The body produces immunological factors that provide appropriate responses to invasions from intruders, whether they be bacteria, virus, fungi, or parasites. They do so by an intricate system of mediators, identifiers, destroyers, and other cellular and biochemical signals, many of which are all involved in the same defensive processes. However, there is an antibody known as immunoglobulin E (IgE) that is specifically made to mediate the fight against parasitic (most commonly helminths) infections by attaching to the parasite surface (marking them) and subsequently sending a signal to destroyer cells (in this case, eosinophils) to come and attack the invader1.
A parasitic infection, such as from helminths, requires a strong reaction from the immune system because such an infection can have serious health consequences. A main feature of IgE mediated reactions is its quick response time, which is just minutes after contact. However, in type 1 hypersensitivity, increased IgE production occurs in the presence of an everyday allergen (dust, pet dander, mites, etc.) instead of a parasite.
As an analogy, this is like using a car to travel half a block instead of just walking; it’s simply not cost-effective for the body to react by IgE mediation in the case of otherwise harmless allergens. The genetic tendency of some individuals to have a disproportionate reaction to the level of threat is called atopy. Because type 1 hypersensitivity responses happen quickly, they’re also referred to as ‘immediate hypersensitivity’ reactions. Like all hypersensitive reactions, it is fundamental to have been previously exposed to the antigen in question for sensitization to take place.
Pathological manifestations include hay fever, urticaria (hives), rhino-conjunctivitis, contact dermatitis, anaphylaxis, eczematous processes (like in atopic dermatitis), and asthma, among others2. Such an overreaction to minor allergens (antigens) is thanks to an increased production and secretion of IgE by plasma cells and their subsequent attachment to mast cells and basophils3, triggering a reaction that can be systemic or local.
But first, sensitization needs to take place, wherein the body has been previously exposed to the antigen and can now recognize it easily and react swiftly thanks to the ability of some mediators to ‘remember’ the offending antigen. Sensitization occurs by:
- IgE synthesis by antibody secretory cells upon first-time contact with the antigen.
- IgE secretion, and attachment to specific receptors on the membranes of mast cells and basophils. 4
It should be noted that a desensitizing process could happen when the patient ceases to respond against the same antigen. This can give rise to the notion that hypersensitivity has been reversed, but it’s not necessarily the case since the lack of a type 1 reaction can be due to other factors.
After IgE antibodies attach to target cells, secretion of mediators takes place in 2 phases.
- Early phase: characterized by the activation and release of histamine, leukotrienes, and prostaglandins within 15 minutes. Their action produces local reactions, such as elevated vascular permeability, smooth muscle contraction of affected tissue, vasodilation, and inflammation.
- Late phase, or recruiter phase: occurs within 24 hours. It involves a call to action for eosinophils, basophils, and Th2 lymphocytes; which in turn promulgate the production of more mediators, worsening the inflammatory process.5
In healthy people, a lab reading of IgE plasma is normally <600 UI/mL, whereas atopic patients have a much higher concentration of plasma IgE. “The IgE blood test only represents a protein which is 1/100th of all the items we think are involved in allergy. IgE is important but it is not the only marker. A high level of IgE can indicate an allergy, but it may not; and some severely allergic people have low IgE scores.” comments Dr. Kari Nadeau at the Stanford School of Medicine.
IgE synthesis is a crucial aspect in type 1 hypersensitivity reactions as it correlates to severity of manifestations. Production is achieved by eloquent communication between activated T cell proteins, interleukins, and mediator cells. “The induction of allergen-specific IgE synthesis requires the cognate interactions between B and T helper (Th) 2 cells. The B cell-activating signal for IgE synthesis is delivered through interleukin (IL)-4 or IL-13 and CD40 ligand, which are provided by activated Th2 cells.” explains Yukiyoshi Yanagihara PhD, Clinical Research Center for Allergy, National Sagamihara Hospital in Japan.6
This interaction is crucial for the production of IgE antibodies, where CD4-T lymphocytes generate an isotype change in the B lymphocytes responsible for secreting antibodies.
