Allergy and hypersensitivity

Question 1

What is hypersesitivity?

Answer 1

hypersensitivity is an inappropriately vigorous innate and/or adaptive response to antigens that pose little or no threat.

Question 2

Hypersensitivities are classically divided into four categories, which?

Answer 2

There are type I-IV hypersensitivity, that differ by the immune molecules and cells that cause them, and the way they induce damage.

Type I:

Question 3

Describe the four different types of hypersensitivity, what immune cells/molecule cause them? What are common examples?

Answer 3

• Type I hypersensitivity reactions (allergy and atopy) are mediated by IgE antibodies that bind to mast cells or basophils and induce mediator release; these reactions include the most common responses to respiratory allergens, such as pollen and dust mites, and to food allergens, such as peanuts and shellfish.
• Type II hypersensitivity reactions (antibody mediated hypersensitivity) result from the binding of IgG or IgM to the surface of host cells, which are then destroyed by complement- or cell-mediated mechanisms. For example, this is the fate for transfused red blood cells in transfusions between people differing in ABO blood types.
• In type III hypersensitivity reactions (immune complexes), antigen-antibody complexes (such as those generated by the injection of foreign serum proteins) deposited on host cells or tissues activate complement or the release of mediators from granulocytes, often causing inflammatory responses.
• Type IV hypersensitivity reactions (delayed type hypersensitivity) result from excessive and sometimes inappropriate T-cell activation. Common examples are the skin reactions caused by poison oak or poison ivy.

Question 4

What is allergy?

Answer 4

Allergy is the type I hypersensitivity response, mediated by IgE antibodies. Allergy is initiated by an interaction between an IgE antibody and a multivalent antigen. Allergy is defined as “disease which follows an immune response towards an otherwise innocuous antigen”

An allergic reaction has all the characteristics of a normal immune response, but IgE is produced inappropriately

Question 5

Explain what is meant by the term “atopy”.

Answer 5

Atopy is a condition in which one is genetically predisposed to generate IgE antibodies against common environmental agents, instead of only against worms/parasite infections (normal) and thus is more suceptible to allergies developing allergy-related diseases such as asthma, dermatitis, food allergies, or rhinitis.

Question 6

State the four common denominators among different allergens.

Answer 6

• Most allergens are proteins or glycoproteins and possess many antigenic sites (epitopes) per molecule (multivalent)
• Allergens often have intrinsic enzymatic properties (e.g. protease activity disrupting epithelial integrity, cleavage of complement products, stimulation of protease-activated receptors on immune cells, enhancing inflammation)
• Many allergens contain potential PAMPs, stimulating innate immunity cascades, contributing to allergic responses.
• Many allergens enter mucosal tissues at very low concentrations, stimulating TH2 responses, where the IL-4 and IL-13 produced by TH2 cells induce heavy-chain class switching to IgE.

Question 7

Explain the mechanism of the type I hypersensitivity (allergic) reaction.

Answer 7

1. Upon exposure to an allergen, the allergen often goes through the epithelium or damage the epithelium and is taken up by APCs, which migrate to the lymph nodes and activate CD4+ Th cells, and induces differentiation into TH2 cells.
2. The activated TH2 cells activates B cells (which also requires the B cell to recognize the antigen) and stimulate them to proliferate, undergo heavy-chain class switching to IgE, and differentiate into IgE-secreting plasma cells and memory B cells expressing membrane IgE B-cell receptors (mIgE)
3. The IgE binds to the high affinity IgE receptor, FcεRI, on mast cells -> sensitized mast cells. This is the sensitization phase. If no subsequent exposure occurs from here on out, one would not develop symptoms.
4. Upon repeated expoosure to the antigen, the high affinity FcεRI on mast cells will cross link, inducing degranulation.
5. The degranulation leads to secretion of histamine, heparin and proteases, which can cause smooth muscle cell contraction, vasodialiation etc, a pro-inflammatory response. Together with other molecules (leukotrienes, prostaglandins, chemokines, and cytokines) that are synthesized by these activated granulocytes, these mediators act on surrounding tissues and other immune cells, causing allergy symptoms

Depending on where this reaction occur, the symptoms can differ. Inflammation in the upper respiratory tract can lead to asthma while in the skin can lead to eczema.

Question 8

The high affinity IgE receptor FcεRI is responsible for most allergy symptoms, why does it have so high affinity? How does if affect IgE when bound?

