suggest a diagnosis of eosinophilic esophagitis (EE) if eosinophils are present in high enough numbers. Less than 20 eosinophils per high-power microscopic field in the distal esophagus, in the presence of other histologic features of GERD, is more consistent with GERD than EE.
  • Goblet cell intestinal metaplasia or Barrett's esophagus
  • Elongation of the papillae
  • Thinning of the squamous cell layer
  • Dysplasia
  • Carcinoma

Reflux changes that are not erosive in nature lead to "nonerosive reflux disease".

Severity

Severity may be documented with the Johnson-DeMeester's scoring system: 0 – None 1 – Minimal – occasional episodes 2 – Moderate – medical therapy visits 3 – Severe – interference with daily activities

Differential diagnosis

Other causes of chest pain such as heart disease should be ruled out before making the diagnosis. Another kind of acid reflux, which causes respiratory and laryngeal signs and symptoms, is called laryngopharyngeal reflux (LPR) or extraesophageal reflux disease (EERD). Unlike GERD, LPR rarely produces heartburn, and is sometimes called silent reflux. Differential diagnosis of GERD can also include dyspepsia, peptic ulcer disease, esophageal and gastric cancer, and food allergies.

Treatment

The treatments for GERD may include food choices, lifestyle changes, medications, and possibly surgery. Initial treatment is frequently with a proton-pump inhibitor such as omeprazole. In some cases, a person with GERD symptoms can manage them by taking over-the-counter drugs. This is often safer and less expensive than taking prescription drugs. Some guidelines recommend trying to treat symptoms with an H2 antagonist before using a proton-pump inhibitor because of cost and safety concerns.

Medical nutrition therapy and lifestyle changes

Medical nutrition therapy plays an essential role in managing the symptoms of the disease by preventing reflux, preventing pain and irritation, and decreasing gastric secretions.

Some foods such as chocolate, mint, high-fat food, and alcohol have been shown to relax the lower esophageal sphincter, increasing the risk of reflux. Weight loss is recommended for the overweight or obese, as well as avoidance of bedtime snacks or lying down immediately after meals (meals should occur at least 2–3 hours before bedtime), elevation of the head of the bed on 6-inch blocks, avoidance of smoking, and avoidance of tight clothing that increases pressure in the stomach. It may be beneficial to avoid spices, citrus juices, tomatoes and soft drinks, and to consume small frequent meals and drink liquids between meals. Some evidence suggests that reduced sugar intake and increased fiber intake can help. Although moderate exercise may improve symptoms in people with GERD, vigorous exercise may worsen them. Breathing exercises may relieve GERD symptoms.

Medications

The primary medications used for GERD are proton-pump inhibitors, H2 receptor blockers and antacids with or without alginic acid. The use of acid suppression therapy is a common response to GERD symptoms and many people get more of this kind of treatment than their case merits. The overuse of acid suppression is a problem because of the side effects and costs.

Proton-pump inhibitors

Proton-pump inhibitors (PPIs), such as omeprazole, are the most effective, followed by H2 receptor blockers, such as ranitidine. If a once-daily PPI is only partially effective they may be used twice a day. They should be taken one half to one hour before a meal. There is no significant difference between PPIs. When these medications are used long-term, the lowest effective dose should be taken. They may also be taken only when symptoms occur in those with frequent problems. H2 receptor blockers lead to roughly a 40% improvement.

Antacids

The evidence for antacids is weaker with a benefit of about 10% (NNT=13) while a combination of an antacid and alginic acid (such as Gaviscon) may improve symptoms by 60% (NNT=4). Metoclopramide (a prokinetic) is not recommended either alone or in combination with other treatments due to concerns around adverse effects. The benefit of the prokinetic mosapride is modest.

Other agents

Sucralfate has similar effectiveness to H2 receptor blockers; however, sucralfate needs to be taken multiple times a day, thus limiting its use. Baclofen, an agonist of the GABAB receptor, while effective, has similar issues of needing frequent dosing in addition to greater adverse effects compared to other medications.