IgE synthesis regulation depends on several other factors:
- Genetics: Studies demonstrate atopic diseases are transmitted by autosomal mechanisms. Mutations located in different chromosomes that predispose humans to this pathology have been identified, such as the gene that encodes IgE receptors and cytokines IL-4. Within atopic family members, target organs of IgE mediated reactions aren’t always the same, as each person can manifest a different disease and at varying degrees of severity. For example, one person can suffer asthmatic episodes, while another develops atopic dermatitis. Regardless, all of those affected present higher concentrations of IgE than normal. 7
- Environmental factors: for example, exposure to pollen, mold, dander, tobacco smoke, cockroaches and mites. The spectrum of allergens in which people are exposed to in a lifetime represent a significant environmental influence. A repetitive subjection to a determined antigen is necessary for the development of atopic reactions.7
- Gestational factors: Women who are pregnant and have acquired an infection of some kind contribute to the risk of the infant becoming sensitized. There are also food allergens that can be consumed by the mother that triggers IgE production on behalf of the fetus.8
A pregnant woman with a history of asthma can also coax the fetus to begin producing IgE. This is even more significant in the US, where an estimated 18% – 30% of expecting mothers suffer from an atopic condition.9 Certain medications during pregnancy, such as progesterone, can also present a risk of sensitization.
- Type of Antigen: also called allergens, they’re very diverse in nature. For the most part, they are harmless and do not present a threat to a non-atopic person. However, it’s believed that the antigen itself isn’t the issue, rather, it’s the capacity to summon IgE antibodies that causes problems. There is nothing physical, chemical, or structural about allergens like pollen, dust, or mites that should trigger a reaction mediated by IgE. This capacity is reflective of a multitude of complex genetic and environmental factors.
IgE secretion and attachment to high affinity receptors, such as Fc and RI, occurs after contact with an allergen. At this point, the sensitization phase is complete, with which a future exposure will arouse yet another phase of liberation of mediators. When allergens interact with IgE molecules on mastocyte membranes, it produces a cross-linking between Fc epsilon RI of at least 2 adjacent receptors; a mechanism required for the activation of these cells. Mastocytes are located in the most important entryways of antigen invasion, namely, the epithelium of the respiratory system, gastrointestinal tract, and integumentary system. They’re in charge of alerting the immune system of certain aggressions and promoting an inflammatory reaction. In other words, there’s an overreaction if we consider the allergen is not a dangerous pathogen (as is the case with microbes). As such, the consequence of the activation of IgE dependent mastocytes is directly related to the point of entry into the body, which can be the lungs (dust, pollen), gastrointestinal (via food or medication) tract, of parenteral origin (injections, insect bites), and mucouscutaneous. As a result, the implied point of access will determine the clinical manifestations from type 1 reactions.11
Sensitization happens in such a way where a significant proportion of the IgE attached to mastocytes have the ability to recognize the same antigen in case of future encounters. When these individuals come into contact with the allergen again, an immediate response is generated, a product of the direct activation of mastocytes.
Activation of Granulocytes – White Blood Cells Involved in Type 1
Mastocytes originate from the stem cells present in bone marrow and are distributed throughout the connective tissue. Anatomically, they can be found adjacent to blood and lymph vessels, inside or near nerves, and under epithelial surfaces. Inside the cell, they present cytoplasmic granules that store previously formed chemical mediators called cytokines, which mediate cellular interactions.
Under normal circumstances, mastocytes are not a component of blood circulation. Instead, their immature progenitors migrate to peripheral tissue, where they then differentiate in situ.12 Their membrane surface express Fc and RI receptors, which become activated when an antigen combines with at least two continuous IgE antibodies, effectuating the previously mentioned crosslinking.13 This activation is unleashed in seconds, followed by the liberation of different mediators.
