Presently, allergy and allergic drug reactions are coming to be more frequently in the industrial countries and can lead to serious health problems. Around 10 of hospitalized patients have drug allergy and about 7 % of these patients who need ambulatory care .The World Health Organization outline adverse drug reactions (ADRs) as a unhealthy and unintended response to a drug, that arise at a dose normally used in man . The allergic drug reactions can cause different causes such as angioedema, urticaria, rhinitis and more. These reactions can rapidly come to a life-threatening situations special if the event occurs during anaesthesia . Therefore, investigations are applied to understand the immunology mechanism behind allergic drug reaction and to invent new detection methods.
Allergy is a common disease which can be caused by antigen such as food, drugs or insect bite. The mechanisms behind allergic reactions are well known. The common two different mechanisms are IgE mediated and non-IgE mediated. The IgE concentration in the serum is the lowest of the five Ig subtypes. It also has the shortest half-time (around two hours). The level of IgE can be influence by genetic factors, race immune status and environmental factors. They are two receptors for IgE known: low-affinity IgE receptor (FcεRII; CD23) which is expressed on the B-cell surface and on other hematopioietic cells and the high affinity IgE receptor (FcεR1). The density of human basophil FcεR1 expression correlates directly parasitic infections, non-parasitic infections, and inflammatory diseases with the serum IgE levels. The same was seen with the density of human mast cell FcεR1 level and the free IgE level in vitro [4, 5]. IgE level is involved in different type of disease such atopic diseases, atopic dermatitis, atopic asthma, perennial allergic rhinitis and seasonal allergic rhinitis, parasitic infections, non-parasitic infections, inflammatory diseases and more . The role of IgE in allergic inflammation is well known .
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The Th2 lymphocytes are set free IL-4 which stimulates the B-cells to create specific IgE- Antibody. The FcεRI binding sites recognise the high affinity IgE receptor on the mast cell and basophil surface and bind to it. Allergen binds cross-linking to IgE and FcεRI and cause the degranulation of mast cell and basophil. Mast cell and Basophil release inflammatory mediators including histamine and tryptase. In addition, they synthesis and release new preformed lipid mediators and cytokines . The B-cells need for the isotype switch for synthesizing IgE two signals; cytokines IL-4 and 13 send first signal after this the CD 40 ligand bind on the T-cells surface via the CD40 receptor on the B-cell membrane 
Allergic drug reactions
IgE antibodies and T cells drive the most immune hypersensitivity reaction to drugs. IgE mediated reactions are mostly investigated. In contrast, drug- induced allergy by T-cells is still not well understood. Around 10 % of hospitalized patients have drug allergy and about 7 % of these patients who need ambulatory care. The classifications system separate into two types: Type A and B. Type A reaction is defined as dependent and predictable. It also has the high ration on ADRs. Type B is independent and unpredictable. Hypersensitvity drug reactions belong to type B and are marked as immunological mechanisms (IgE or non-IgE- mediated). Different clinical studies where done to ADR over the world. An America study that of the 731 identified reactions over 18 month 32.7% had an allergic reaction. A French clinical study investigated anaphylaxis during general anaesthesia and found 789 cases under this was 518 cases which had an immune response to neuromuscular blocking agents, antibiotics and other drugs. Another group investigated the mortality of drug allergy and found out that 0.09 per 1000 hospitalization die on drug allergy. A UK study showed that from 1992-2001 more people die from an anaphylactic shock and drugs was the common causing antigen. The group of Pen shows that 8.4 per 100 000 person- year of anaphylaxis are triggered by oral drug in the UK. However, not only drug introduced anaphylaxis can lead to mortality also Stevens-Johnson syndrome (SJS) and Toxic epidermal necrolysis (TEN) which are also drug-related .