Surgery

The standard surgical treatment for severe GERD is the Nissen fundoplication. In this procedure, the upper part of the stomach is wrapped around the lower esophageal sphincter to strengthen the sphincter and prevent acid reflux and to repair a hiatal hernia. It is recommended only for those who do not improve with PPIs. Quality of life is improved in the short term compared to medical therapy, but there is uncertainty in the benefits of surgery versus long-term medical management with proton pump inhibitors. When comparing different fundoplication techniques, partial posterior fundoplication surgery is more effective than partial anterior fundoplication surgery, and partial fundoplication has better outcomes than total fundoplication.

Esophagogastric dissociation is an alternative procedure that is sometimes used to treat neurologically impaired children with GERD. Preliminary studies have shown it may have a lower failure rate and a lower incidence of recurrent reflux.

In 2012 the U.S. Food and Drug Administration (FDA) approved a device called the LINX, which consists of a series of metal beads with magnetic cores that are placed surgically around the lower esophageal sphincter, for those with severe symptoms that do not respond to other treatments. Improvement of GERD symptoms is similar to those of the Nissen fundoplication, although there is no data regarding long-term effects. Compared to Nissen fundoplication procedures, the procedure has shown a reduction in complications such as gas bloat syndrome that commonly occur. Adverse responses include difficulty swallowing, chest pain, vomiting, and nausea. Contraindications that would advise against use of the device are patients who are or may be allergic to titanium, stainless steel, nickel, or ferrous iron materials. A warning advises that the device should not be used by patients who could be exposed to, or undergo, magnetic resonance imaging (MRI) because of serious injury to the patient and damage to the device.

Some patients who are at an increased surgical risk or do not tolerate PPIs may qualify for a more recently developed incisionless procedure known as a TIF transoral incisionless fundoplication. Benefits of this procedure may last for up to six years.

Special populations

Pregnancy

GERD is a common condition that develops during pregnancy, but usually resolves after delivery. The severity of symptoms tend to increase throughout the pregnancy. In pregnancy, dietary modifications and lifestyle changes may be attempted, but often have little effect. Some lifestyle changes that can be implemented are elevating the head of the bed, eating small portions of food at regularly scheduled intervals, reduce fluid intake with a meal, avoid eating three hours before bedtime, and refrain from lying down after eating. Calcium-based antacids are recommended if these changes are not effective; aluminum- and magnesium hydroxide-based antacids are also safe. Antacids that contain sodium bicarbonate or magnesium trisilicate should be avoided in pregnancy. Sucralfate has been studied in pregnancy and proven to be safe  as is ranitidine and PPIs.

Babies

Babies may see relief with smaller, more frequent feedings, more frequent burping during feedings, holding the baby in an upright position 30 minutes after feeding, keeping the baby's head elevated while laying on the back, removing milk and soy from the mother's diet or feeding the baby milk protein-free formula. They may also be treated with medicines such as ranitidine or proton pump inhibitors. Proton pump inhibitors, however, have not been found to be effective in this population and there is a lack of evidence for safety. The role of an occupational therapist with an infant with GERD includes positioning during and after feeding. One technique used is called the log-roll technique, which is practiced when changing an infant's clothing or diapers. Placing an infant on their back while having their legs lifted is not recommended since it causes the acid to flow back up the esophagus. Instead, the occupational therapist would suggest rolling the child on the side, keeping the shoulders and hips aligned to avoid acid rising up the baby's esophagus. Another technique used is feeding the baby on their side with an upright position instead of lying flat on their back. The final positioning technique used for infants is to keep them on their stomach or upright for 20 minutes after feeding.

Epidemiology

In Western populations, GERD affects approximately 10% to 20% of the population and 0.4% newly develop the condition. For instance, an estimated 3.4 million to 6.8 million Canadians have GERD. The prevalence rate of GERD in developed nations is also tightly linked with age, with adults aged 60 to 70 being the most commonly affected. In the United States 20% of people have symptoms in a given week and 7% every day. No data supports sex predominance with regard to GERD.