Natural Killer Cells (NK)
The name isn’t too subtle, is it? It derives from their cytotoxic effect on target cells that were invaded by a virus, or they can also act on tumoral growths. Inside the cell, their granules produce powerful proteins, such as protease and perforin, both of which are highly cytolytic. NK cells activate by interacting with receptors of other cells. An important marker is MHC-1 receptor, which is found in healthy cells but not in cancerous or infected cells. NKs detect this lack of MHC-1 and react by killing it. However, if MHC-1 is present, certain inhibitor receptors on the membrane of NK cells shut down any attempt at provoking lysis or apoptosis to the target cell. In this way, it’s able to regulate cytotoxic action.14
Basophils present structural and functional similarities to mastocytes. What’s more, they also originate in the bone marrow from stem cells. However, they differentiate and mature in the bone marrow first and then they subsequently join the blood circulation. Under normal circumstances, they do not reside in peripheral tissue, but are capable of infiltrating sites where immunological processes occur. Like mastocytes, basophils store pre-formed mediators within their cytoplasmic granules. Basophils also express Fc and RI, so they are capable of fixing IgE antibodies on their membranes and become active by the attachment of an antigen. Therefore, basophils that migrate to tissue where allergens are present contribute to immediate hypersensitivity reactions.15
Like basophils, these granulocytes originate and mature in the bone marrow first and join the bloodstream second. They are normally found in peripheral tissue, especially the mucosa of the respiratory, digestive, and urinary tract. Their main function is to recognize and eliminate parasites that are coated with IgE antibodies. The proteinic mediators released by the granules of eosinophils are toxic to parasites, but they can also damage normal tissue.
The cytokines produced by TH2 lymphocytes stimulate the activation of eosinophils, who then get attracted to the site of inflammation. A powerful eosinophil activator is cytokine IL5. It stimulates the maturation of eosinophils from its precursors and improves their ability to release the histaminic content of their intracellular granules.16 The infiltration of eosinophils to sites infected by helminths (macro-parasitic worms) depends on the combination of interactions between adhesion molecules and chemokines – a type of cytokine whose function is to coax white blood cells to infection sites.17
Lipid mediators secreted by mastocytes stimulate eosinophils (during the late phase), activating them and causing their migration to inflammatory sites, where they release the content of their granules and amplify the immunological response.18 Mediators produced by eosinophils are efficient antifungal, antiparasitic, and antibacterial agents.
- Lipid mediators (leukotrienes, prostaglandins, and PAF)
- Cytokines (over 35 types)
- Chemical mediators
Counterproductively, other mediators like the acid hydrolases contained within granulocytes can destroy host cells besides invading pathogens.19
Examples of acid hydrolases:
- Proteoglycan 2 (PRG2), also known as major basic protein (MBP) – toxic to helminths, microbes, tumors, and host cells. It directly increases the reactivity of smooth muscles due to the dysfunction of the vagus nerve.20 It also triggers the degranulation of basophils and mastocytes.
- Ribonuclease 3 – part of the human RNase family, it’s also known as eosinophil cationic protein, or ECP – helps fight against fungi, bacteria, and parasites.17
- Eosinophil derived neurotoxin (EDN) – one of the most prolific RNases in humans, they promote dendritic differentiation, alert Th2 cells, and reduce the infectious ability of single RNA viruses.21
- Eosinophil peroxidase – toxic to helminths, protozoans, bacteria, and tumors. 22
In the initial phase, released mediators do not last long, so their potent effects are limited to the vicinity where mast cell activation initially occurred. The effects of the late phase also occur at the site of activation, but in this case, the recruited cells that amplify and intensify the response will determine the speed in which the inflammation is resolved, and thus, the consequences it will produce in the individual.18
Preformed mediators are found synthesized and stored inside the cytoplasmic granules of basophils and mast cells ready to be released once activation occurs. This release occurs through exocytosis, a process that ensures preformed mediators arrive at the site of the lesion quickly, a characteristic that allows us to differentiate them from mediators that are synthesized anew.