The mechanisms of sensitization to drugs are divided in two steps; sensitization and second exposure. The sensitization step includes the first exposure to the drug and is mostly uneventful. It comes to a sensitization where the drug specific IgE receptor a produced. If then the individual is exposed a second time it comes to an allergic drug reaction. This can cause different syndromes including anaphylaxis, urticarial, contact sensitivity, and more. It was shown that Eosinophilia detected in blood or tissue at a reaction. However, it is not sure if eosinophilia is evidence for an allergic reaction. Drugs have mostly a low molecular weight and have to be bioactivated before they can lead to hypersensitivity reactions. Penicillin is one of the few drugs which can directly affect mast cell and basophil. It doesn't have to be metabolism and has already a reactive form. It is a limit amount of diagnostic testing existing to test drug .
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It has been evidence that not all drugs bind to the major histocompatibility complex and induce an immune response. Some drugs bind directly to the immune receptors and initiate the immune reaction. This phenomenon is called (p-i) concept. In addition, various risk factors can influence hypersensitivity drug reactions such as age, sex, previous reaction to the drug, other diseases and more. Studies showed that the female population are more affected by drug allergy than men . Allergic drug reaction are classified in four types; Immediate hypersensitivity reactions (type I), cytotoxic antibody reactions (type II), immune complex reactions (type III), and delayed-type hypersensitivity reactions (type IV). Penicilins, cephalosporins, and neuromuscular blocking agents can lead to an IgE-mediated drug hypersensitivity (Type I). Drug-specific IgE come in contact with a small amount of allergen. The allergen-specific IgE binds on the high-affinity FC receptor (FcεRI) which is on the mast cell surface. The allergen bind to the fragment antigen-binding region of the IgE molecules and if bind two or more cell-bound IgE molecules (cross-linking) induces the mast cell activation. The mast cell release then different factors including histamine, leukotrienes, prostaglandins, and cytokines. These molecules elicit vasodilation, increase vascular permeability, enhance mucus production and bronchoconstriction, and contribute to eosinophil recruitment. Symptoms of this release are shock and severe cardiac complications. . Type I is the most common in the general population. The detection of drug hypersensitivity is mostly done with considering clinical histories, skin test, patch test, and a few in vitro tests. The little information about drug hypersensitivity has to be careful investigated because the pathogenic mechanism or even the responsibility of the drug itself has not been demonstrated until now.
Anaphylaxis is described as an acute-onset and fatal systemic allergic reactions. It can be caused by different agent such as insect sting, food, or medications. The development of optimal risk reduction strategies and prevent recurrence becomes more and more important and understanding of effector mechanisms are required for the development. The rate of anaphylaxis cases is unknown but it becomes to be rising. Under-diagnosis, under-reporting, variation of case definitions complicates the recording of anaphylaxis events. It was shown that in the 80s 21 per 100,000 person-years with anaphylaxis was reported which increased to 49.8 per 100,000 person-years in the 90s. 70 per 100,000 person-years were under 19 years [8, 9]. Studies shown that under age 15 years, anaphylaxis events are more common in males than in females. In contrast, after age 15 years more females have an anaphylactic reaction [8, 10]. Different trigger factor can cause an anaphylaxis and studies shown that food induced anaphylaxis is more characteristic for young adults. In contrast to food, insect stings, diagnostic agents, and medications affect more middle-aged and older adults .
The anaphylaxis mechanisms are divided in immunologic mechanisms or non-immunologic mechanisms. IgE and the high-affinity IgE receptor on mast cells or basophils drive the most anaphylactic reaction. It is investigated that IgE has an important role in anaphylaxis. Furthermore, IgE is involved in anaphylaxis intensity but also in sensitizing, riming, activation and mediator release. IgE does also enhance expression of FcεRI on mast cells and basophils. Peanut, tree nuts, shellfish, fish, milk, and egg are the most common food antigens which lead to anaphylaxis [8, 10]. Different types of medication can cause anaphylaxis such as β-lactam, aspirin, ibuprofen, neuromuscular blocking agents and more [8, 10-13]. In addition, oversulfated chondroitin sulphate contaminated heparin and folic acid which are in vitamins and supplements can trigger anaphylaxis.