History

An obsolete treatment is vagotomy ("highly selective vagotomy"), the surgical removal of vagus nerve branches that innervate the stomach lining. This treatment has been largely replaced by medication. Vagotomy by itself tended to worsen contraction of the pyloric sphincter of the stomach, and delayed stomach emptying. Historically, vagotomy was combined with pyloroplasty or gastroenterostomy to counter this problem.

Research

A number of endoscopic devices have been tested to treat chronic heartburn.

  • Endocinch puts stitches in the lower esophogeal sphincter (LES) to create small pleats to help strengthen the muscle. However, long-term results were disappointing, and the device is no longer sold by Bard.
  • The Stretta procedure uses electrodes to apply radio-frequency energy to the LES. A 2015 systematic review and meta-analysis in response to the systematic review (no meta-analysis) conducted by SAGES did not support the claims that Stretta was an effective treatment for GERD. A 2012 systematic review found that it improves GERD symptoms.
  • NDO Surgical Plicator creates a plication, or fold, of tissue near the gastroesophageal junction, and fixates the plication with a suture-based implant. The company ceased operations in mid-2008, and the device is no longer on the market.
  • Transoral incisionless fundoplication, which uses a device called Esophyx, may be effective.

Basophil

From Wikipedia, the free encyclopedia
 
Basophil
3D rendering of a basophil
 
Dyed basophil among red blood cells
 
Details
SystemImmune system
Identifiers
MeSHD001491
THH2.00.04.1.02022
FMA62862

Basophils are a type of white blood cell. Basophils are the least common type of granulocyte, representing about 0.5% to 1% of circulating white blood cells. They are the largest type of granulocyte. They are responsible for inflammatory reactions during immune response, as well as in the formation of acute and chronic allergic diseases, including anaphylaxis, asthma, atopic dermatitis and hay fever. They also produce compounds that coordinate immune responses, including histamine and serotonin that induce inflammation, and heparin that prevents blood clotting, although there are less than that found in mast cell granules. Mast cells were once thought to be basophils that migrated from the blood into their resident tissues (connective tissue), but they are now known to be different types of cells.

Basophils were discovered in 1879 by German physician Paul Ehrlich, who one year earlier had found a cell type present in tissues that he termed mastzellen (now mast cells). Ehrlich received the 1908 Nobel Prize in Physiology or Medicine for his discoveries.

The name comes from the fact that these leukocytes are basophilic, i.e., they are susceptible to staining by basic dyes, as shown in the picture.

Structure

Basophils contain large cytoplasmic granules which obscure the cell nucleus under the microscope when stained. However, when unstained, the nucleus is visible and it usually has two lobes. The mast cell, another granulocyte, is similar in appearance and function. Both cell types store histamine, a chemical that is secreted by the cells when stimulated. However, they arise from different branches of hematopoiesis, and mast cells usually do not circulate in the blood stream, but instead are located in connective tissue. Like all circulating granulocytes, basophils can be recruited out of the blood into a tissue when needed.

Function

Reference ranges for blood tests of white blood cells, comparing basophil amount (shown in violet) with other cells.

Basophils appear in many specific kinds of inflammatory reactions, particularly those that cause allergic symptoms. Basophils contain anticoagulant heparin, which prevents blood from clotting too quickly. They also contain the vasodilator histamine, which promotes blood flow to tissues. They can be found in unusually high numbers at sites of ectoparasite infection (e.g., ticks).

Like eosinophils, basophils play a role in both parasitic infections and allergies. They are found in tissues where allergic reactions are occurring and probably contribute to the severity of these reactions. Basophils have protein receptors on their cell surface that bind IgE, an immunoglobulin involved in macroparasite defense and allergy. It is the bound IgE antibody that confers a selective response of these cells to environmental substances (e.g., pollen proteins or helminth antigens).

Recent studies in mice suggest that basophils may also regulate the behavior of T cells and mediate the magnitude of the secondary immune response.

CD200

Basophil function is inhibited by CD200. Herpesvirus-6, herpesvirus-7, and herpesvirus-8 produce a CD200 homolog which also inhibits basophil function. This suggests that basophils may play a role in the immune response to these viruses. The role of basophils in the immune response to these viruses is further supported by findings that the CD200 receptor is expressed more frequently in basophils than in other circulating leukocytes.