In the context of immunological responses, the main preformed mediators are tryptase & chymase (both are neutral proteases), histamine (a biogenic amine), and chondroitin sulfate & heparin (they’re both proteoglycans). 23
Tryptase and Chymase
They’re a major protein component of secretory granules of mastocytes. The exact mechanism by which they act is unknown. Nevertheless, it has been demonstrated in vitro that tryptase degrades fibrinogen and activates collagenase; while chymase can degrade the basal membrane of the epidermis and stimulate the secretion of mucus.24
Histamine is an extremely important vasoactive amine in the body and are secreted by granular organelles found inside some cells, most of which are mastocytes. Mast cells serve to store histamine for immediate availability to surrounding tissue and can bind to a diversity of cells that express H1, H2, and H3 histamine receptors. This binding triggers a cascade of intracellular signals that give rise to modified vascular behavior by inducing vascular epithelial cell contraction and causing a gap at the junction between each epithelial cell.25 This allows leukocytes and other immunological factors to permeate through the vascular wall and engage the aggressor at the site of injury. Histamine also produces arteriole dilation (by promoting the cellular synthesis of prostacyclin and nitrous oxide) for increased blood flow to the area to ensure all the necessary immunological components arrive to the site of interest, including the all-important clotting factors like platelets26. Basically, histamine induces vascular leakage to achieve a subsequent increased influx of lymphocytic volume. “Histamine is also essential in defending the body against invasion by potentially disease-causing agents such as bacteria, viruses and other foreign bodies” said Dr. Janice Joneja, a world expert on histamine intolerance who holds a Ph.D. in Medical Microbiology and Immunology, she is also a registered dietitian (RD)27.
In the blood, basophils are the main source of histamine.
Heparin and Chondroitin Sulfate
Acting as matrixes for the storage of biogenic amines, proteases, and other preformed mediators inside granules, they retain and avoid their access to the rest of the cell. After excitation of the granule, the mediators free themselves from proteoglycans in different velocities, with the biogenic amines releasing at a higher speed than the rest. This way, proteoglycans can control the kinetics of immediate hypersensitivity reactions.
Factors of Chemotaxis
As stimulators of cell migration, eosinophil chemotactic factor (ECF) and neutrophil chemotactic factor (NCF) play a crucial role in the late response reaction by attracting inflammatory cells to the core site of degranulation.28
Mediators Synthesized Anew
Mastocytes and basophils produce a variety of notable cytokines that may promote allergic inflammation, including IL-1, IL-3, IL-4, IL-5, IL-6, IL-13, MIP-1, GM-CSF, and TNF-α. These play an important role in isotope changes, contribute to the survival of eosinophils, and sparks the rapid increase of mastocytes. Furthermore, preformed TNF can be stored in cytoplasmic granules, ready for a quick release. TNF activates the expression of endothelial adhesion molecules that allow an influx of monocytes, PMN (polymorphonuclear lymphocytes) and TH2 lymphocytes, all of which synthesize some of the aforementioned cytokines.
The most significant lipid mediators originate from the enzymatic action of lipoxygenase and cyclooxygenase on arachidonic acid. Part of their function is to effect smooth muscles of bronchioles, leukocytes, and blood vessels. However, research has shown linoleic acid as another source of lipid mediators. “Our team recently discovered a new family of lipid mediators derived from linoleic acid that are abundant in inflamed human skin and other tissues, which appear to play a role in pain and itch”, said Christopher Ramsden, M.D., the principal investigator on the Laboratory of Clinical Investigation / Lipid Mediators, Inflammation, and Pain Unit.29
In the cyclooxygenase pathway, the main mediator is prostaglandin D2 (PGD2), which binds to receptors of smooth muscle cells to induce vasodilation and bronchoconstriction. It also stimulates chemotaxis of neutrophils and encourages self-accumulation at sites of inflammation.