The nonimmunologic mechanism is not known. It includes exercise, cold air or water exposure, radiation, ethanol. It seems that not only one mechanism is responsible for an anaphylactic shock. However, the cellular mechanism is independent of trigger and mechanism. The tyrosine kinases and calcium influx in mast cells and basophils are activated and release immediately different granuleassociated preformed mediators including histamine, tryptase, carboxypeptidase A3, chymase, and proteoglycans. In both mechanisms (immunologic and nonimmunologic) mast cells and basophils were activated and introducing the allergic reaction. The balance of positive and negative intracellular molecular factor affects the mast cell response. It is known that the stem cell factor especially the Kit receptor is important in IgE/antigen-induced mast cell degranulation and cytokine production. In addition, it is investigated that the inhibitory sialic acid-binding immunoglobulin-like lectins are located on human mast cells . The involvement of genetic factors in human anaphylaxis should be considered however studies showed that are only a few involved .
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At the moment, the clinical diagnosis is made on meticulous history and physical examination. The clinical diagnosis can be supported by laboratory test which measured plasma histamine levels and total trytase level in serum or plasma. The timing is important for the tests. Histamine need to be tested in blood samples between 15 and 60 minutes: tryptase has to be tested in 15 to 180 minutes. However, not every time the tryptase or histamine levels are rised. Special, food-triggered anaphylaxis showed no rise in tryptase level. Therefore, other mast cell or basophil activation markers should be measured [3, 8, 10, 14]. After an anaphylaxis event, additional tests should be done to minimize risks for future anaphylaxis. Injection of Epinephrine is used in anaphylaxis cases. Next to ephinephrine, H1-antihistamines and inhaled β2 -adrenergic can be also used in anaphylaxis events [8, 10].
The cases of anaphylaxis are increased over the last two decades and the most common factors are foods, medications and insect stings. In some rare anaphylaxis cases no factor is exist (confirmation with skin testing or IgE test) and the possibility of mastocytosis or a clonal mast cell disorder must be pondered. In emergency, epinephrine autoinjectors have to be available. In addition, the user has to know when and how to use it. A personal emergency action plan and up-to date medical identification has to be available. Anaphylaxis was defined as a serious allergic reaction which happens rapid and can lead to death . Different symptoms are caused by anaphylaxis; skin (90% of episodes, respiratory tract (70%), gastrointestinal tract (30%-45%), cardiovascular system (10% to 45%), and central nervous system (CNS: 10%-15%). Asthma, COPD, mastocytosis, nonselctive β-blockers, or stinging insect species increase the clinical risk of anaphylaxis . Special the heart can be affect. Mast cells are located in the myocardium and in the intima of the coronary arteries. Anaphylaxis can uncover subclinical coronary artery disease 
Mast cell and Basophil
Mast cells are located general in skin and all mucosal tissues. In addition, they were also found in asthmatics lungs and connective tissue [15, 16]. In contrast to Mast cells, Basophils are blood leukocytes. They both share morphological and functional similarities such as same casophilic granules, expression of αβγ2 form of FcεRI . Both cell types play a central role in inflammatory and immediate allergic reactions . In the flowing subchapters, the basophils, mast cells and granular constituents were described in detail.
Mast cells are based in blood vessels and at epithelial surfaces and play a major role in diseases of immediate hypersensitivity and of mastocytosis but also in responses to pathogens, autoimmune diseases, fibrosis and wound healing . They are produced in the bone marrow. The maturation is influenced by stem cell factor binding to the receptor c-kit and by other cytokines such as interleukin. SCF receptor which belongs to the c-kit is an important factor in the embryonic development. SCF is also responsible for the mast cell adhesion, migration, proliferation, survival and release of histamine and tryptase. Mast cells contain the majority of the body's histamine. Mast cells are long-lived, surviving for month or even years in the tissue .