Answer 8

The high-affinity IgE receptor, FcεRI binds IgE with an exceptionally high affinity constant which helps overcome the difficulties associated with binding IgE antibodies, which are present at an extremely low concentration in the serum under normal conditions.

IgE free in serum have the shortest half life of all the Ig classes, 2-3 days. However, when bound to its receptor on a granulocyte, IgE is stable for weeks.

Question 9

Which cells express FcεRI?

Answer 9

The high-affinity IgE receptor, FcεRI is primarily found on basophils and mast cells.

Question 10

There is another IgE receptor, what is it called? and what is it’s function?

Answer 10

The second IgE receptor, the low-affinity FcεRII (also known as CD23), is found on IgE-expressing B cells and on other cells; it helps regulate IgE responses, transports IgE across the intestinal epithelium, and induces inflammatory cytokine production by macrophages.

Question 11

The low affinity IgE receptor CD23 have two different ligands, which? What is the outcome of binding the different ligands?

Answer 11

CD23 binds both IgE and the complement receptor CD21 expressed on B cells (BCR coreceptor), the outcome of CD23 ligation depends on which ligands it binds to and whether it is soluble or membrane-bound.

• When soluble CD23 (sCD23) binds to CD21 on the surface of IgE-synthesizing B cells, IgE synthesis is increased. (Atopic individuals express relatively high levels of surface and soluble CD23)
• However, when membrane-bound CD23 binds soluble IgE, further IgE synthesis is suppressed. This is a negative feedback pathway whose function seems to be to limit the amount of IgE that is synthesized.

Question 12

Explain FcεRI signalling in short.

Answer 12

By cross-linking FcεRI receptors, IgE initiates signals that lead to mast cell degranulation and release of prepackaged mediators, cytokine production, and leukotriene and prostaglandin generation.

The signaling cascades initiated by the FcεRI are generally similar to those initiated by antigen receptors. Briefly, cross-linking of FcεRI activates the tyrosine kinase Lyn, which phosphorylates the receptor ITAMs and activates the tyrosine kinase Syk, which phosphorylates adapter molecules that organize signaling responses. Multiple kinases are activated, including protein kinase C (PKC) and various mitogen-activated protein kinases (MAPKs). These, in turn, activate transcription factors (e.g., NF-κB) that regulate cytokine production. They also activate lipases, including phospholipase D (PLD), and stimulate an increase in intracellular free calcium ions and a transient increase in cAMP, all of which induce degranulation. Phospholipase A (PLA) is activated, initiating the production of leukotrienes and prostaglandins from the metabolism of arachidonic acid.

Question 13

What does FcεRI lead to?

Answer 13

FcεRI signaling leads to several mast cell and basophil responses:
(1) degranulation—the fusion of vesicles containing multiple inflammatory mediators with the plasma membrane and release of their contents (Figure 15-5a), (2) synthesis of inflammatory cytokines, and (3) conversion of arachidonic acid into leukotrienes and prostaglandins, two important lipid mediators of inflammation.

After degranulation, the mast cells and basophils look “empty”, but immedeately start to produce granule contents again.

Question 14

IgE receptor signaling is tightly regulated, give two examples of regulatory mechanisms for FcεRI signalling.

Answer 14

• Co-clustering with inhibitory receptors:
  Mast cells express both FcεRI (activating) and FcγRIIB (inhibiting) Ig
  receptors with ITIMs. cross linking of the inhibitory receptors leads to inhibition of cellular responses. If a cell binds IgE and IgG, the inhibiting signal induced by IgG binding wins. This is partially why inducing IgG in atopic individuals (usually through “allergy shots”) helps treat their allergies (ITIMs)
• FcεRI signaling through Lyn and Syk kinases also activates E3 ubiquitin ligases, including c-Cbl. c-Cbl ubiquitinylates Lyn and Syk, as well as FcεRI itself, triggering their degradation. Thus, FcεRI activation contributes to its own demise, thereby limiting the duration of the response.

Question 15

The effector mediators in type 1 hypersensitivity can be divided into primary and secondary mediators, what differs between them?

Answer 15

Primary mediators are pre-formed and stored in granules prior to cell activation, whereas secondary mediators are either synthesized after target-cell activation or released by the breakdown of membrane phospholipids during the degranulation process.

Question 16

Give two examples each of primary and secondary mediators involved in type 1 hypersensitivity.