Secretions

Basophils arise and mature in bone marrow. When activated, basophils degranulate to release histamine, proteoglycans (e.g. heparin and chondroitin), and proteolytic enzymes (e.g. elastase and lysophospholipase). They also secrete lipid mediators like leukotrienes (LTD-4), and several cytokines. Histamine and proteoglycans are pre-stored in the cell's granules while the other secreted substances are newly generated. Each of these substances contributes to inflammation. Recent evidence suggests that basophils are an important source of the cytokine, interleukin-4, perhaps more important than T cells. Interleukin-4 is considered one of the critical cytokines in the development of allergies and the production of IgE antibody by the immune system. There are other substances that can activate basophils to secrete which suggests that these cells have other roles in inflammation.

The degranulation of basophils can be investigated in vitro by using flow cytometry and the so-called basophil-activation-test (BAT). Especially, in the diagnosis of allergies including of drug reactions (e.g. induced by contrast medium), the BAT is of great impact.

Basopenia (a low basophil count) is difficult to demonstrate as the normal basophil count is so low; it has been reported in association with autoimmune urticaria (a chronic itching condition). Basophilia is also uncommon but may be seen in some forms of leukemia or lymphoma.

Clinical significance

Immunophenotyping

Basophils of mice and humans have consistent immunophenotypes, including FcεRI+, CD123, CD49b(DX-5)+, CD69+, Thy-1.2+, 2B4+, CD11bdull, CD117(c-kit), CD24, CD19, CD80, CD14, CD23, Ly49c, CD122, CD11c, Gr-1, NK1.1, B220, CD3, γδTCR, αβTCR, α4 and β4-integrin negative.

Recently, Heneberg proposed that basophils may be defined as the cellular population positive for CD13, CD44, CD54, CD63, CD69, CD107a, CD123, CD164, CD193/ CCR3, CD203c, TLR-4, and FcεRI. When activated, some additional surface markers are known to be upregulated (CD13, CD107a, CD164), or surface-exposed (CD63, and the ectoenzyme CD203c).

Allergy diagnosis

Basophils are easily isolated from venous blood and present good "indicator cells" of an IgE-mediated allergic response based on the upregulation of activation markers such as CD63 and/or CD203c upon suspect allergen stimulation. Therefore, the BAT serves to confirm IgE-mediated allergy following uncertain results from classical testing based on anamnesis, skin testing or specific IgE results. More recently, BAT has also been used for the monitoring of successful allergen immunotherapy (desensitization) to differentiate short-term desensitization versus sustained unresponsiveness to the allergen.

Etymology and pronunciation

The word basophil uses combining forms of baso- + -phil, yielding "base-loving".

Mast cell

From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Mast_cell
 
Mastocyte
Two mast cells in bone marrow
Details
SystemImmune system
Identifiers
Latinmastocytus
MeSHD008407
THH2.00.03.0.01010
FMA66784

A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a part of the immune and neuroimmune systems. Mast cells were discovered by Paul Ehrlich in 1877. Although best known for their role in allergy and anaphylaxis, mast cells play an important protective role as well, being intimately involved in wound healing, angiogenesis, immune tolerance, defense against pathogens, and vascular permeability in brain tumors.

The mast cell is very similar in both appearance and function to the basophil, another type of white blood cell. Although mast cells were once thought to be tissue-resident basophils, it has been shown that the two cells develop from different hematopoietic lineages and thus cannot be the same cells.

Structure

Illustration depicting mast cell activation and anaphylaxis
Mast cell

Mast cells are very similar to basophil granulocytes (a class of white blood cells) in blood, in the sense that both are granulated cells that contain histamine and heparin, an anticoagulant. Their nuclei differ in that the basophil nucleus is lobated while the mast cell nucleus is round. The Fc region of immunoglobulin E (IgE) becomes bound to mast cells and basophils, and when IgE's paratopes bind to an antigen, it causes the cells to release histamine and other inflammatory mediators. These similarities have led many to speculate that mast cells are basophils that have "homed in" on tissues. Furthermore, they share a common precursor in bone marrow expressing the CD34 molecule. Basophils leave the bone marrow already mature, whereas the mast cell circulates in an immature form, only maturing once in a tissue site. The site an immature mast cell settles in probably determines its precise characteristics. The first in vitro differentiation and growth of a pure population of mouse mast cells has been carried out using conditioned medium derived from concanavalin A-stimulated splenocytes. Later, it was discovered that T cell-derived interleukin 3 was the component present in the conditioned media that was required for mast cell differentiation and growth.