The extracellular release of mast cells mediator and exocytosis occur by organelles which are located in the mast cells cytoplasm. Three possible reasons of exocytosis and extracellular release are possible. Chemical substances, such as toxins, venoms, and proteases are one of the possible reasons for release. Second reason, endogenous mediator, including tissue proteases, cationic proteins derived from eosinophils and neutrophils. Immune mechanisms can maybe lead to exocytosis and extracellular release that may be IgE-dependent or IgE-independent. IgE-dependent degranulation is a consequence of an antigen. During allergic response the IgE are release from B-cells and bind to the mast cells. The IgE molecules bind to the high-affinity IgE receptor on the surface of mast cells. The FC portion leaves their Fab or antigen binding segment which binds the antigen. A subsequent exposure to the same allergen cross-links the cell-bound IgE and triggers the release of preformed prostaglandins, histamines and cytokines. The Ca2+ influx is increased and promotes the mast cells degranulation; ionophores that increase cytoplasmic Ca2+ also promote degranulation, whereas agents who deplete cytoplasmic Ca2+ suppress degranulation. IgE-independent degranulation is also caused by antigen. However, activation of mast cells occurs direct without pre-sensitisation .
Two types of mast cells are known; mucosal and connective tissue mast cells (MCTC). The MCTC mast cells express tryptase and chymase . MCT cells are present inside of the mucosa of the respiratory and gastrointestinal tracts and raise the mucosal inflammation. MCTC cells are present in connective tissues such as the dermis, submucosa of the gastrointestinal tract, heart, conjunctivae, and perivascular tissues .
Mast cell produced mediators are divided into preformed mediator, newly synthesized lipid mediator and cytokines/chemokines. TNF-α belongs to preformed and a newly synthesized molecule but is also a major cytokine. Preformed mediators such as histamine, serine proteases (tryptase and chymase), carboxypeptidase A, and proteoglycans (stored in cytoplasmic granules). Proteoglycans including heparin and chondroitin sulfates . Human mast cells also generate IL-4,5 and 6 and also several neutral protease including tryptase and chymas. Thus, mast cells are key players in host defense, with a role in immune surveillance, phagocytosis, and immune activation .
Figure : Products of Mast cell after cell activation .
Basophils are involved in artificial cantharidin blisters or spontaneous bullous lesions in atopic dermatitis (AD) and other eczematous diseases . Basophil is like mast cells produced in bone marrow. They differentiate and mature there and develop from CD34+ progenitors. The half-life of basophil is a few days and express integrin and chemokine receptors and is able to infiltrate inflamed tissues special in the skin disease atopic dermatitis and the airway with respiratory allergies. Basophils are almost similar to mast cells and also express the FcεR1, secretion of Th2 cytokines, metachromatic staining and release of histamine after activation . A major characteristic of basophils is their quick and strong expression of Il-4 and IL-13 and they are also involved in allergic responses and immune regulation . Beside IL-4 and IL-13, basophils set fee pre stored and newly sensitized pro-inflammatory mediator such as Histamine and cytokines (IL-3, IL-4, IL-13 and VEGF) . It was also showed that basophil have small proliferative capacity and express a variety of cytokine receptors (e.g. IL-3R,IL-5R, and GM-CSFR), chemokine receptors ( CCR2 and CCR3), complement receptors (CD11b, CD11c, CD35, and CD88), prostaglandin receptors ( CRTH2), immunoglobulin Fc receptors (FcεRI and FCγRIIB) and TLRs .
Figure : Products of Basophil after cell activation .
It was shown that basophil have small proliferative capacity and express a variety of cytokine receptors (e.g. IL-3R,IL-5R, and GM-CSFR), chemokine receptors ( CCR2 and CCR3), complement receptors (CD11b, CD11c, CD35, and CD88), prostaglandin receptors ( CRTH2), immunoglobulin Fc receptors (FcεRI and FCγRIIB) and TLRs 
Recent studies found out that in mice mast cells are dispensable in IgG-, but not IgE-mediated systemic anaphylaxis and it could be that basophil are responsible for the IgG in anaphylaxis. In addition, basophils play a critical role in the development of IgE-mediated chronic allergic reactions by functioning as initiator cells. It was also shown that the depletion of basophils lead to an almost complete abrogation of skin inflammation IGE-CAI .