Non-steroidal anti-inflammatory drugs (NSAIDs) block the cyclooxygenase enzyme pathway, offering a deviation towards the lipoxygenase pathway, whose main mediators are leukotriene C4 (LTC4) and the products of their disintegration, namely, D4 and E4.30 As a whole, leukotrienes C4, D4, and E4 are called slow reacting substances of anaphylaxis (SRS-A) and are fundamental in the pathogeny of asthma. Leukotrienes produced by mastocytes bind to specific receptors of smooth muscle cells and cause bronchoconstriction.31 There is yet another mediator, called platelet-activating factor or PAF. It’s derived from the acetylation of lyso-glycerophospholipids (lyso-PAF)32.
The name stems from its capacity to produce platelet aggregation. Its effects include bronchoconstriction, retraction of endothelial cells, and the relaxation of vascular smooth muscles. The action time is short because it degrades quickly. 33
Examples of Atopic Diseases
‘Atopic’ means ‘out of place’. It’s a word that is used when a host overreacts to certain allergens. The most frequent clinical forms of atopic diseases are allergic rhinitis, atopic eczema, asthma, hay fever, and urticaria34. Clinical manifestations vary according to the anatomical location of the hypersensitive reaction; the severity of which depends on the concentration of mastocytes in different organs. Typically, the digestive tract, the skin, and the respiratory airways frequently show symptomatology against hypersensitive reactions, since contact location of allergens determines the affected tissue. Hence, inhalation of allergens triggers asthma (or rhinitis); ingestion may cause diarrhea and vomiting; while entry to the bloodstream usually cause systemic manifestations.
We’ll take a look at 2 examples of atopic diseases. One is a localized condition (asthma), and the other is high risk and systemic (anaphylaxis).
A complete definition of asthma has yet to be determined, despite the medical community’s long history of familiarity with the disease. It’s a chronic inflammatory disease of the respiratory tract, caused by repetitive immediate hypersensitivity reactions of the respiratory mucosa. In susceptible patients, inflammatory processes lead to acute episodes of wheezing, coughing, high thoracic pressure, and dyspnea. These symptoms are associated with a generalized obstruction of the respiratory airways, which can subside with medication or on its own. The inflammation also causes hyperreactivity to a variety of broncho-constricting stimulants.
There are 3 aspects that are considered characteristic of asthma36:
- Reversibility of airway narrowing
Asthma is a major health issue. In the last 30 years, the prevalence and severity of asthma has been on the rise, but there is significant geographical variability of prevalence. For example, it’s close to 22% of Australian children, while it’s barely 13% in Brazil. 37 According to a recent study, and estimated 235 million people across the globe suffer from asthma38 .
When previously sensitized mastocytes in the respiratory mucosa in asthmatic individuals are exposed to their specific antigen, a stimulus for the release of chemical mediators is produced. Resulting in the archetypal bronchial spasms, sputum, and edema. Mastocytes also release cytokines as a recruiter of eosinophils and other inflammatory mediators that play a role in epithelial damage.
It’s an aggressive systemic reaction due to the presence of an allergen that has successfully invaded the body by absorption through an epithelial surface like the skin, or digestive mucosa. It could also occur from vaccinations.
It is caused by the massive liberation of inflammatory mediators, mainly histamine and leukotrienes, by basophils and mastocytes. The brusque appearance of clinical manifestations in the cardiovascular system (hypertension), respiratory tract (bronchospasms), skin (angioedema), and digestive tract (diarrhea and vomiting). The triggering allergens are diverse: medications (penicillin), hormones, venom, food (fish, mollusks, chocolate, eggs, etc.) and food additives (sulfites), among others.