Mast cells in rodents are classically divided into two subtypes: connective tissue-type mast cells and mucosal mast cells. The activities of the latter are dependent on T-cells.

Mast cells are present in most tissues characteristically surrounding blood vessels, nerves and lymphatic vessels, and are especially prominent near the boundaries between the outside world and the internal milieu, such as the skin, mucosa of the lungs, and digestive tract, as well as the mouth, conjunctiva, and nose.

Function

The role of mast cells in the development of allergy.

Mast cells play a key role in the inflammatory process. When activated, a mast cell can either selectively release (piecemeal degranulation) or rapidly release (anaphylactic degranulation) "mediators", or compounds that induce inflammation, from storage granules into the local microenvironment. Mast cells can be stimulated to degranulate by allergens through cross-linking with immunoglobulin E receptors (e.g., FcεRI), physical injury through pattern recognition receptors for damage-associated molecular patterns (DAMPs), microbial pathogens through pattern recognition receptors for pathogen-associated molecular patterns (PAMPs), and various compounds through their associated G-protein coupled receptors (e.g., morphine through opioid receptors) or ligand-gated ion channels. Complement proteins can activate membrane receptors on mast cells to exert various functions as well.

Mast cells express a high-affinity receptor (FcεRI) for the Fc region of IgE, the least-abundant member of the antibodies. This receptor is of such high affinity that binding of IgE molecules is in essence irreversible. As a result, mast cells are coated with IgE, which is produced by plasma cells (the antibody-producing cells of the immune system). IgE antibodies are typically specific to one particular antigen.

In allergic reactions, mast cells remain inactive until an allergen binds to IgE already coated upon the cell. Other membrane activation events can either prime mast cells for subsequent degranulation or act in synergy with FcεRI signal transduction. In general, allergens are proteins or polysaccharides. The allergen binds to the antigen-binding sites, which are situated on the variable regions of the IgE molecules bound to the mast cell surface. It appears that binding of two or more IgE molecules (cross-linking) is required to activate the mast cell. The clustering of the intracellular domains of the cell-bound Fc receptors, which are associated with the cross-linked IgE molecules, causes a complex sequence of reactions inside the mast cell that lead to its activation. Although this reaction is most well understood in terms of allergy, it appears to have evolved as a defense system against parasites and bacteria.

Mast cell mediators

A unique, stimulus-specific set of mast cell mediators is released through degranulation following the activation of cell surface receptors on mast cells. Examples of mediators that are released into the extracellular environment during mast cell degranulation include:

Structure of histamine

Histamine dilates post-capillary venules, activates the endothelium, and increases blood vessel permeability. This leads to local edema (swelling), warmth, redness, and the attraction of other inflammatory cells to the site of release. It also depolarizes nerve endings (leading to itching or pain). Cutaneous signs of histamine release are the "flare and wheal"-reaction. The bump and redness immediately following a mosquito bite are a good example of this reaction, which occurs seconds after challenge of the mast cell by an allergen.

The other physiologic activities of mast cells are much less-understood. Several lines of evidence suggest that mast cells may have a fairly fundamental role in innate immunity: They are capable of elaborating a vast array of important cytokines and other inflammatory mediators such as TNF-α; they express multiple "pattern recognition receptors" thought to be involved in recognizing broad classes of pathogens; and mice without mast cells seem to be much more susceptible to a variety of infections.

Mast cell granules carry a variety of bioactive chemicals. These granules have been found to be transferred to adjacent cells of the immune system and neurons in a process of transgranulation via mast cell pseudopodia.