Histamine is best investigated inflammatory mediator and existing amount in human mast cell is average 3-5 pg/cell . Histamine has a half-life of approximately 1 minute. Histamine N-methyltransferase degraded histamine to tele-methyl histamine and also diamine ocidase degraded it to immidazole acetaldehyde. Sodium ions effect the dissociation of granule with histamine from the proteoglycans in the extracellular fluid. Histamine affects different areas such as smooth muscle, endothelial cells, nerve endings, and mucous secretion . Histamine is released when the body detects toxic substance and it will be also released when the mast cells detect injury. It causes nearby blood vessels to dilate allowing more blood to reach the site of the injury or infection . It has been shown that injection of histamine induce hear rate increasing, increased skin temperature, flushing, itching, bronchospasm, headache and fall of blood pressure.
MCT cells contain tryptase as neutral proteases and tryptase, chymase, cathepsin G, and carboxypeptidase in MCTC cells. Human cells have α-andβ-tryptase .
In addition to histamine, tryptase is set free after degranulation of mast cells. It can lead to inflammation, matric destruction and tissue remodelling. Therefore, different mechanisms are applied such as damaging pocagulant, matrix, growth and more. In human mast cells exist four tryptase genes (TPSG1, TBSB2, TPSAB1, and TPSD1) which are divided in two general groups: membrane anchored and soluble. It is known that the membrane-anchored γ tryptase has inflammatory potential. In contrast, soluble human trypase β is involved outside the cells. It also should be inovled in pathogenic inflammatory episodes and exist in basophils .
Tryptase is increased in an anaphylactic event and can be detected one hour after the event. Anaphylaxis to parenteral agents (drug and insect venom) is associated with increased tryptase level, whereas anaphylaxis to oral agents, particularly food, is often not accompanied by elevated tryptase levels in the serum. It is known that tryptase digest fibrinogen, fibronectin, pro-urokinase, pro-matrix metalloprotease-3, protease activated receptor-2 and complement component C3 in vitro. However, the tryptase function in vivo is unknown. Tryptase can also induce fibroblast, promote accumulations of inflammatory cells, and potentiate histamine-induced airway bronchoconstriction .
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Diagnosis of allergic drug reactions
The detection of Drug allergy is limited. A few tests are available to measure drug-specific antibodies, drug-specific T lymphocytes or mediator of Basophil/Mast cells . Histamine, Tryptase and IgE were measured to identify drug allergy . Histamine and Tryptase measurement is general used to detect anaphylaxis. Next to laboratory test, skin test is available for allergy testing.
Oral food challenge (OFC) can be avoid because of the patient's age, clinical history or physical condition. This allergy test is mostly for food allergy . Skin test should be carried out after an allergic reaction. In order that the skin test is succesfull different standard should be performed. A series of different trigger should be test to make sure every possible risk trigger is found. Positive and negative controls should be always carried out . The trigger agent is put directly to the skin and picked with a lancet under the skin surface. The result can be interpreted and compared with the controls after 15-20 min . Every positive result should be note in the clinical history. The skin test, all used instrument, and protocol should be validated and a standardized system should be applied. Skin test cannot always an anaphylactic shock confirm. In addition, some drug allergens are not available for skin test and the reaction has to be IgE mediated . Special when the antigen is an unidentified breakdown product or a metabolite of a medication. Β-lactam and a rare other medications are available for skin test .However, skin test is a safe procedure and can be used to detect some drug and food allergies.
Of the more than 100 biomarkers of mast cell and basophil only Histamine and total tryptase can be measured in clinical laboratories. . It also available an immunoCAP which test in vitro the serum of the patient for allergen-specific IgE. This test is very sensitive, easy and automated. However, the result does not give always a clear diagnosis about the allergy special in food allergy cases . The histamine level should be measured in 15-60 minutes after the symptoms onset. In contrast to histamine, serum total tryptase levels can be still detected after 3 hours. However, tryptase levels are rarely raised in food-introduced anaphylaxis. Possible mast cell activation products are existed such as carboxypeptidase A3, chymase, plate-let-activating factor, and cytokines. Therefore, it is an aim to develop timeless, sensitive, and specific laboratory tests which can confirm diagnosis of anaphylaxis .
PhD project: Allergic drug reactions and the identification of those at risk of severe symptoms: Mast cells and basophils activation as key cellular mechanisms
Experimental work carried out so far
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