Within just 2 minutes after allergen exposure, anaphylactic symptoms subsequently begin to appear, such as heightened thoracic pressure, pruritus, rhinitis, anguish, and conjunctivitis. If left unaddressed, the appearance of hypotension, bronchospasms, and laryngeal edema begin to develop.41
Diagnosis is determined by the levels of histamine, tryptase, and prostaglandin D2. Anaphylaxis present a potentially severe clinical picture, even deadly if not treated immediately and appropriately.42 “Anaphylaxis has for decades been considered a rare disease, even by physicians, even by other health care professionals,” said F. Estelle R. Simons, M.D., of the University of Manitoba in Winnipeg, who is president of the American Academy of Allergy, Asthma and Immunology. 43
1) The Merck Manual: Disorders with Type I Hypersensitivity Reactions (2005) http://www.merck.com/mrkshared/mmanual/section12/chapter148/148b.jsp
2) Colin Matthew Fitzsimmons, et al. Helminth Allergens, Parasite-Specific IgE, and Its Protective Role in Human Immunity (Front Immunol, 2014) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3924148/
3) Melissa Krystel-Whittemore, et al. Mast Cell: A Multi-Functional Master Cell (Front Immunol. 2015) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701915/
4) Stephen J. Galli, et al. The development of allergic inflammation (Nature, 2008) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3573758/
5) Melanie Thernstrom. New Blood Tests Aim to Predict Food Allergies – and Severity (Allergic Living, 2014) https://www.allergicliving.com/2014/12/04/new-blood-tests-aim-to-predict-food-allergies-and-severity/
6) Jay Portnoy, MD. IgE in Clinical Allergy and Allergy Diagnosis (University of Missouri-Kansas City School of Medicine, 2003) http://www.worldallergy.org/education-and-programs/education/allergic-disease-resource-center/professionals/ige-in-clinical-allergy-and-allergy-diagnosis
7) Simon F. Thomsen. Epidemiology and natural history of atopic diseases (Eur Clin Respir J. 2015) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4629767/
8) Xiumei Hong, et al. IgE but not IgG4 Antibodies to Ara h 2 Distinguish Peanut Allergy from Asymptomatic Peanut Sensitization (Allergy. 2012) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3499645/
9) Elaine Zayas Marcelino da Silva. Mast Cell Function / A New Vision of an Old Cell (J Histochem Cytochem. 2014) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4230976/
10) Wedi B, et al. Human HMC-1 mast cells exclusively express the Fc gamma RII subtype of IgG receptor. (Arch Dermatol Res. 1996) https://www.ncbi.nlm.nih.gov/pubmed/9017131
11) Dr. Lisa A Spencer, Peter F Weller. Eosinophils and Th2 immunity: contemporary insights (Immunol Cell Biol. 2010) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3589820/
12) RNASE3 ribonuclease A family member 3 [ Homo sapiens (human) ] (Gene, 2018) https://www.ncbi.nlm.nih.gov/gene/6037
13) Tae Chul Moon, et al. Mast Cell Mediators: Their Differential Release and the Secretory Pathways Involved (Front Immunol. 2014) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231949/
14) Dr Janice Joneja, Ph.D. Histamine intolerance: The Comprehensive Guide for Healthcare Professionals (Histamine-sensitivity.com, 2010) https://www.histamine-sensitivity.com/histamine_joneja.html
15) Dragana Nikitovic, et al. Proteoglycans—Biomarkers and Targets in Cancer Therapy (Front Endocrinol / Lausanne. 2018) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5845539/
16) Hongyan Dai, Ronald J. Korthuis. Mast Cell Proteases and Inflammation (Drug Discov Today Dis Models. 2011) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3223931/
17) Harvath L. Neutrophil chemotactic factors (EXS. 1991) https://www.ncbi.nlm.nih.gov/pubmed/1655519
18) Christopher Ramsden, M.D., Chief. Lipid Mediators, Inflammation, and Pain Unit (National Institute on Aging) https://www.nia.nih.gov/research/labs/lci/lipid-mediators-inflammation-and-pain-unit