In the nervous system

Unlike other hematopoietic cells of the immune system, mast cells naturally occur in the human brain where they interact with the neuroimmune system. In the brain, mast cells are located in a number of structures that mediate visceral sensory (e.g. pain) or neuroendocrine functions or that are located along the blood–cerebrospinal fluid barrier, including the pituitary stalk, pineal gland, thalamus, and hypothalamus, area postrema, choroid plexus, and in the dural layer of the meninges near meningeal nociceptors. Mast cells serve the same general functions in the body and central nervous system, such as effecting or regulating allergic responses, innate and adaptive immunity, autoimmunity, and inflammation. Across systems, mast cells serve as the main effector cell through which pathogens can affect the gut–brain axis.

In the gut

In the gastrointestinal tract, mucosal mast cells are located in close proximity to sensory nerve fibres, which communicate bidirectionally. When these mast cells initially degranulate, they release mediators (e.g., histamine, tryptase, and serotonin) which activate, sensitize, and upregulate membrane expression of nociceptors (i.e., TRPV1) on visceral afferent neurons via their receptors (respectively, HRH1, HRH2, HRH3, PAR2, 5-HT3); in turn, neurogenic inflammation, visceral hypersensitivity, and intestinal dysmotility (i.e., impaired peristalsis) result. Neuronal activation induces neuropeptide (substance P and calcitonin gene-related peptide) signaling to mast cells where they bind to their associated receptors and trigger degranulation of a distinct set of mediators (β-Hexosaminidase, cytokines, chemokines, PGD2, leukotrienes, and eoxins).

Physiology

Structure of FcεR1 on mast cell. FcεR1 is a tetramer made of one alpha (α) chain, one beta (β) chain, and two gamma (γ) chains. IgE is binding to α chain, signal is transduced by ITAM motifs on β and γ chains.

Structure of the high-affinity IgE receptor, FcεR1

FcεR1 is a high affinity IgE-receptor that is expressed on the surface of the mast cell. FcεR1 is a tetramer made of one alpha (α) chain, one beta (β) chain, and two identical, disulfide-linked gamma (γ) chains. The binding site for IgE is formed by the extracellular portion of the α chain that contains two domains that are similar to Ig. One transmembrane domain contains an aspartic acid residue, and one contains a short cytoplasmic tail. The β chain contains, a single immunoreceptor tyrosine-based activation motif ITAM, in the cytoplasmic region. Each γ chain has one ITAM on the cytoplasmic region. The signaling cascade from the receptor is initiated when the ITAMs of the β and γ chains are phosphorylated by a tyrosine kinase. This signal is required for the activation of mast cells. Type 2 helper T cells,(Th2) and many other cell types lack the β chain, so signaling is mediated only by the γ chain. This is due to the α chain containing endoplasmic reticulum retention signals that causes the α-chains to remain degraded in the ER. The assembly of the α chain with the co-transfected β and γ chains mask the ER retention and allows the α β γ complex to be exported to the golgi apparatus to the plasma membrane in rats. In humans, only the γ complex is needed to counterbalance the α chain ER retention.

Allergen process

Allergen-mediated FcεR1 cross-linking signals are very similar to the signaling event resulting in antigen binding to lymphocytes. The Lyn tyrosine kinase is associated with the cytoplasmic end of the FcεR1 β chain. The antigen cross-links the FcεR1 molecules, and Lyn tyrosine kinase phosphorylates the ITAMs in the FcεR1 β and γ chain in the cytoplasm. Upon the phosphorylation, the Syk tyrosine kinase gets recruited to the ITAMs located on the γ chains. This causes activation of the Syk tyrosine kinase, causing it to phosphorylate. Syk functions as a signal amplifying kinase activity due to the fact that it targets multiple proteins and causes their activation. This antigen stimulated phosphorylation causes the activation of other proteins in the FcεR1-mediated signaling cascade.