19) Lyso-Glycerophospholipids. (Glycerophospholipids in the Brain. 2007, NY) https://link.springer.com/chapter/10.1007%2F978-0-387-49931-4_8
20) Bennett M, Gilroy DW. Lipid Mediators in Inflammation. (Microbiol Spectr. 2016) https://www.ncbi.nlm.nih.gov/pubmed/27837747
21) Jun-Ming Zhang MD, Jianxiong An MD. Cytokines, Inflammation and Pain (Int Anesthesiol Clin. 2007) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2785020/
22) Simon F. Thomsen. Epidemiology and natural history of atopic diseases (Eur Clin Respir J. 2015) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4629767/
23) Seims A. and White A. The State of Men’s Health in Leeds: Data Report (Leeds Beckett University and Leeds City Council, 2016) https://www.researchgate.net/publication/304778668_The_State_of_Men’s_Health_in_Leeds_Data_Report
24) Ruby Pawankar. Allergic diseases and asthma: a global public health concern and a call to action (World Allergy Organization Journal, 2014) https://waojournal.biomedcentral.com/articles/10.1186/1939-4551-7-12
25) Chandrika Kapagunta, Shruti Datt. Allergic diseases and its prevalence across 5 major countries (Project Guru, 2016) https://www.projectguru.in/publications/allergic-diseases-prevalence-across-countries/
26) Nabil Sami, RN-ADN. FOOD ALLERGY STATISTICS (WordPress.com.) https://nabilsamirn.wordpress.com/food-allergy-statistics/
27) Jennifer Tupper MD, Shaun Visser MD. Anaphylaxis / A review and update (Can Fam Physician. 2010) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2954079/
28) Neil Osterweil. AAAAI: Severe Allergic Anaphylaxis Often Goes Untreated (MedPage Today, 2006) https://www.medpagetoday.com/allergyimmunology/allergy/2793
29) Hypersensitivity reaction type I. (Virtual Medical Centre) https://www.myvmc.com/diseases/hypersensitivity-reaction-type-i/
30) Janeway CA Jr, et al. The production of IgE (Immunobiology: The Immune System in Health and Disease. 5th edition, 2001) https://www.ncbi.nlm.nih.gov/books/NBK27117/
31) Calman Prussin, MD, and Dean D. Metcalfe, MD. IgE, mast cells, basophils, and eosinophils (J ALLERGY CLIN IMMUNOL, 2003) https://www.jacionline.org/article/S0091-6749(02)91382-5/pdf
32) Janeway CA Jr, et al. Effector mechanisms in allergic reactions (Immunobiology: The Immune System in Health and Disease. 5th edition, 2001) https://www.ncbi.nlm.nih.gov/books/NBK27112/
33) Yukiyoshi Yanagihara. Regulatory mechanisms of human IgE synthesis (Allergology International, 2003) https://core.ac.uk/download/pdf/82586203.pdf
34) Arnaldo Cantani. Environmental Factors Urging the Development of Atopic Diseases in 75 Children (International Journal of Critical Care and Emergency Medicine, 2017) https://clinmedjournals.org/articles/ijccem/international-journal-of-critical-care-and-emergency-medicine-ijccem-3-027.php?jid=ijccem#ref14
35) Isabella Pali-Schöll, et al. Asthma and Allergic Diseases in Pregnancy: A Review (World Allergy Organ J. 2009) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2999828/
36) Elaine Zayas Marcelino da Silva, et al. Mast Cell Function A New Vision of an Old Cell (J Histochem Cytochem. 2014) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4230976/
37) Stephen J Galli, Mindy Tsai. IgE and mast cells in allergic disease (Nat Med. 2012) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3597223/
38) Philipp Eissmann. Natural Killer Cells (British Society for Immunology) https://www.immunology.org/public-information/bitesized-immunology/cells/natural-killer-cells
39) Reuben P. Siraganian. Basophils (Encyclopedia of Immunology Second Edition, 1998) https://www.sciencedirect.com/topics/immunology-and-microbiology/basophil-granulocyte
40) Scott Greenfeder, et al. Th2 cytokines and asthma — The role of interleukin-5 in allergic eosinophilic disease (Respir Res. 2001) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC59571/