Degranulation and fusion

An important adaptor protein activated by the Syk phosphorylation step is the linker for activation of T cells (LAT). LAT can be modified by phosphorylation to create novel binding sites. Phospholipase C gamma (PLCγ) becomes phosphorylated once bound to LAT, and is then used to catalyze phosphatidylinositol bisphosphate breakdown to yield inositol trisphosphate (IP3) and diacyglycerol (DAG). IP3 elevates calcium levels, and DAG activates protein kinase C (PKC). This is not the only way that PKC is made. The tyrosine kinase FYN phosphorylates Grb2-associated-binding protein 2 (Gab2), which binds to phosphoinositide 3-kinase, which activates PKC. PKC leads to the activation of myosin light-chain phosphorylation granule movements, which disassembles the actin–myosin complexes to allow granules to come into contact with the plasma membrane. The mast cell granule can now fuse with the plasma membrane. Soluble N-ethylmaleimide sensitive fusion attachment protein receptor SNARE complex mediates this process. Different SNARE proteins interact to form different complexes that catalyze fusion. Rab3 guanosine triphosphatases and Rab-associated kinases and phosphatases regulate granule membrane fusion in resting mast cells.

MRGPRX2 mast cell receptor

Human mast-cell-specific G-protein-coupled receptor MRGPRX2 plays a key role in the recognition of pathogen associated molecular patterns (PAMPs) and initiating an antibacterial response. MRGPRX2 is able to bind to competence stimulating peptide (CSP) 1 - a quorum sensing molecule (QSM) produced by Gram-positive bacteria. This leads to signal transduction to a G protein and activation of the mast cell. Mast cell activation induces the release of antibacterial mediators including ROS, TNF-α and PRGD2 which institute the recruitment of other immune cells to inhibit bacterial growth and biofilm formation.

The MRGPRX2 receptor is a possible therapeutic target and can be pharmacologically activated using the agonist compound 48/80 to control bacterial infection. It is also hypothesised that other QSMs and even Gram-negative bacterial signals can activate this receptor. This might particularly be the case during Bartonella chronic infections where it appears clearly in human symptomatology that these patients all have a mast cell activation syndrome due to the presence of a not yet defined quorum sensing molecule (basal histamine itself?). Those patients are prone to food intolerance driven by another less specific path than the IgE receptor path: certainly the MRGPRX2 route. These patients also show cyclical skin pathergy and dermographism, every time the bacteria exits its hidden intracellular location.

Enzymes

Enzyme Function
Lyn tyrosine kinase Phosphorylates the ITAMs in the FcεR1 β and γ chain in the cytoplasm. It causes Syk tyrosine kinase to get recruited to the ITAMS located on the γ chains. This causes activation of the Syk tyrosine kinase, causing it to phosphorylate
Syk tyrosine kinase Targets multiple proteins and causes their activation
Phospholipase C Catalyzes phosphatidylinositol 4,5-bisphosphate
Inositol trisphosphate Elevates calcium levels
Diacylglycerol Activates protein kinase C
FYN Phosphorylates GAB2
GAB2 Binds to phosphoinositide 3-kinase
Phosphoinositide 3-kinase Activates protein kinase C
Protein kinase C Activates myosin light-chain phosphorylation granule movements that disassemble the actin-myosin complexes
Rab-associated kinases and phosphatases Regulate cell granule membrane fusion in resting mast cells

Clinical significance

Parasitic infections

Mast cells are activated in response to infection by pathogenic parasites, such as certain helminths and protozoa, through IgE signaling.

Mast cell activation disorders

Mast cell activation disorders (MCAD) are a spectrum of immune disorders that are unrelated to pathogenic infection and involve similar symptoms that arise from secreted mast cell intermediates, but differ slightly in their pathophysiology, treatment approach, and distinguishing symptoms. The classification of mast cell activation disorders was laid out in 2010.

Allergic disease

Allergies are mediated through IgE signaling which triggers mast cell degranulation. Recently, IgE-independent "pseudo-allergic" reactions are thought to also be mediated via the MRGPRX2 receptor activation of mast cells (e.g. drugs such as muscle relaxants, opioids, Icatibant and fluoroquinolones).

Many forms of cutaneous and mucosal allergy are mediated in large part by mast cells; they play a central role in asthma, eczema, itch (from various causes), allergic rhinitis and allergic conjunctivitis. Antihistamine drugs act by blocking histamine action on nerve endings. Cromoglicate-based drugs (sodium cromoglicate, nedocromil) block a calcium channel essential for mast cell degranulation, stabilizing the cell and preventing release of histamine and related mediators. Leukotriene antagonists (such as montelukast and zafirlukast) block the action of leukotriene mediators and are being used increasingly in allergic diseases.

Calcium triggers the secretion of histamine from mast cells after previous exposure to sodium fluoride. The secretory process can be divided into a fluoride-activation step and a calcium-induced secretory step. It was observed that the fluoride-activation step is accompanied by an elevation of cyclic adenosine monophosphate (cAMP) levels within the cells. The attained high levels of cAMP persist during histamine release. It was further found that catecholamines do not markedly alter the fluoride-induced histamine release. It was also confirmed that the second, but not the first, step in sodium fluoride-induced histamine secretion is inhibited by theophylline. Vasodilation and increased permeability of capillaries are a result of both H1 and H2 receptor types.

Stimulation of histamine activates a histamine (H2)-sensitive adenylate cyclase of oxyntic cells, and there is a rapid increase in cellular [cAMP] that is involved in activation of H+ transport and other associated changes of oxyntic cells.

Anaphylaxis

In anaphylaxis (a severe systemic reaction to allergens, such as nuts, bee stings, or drugs), the body-wide degranulation of mast cells leads to vasodilation and, if severe, symptoms of life-threatening shock.

Histamine is a vasodilatory substance released during anaphylaxis.

Autoimmunity

Mast cells may be implicated in the pathology associated with autoimmune, inflammatory disorders of the joints. They have been shown to be involved in the recruitment of inflammatory cells to the joints (e.g., rheumatoid arthritis) and skin (e.g., bullous pemphigoid), and this activity is dependent on antibodies and complement components.

Mastocytosis and clonal disorders

Mastocytosis is a rare clonal mast cell disorder involving the presence of too many mast cells (mastocytes) and CD34+ mast cell precursors. Mutations in c-Kit are associated with mastocytosis. More specifically, the majority of patients with mastocytosis have a mutation at codon 816 in the kinase domain of KIT, known as the KIT D816V mutation.

Neoplastic disorders

Mastocytomas, or mast cell tumors, can secrete excessive quantities of degranulation products. They are often seen in dogs and cats. Other neoplastic disorders associated with mast cells include mast cell sarcoma and mast cell leukemia.

Mast cell activation syndrome

Mast cell activation syndrome (MCAS) is an idiopathic immune disorder that involves recurrent and excessive mast cell degranulation and which produces symptoms that are similar to other mast cell activation disorders. The syndrome is diagnosed based upon four sets of criteria involving treatment response, symptoms, a differential diagnosis, and biomarkers of mast cell degranulation.

History

Mast cells were first described by Paul Ehrlich in his 1878 doctoral thesis on the basis of their unique staining characteristics and large granules. These granules also led him to the incorrect belief that they existed to nourish the surrounding tissue, so he named them Mastzellen (from German Mast 'fattening', as of animals). They are now considered to be part of the immune system.

Research

Autism

Research into an immunological contribution to autism suggests that autism spectrum disorder (ASD) children may present with "allergic-like" problems in the absence of elevated serum IgE and chronic urticaria, suggesting non-allergic mast cell activation in response to environmental and stress triggers. This mast cell activation could contribute to brain inflammation and neurodevelopmental problems.

Histological staining

Toluidine blue: one of the most common stains for acid mucopolysaccharides and glycoaminoglycans, components of mast cells granules.

Bismarck brown: stains mast cell granules brown.

Surface markers: cell surface markers of mast cells were discussed in detail by Heneberg, claiming that mast cells may be inadvertently included in the stem or progenitor cell isolates, since part of them is positive for the CD34 antigen. The classical mast cell markers include the high-affinity IgE receptor, CD117 (c-Kit), and CD203c (for most of the mast cell populations). Expression of some molecules may change in course of the mast cell activation.

Other organisms

Mast cells and enterochromaffin cells are the source of most serotonin in the stomach in rodents.

Renaissance philosophy

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