41) C.A. Behm and K.S. Ovington. The Role of Eosinophils in Parasitic Helminth Infections: Insights from Genetically Modified Mice (Parasitology Today, 2000) http://www.higiene.edu.uy/ubp/ubp_files/papers/2-4_Role_Eosinophils_helminth.pdf
42) Josiane S. Neves, et al. Eosinophil granules function extracellularly as receptor-mediated secretory organelles (PNAS, 2008) https://www.pnas.org/content/105/47/18478
43) K. Ravi Acharya, Steven J. Ackerman. Eosinophil Granule Proteins: Form and Function (The American Society for Biochemistry and Molecular Biology, 2014) http://www.jbc.org/content/289/25/17406.full
44) F. Rosenberg Helene, B. Domachowske Joseph. Eosinophil-Derived Neurotoxin (Methods in Enzymology, 2001) https://doi.org/10.1016/S0076-6879(01)41158-X
45) K. Ravi Acharya, Steven J. Ackerman. Eosinophil Granule Proteins: Form and Function (J Biol Chem. 2014) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4067173/
46) George H. Caughey. Mast cell tryptases and chymases in inflammation and host defense (Immunol Rev. 2007) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275918/
47) Borriello F, et al. Histamine Release from Mast Cells and Basophils (Handb Exp Pharmacol. 2017) https://www.ncbi.nlm.nih.gov/pubmed/28332048
48) Benly. P. Role of Histamine in Acute Inflammation (J. Pharm. Sci. & Res, 2015) https://www.jpsr.pharmainfo.in/Documents/Volumes/vol7Issue06/jpsr07061526.pdf
49) Dr Janice Joneja. Histamine Intolerance (2015) https://www.histamine-sensitivity.com/histamine_joneja.html
50) Christopher Ramsden, M.D., Chief. Lipid Mediators, Inflammation, and Pain Unit (National Institute of Aging) https://www.nia.nih.gov/research/labs/lci/lipid-mediators-inflammation-and-pain-unit
51) Emanuela Ricciotti, PhD, Garret A. FitzGerald, MD. Prostaglandins and Inflammation (Arterioscler Thromb Vasc Biol. 2011) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3081099/
52) Abi Berger. What are leukotrienes and how do they work in asthma? (BMJ 1999) https://doi.org/10.1136/bmj.319.7202.90
53) Michał Flasiński, et al. Influence of platelet-activating factor, lyso-platelet-activating factor and edelfosine on Langmuir monolayers imitating plasma membranes of cell lines differing in susceptibility to anti-cancer treatment: the effect of plasmalogen level (J R Soc Interface. 2014) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4006236/
54) Kathryn L. McCance, Sue E. Huether. Pathophysiology – E-Book: The Biologic Basis for Disease in Adults and Children. https://books.google.com.ni/books?id=l9XsAwAAQBAJ&pg=PA208&lpg=PA208&dq=platelet-activating+factor+effects+include+bronchoconstriction,+retraction+of+endothelial+cells,+and+the+relaxation+of+vascular+smooth+muscles.&source=bl&ots=7jgkRB2SYl&sig=0v_iwtU34e62y5ifraWQJHPvdiI&hl=en&sa=X&ved=2ahUKEwin7oWV38LfAhUho1kKHcwLBx0Q6AEwAHoECAoQAQ#v=onepage&q=platelet-activating%20factor%20effects%20include%20bronchoconstriction%2C%20retraction%20of%20endothelial%20cells%2C%20and%20the%20relaxation%20of%20vascular%20smooth%20muscles.&f=false
55) Edvard S Falk. Atopic Diseases in Norwegian Lapps (Acta Derm Venereol,1993) https://www.medicaljournals.se/acta/download/10.2340/000155551821014/
56) Teresa To, et al. Global asthma prevalence in adults: findings from the cross-sectional world health survey (BMC Public Health. 2012) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3353191/
57) Asthma (WHO) https://www.who.int/respiratory/asthma/en/
58) Pamela W Ewan. Anaphylaxis (BMJ. 1998) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1113119/
59) Richard D. Peavy, Dean D. Metcalfe. Understanding the mechanisms of anaphylaxis (Curr Opin Allergy Clin Immunol. 2008) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2683407/
60) Parenting a Child with a Food Allergy http://www.childfoodallergy.com/archives/2006/04/