Answer 16

Primary mediators of type 1 hypersensitivity include:
- Histamine and Heparin: effects lead to Increased vascular permeability; smooth muscle contraction. Histamine binding to histamine receptors can also lead to increased mucus secretion, vasodilatation

Secondary:
- Leukotrienes: Increased vascular permeability; contraction of pulmonary smooth muscles
- Prostaglandins: Vasodilation; contraction of pulmonary smooth muscles; platelet aggregation
- Cytokines: e.g. IL-4, IL-13 which stimulates the Th2 response and IL-9 which increases the number and activity of mast cells.

Leukotrienes are approximately 1000 times more effective at mediating bronchoconstriction than is histamine, and they are also more potent stimulators of vascular permeability and mucus secretion. In humans, the leukotrienes are thought to contribute significantly to the prolonged bronchospasm and buildup of mucus seen in people with asthma.

Question 17

Type 1 hypersensitivity responses can be divided as early and late responses, what happen at these stages?

Answer 17

Early responses occur within minutes of allergen exposure and is mediated by mast cell granule contents like histamine (vasodilation), prostagladins (bronchoconstriction), leukotrienes (mucus secretion) - an asthma as an example.

Late responses occur hours later, a result of recruited cells. Often inflammatory cell types such as eosinophils and neutrophils. Degranulation by both cell types induces further inflammation and tissue damage, which can lead to a damaged endothelium and thicker basement membrane. These effects can become permanent if sustained or frequent, so it’s important to treat the effects of allergy.

Question 18

Since IgE mediated FcεRI signalling is responsible for much of type 1 hypersensitivity responses, could kinase inhibitors be used to treat allergy?

Answer 18

Since kinases would be needed to activate FcεRI signalling through phosphorylation of the ITAMs, it would inhibit the type 1 hypersensitivity response, but in practice, kinase inhibitors would hinder a lot of signalling in the body, just for the immune system the patient would be susceptible to pathogens.

Question 19

What determines the nature of the clinical symptoms ina type 1 hypersensitivity response?

Answer 19

The nature of the clinical symptoms depends on the route by which the allergen enters the body, as well as on its concentration and on the prior allergen exposure of the host. Genetics also plays a role. The particular symptoms may evolve in an allergic individual over time.

Question 20

What is the most severe type of allergy response?

Answer 20

Systemic anaphylaxis.

Question 21

Describe systemic anaphylaxis, what is the most common routes and allergens? What are the symptoms? treatment?

Answer 21

Systemic anaphylaxis is often initiated by an injected or gut-absorbed allergen, common allergens include: Bee sting venom, penicillin, seafood, nuts.

Symptoms include:
– Labored respiration
– Precipitous drop in blood pressure (due to increased permeability of blood vessels) leading to anaphylactic shock.
– Contraction of smooth muscles leading to defecation, urination, and bronchiolar constriction
–> May lead to death by asphyxiation

Epinephrine is the immediate treatment, e.g. epipen.

Question 22

Give three examples of local reactions following a type 1 hypersensitivity reaction.

Answer 22

In localized reactions, the pathology is limited to a specific tissue or organ. Includes:
- allergic rhinitis (hay fever)
- asthma
- atopic dermatitis (eczema)
- food allergies

Symptoms result from release of mediators in immediate exposure area.

Question 23

Give two examples of diagnostic tests for type 1 hypersensitivity reactions.

Answer 23

The most common diagnostic test is skin testing (pricktest) where you make small holes in skin of the arm and inject small quantities of known allergens directly into the holes. Swelling and redness (resulting from local mast cell degranulation) indicate allergic response. Very cheap and safe. The magnitude of the response can also bee seen.

There are also pre made ELISA based methods like ThermoScientific’s allergy tests in which you add blood and see a fluorescent signal if IgE antibodies towards the allergen exists. Also quantifiable. Extremely safe as you don’t expose the patient to the antigens, but more expensive.

Question 24

What are the three classical treatments to allergy?

Answer 24

The classical allergy treatments include:
- taking away the antigen (easier for food allergens than airborne for example)
- antihistamines: which bind and block H1 receptors on target cells, no histamine secretion.
- Inhalation of corticosteroids: inhibit innate immune cell activity in airways, treating asthma. (topical corticosteroids for eczema)
There are also leukotriene antagonists.

Question 25

There are some new treatment for allergy being developed, give two examples.

Answer 25

"New" treatments for allergy include: - Humanized anti-IgE mAbs: binds free IgE and blocks it from binding to FceRI (but it doesn't block FceRI-bound IgE) and lowers the serum levels of IgE --> reduces mast cell/basophil/eosinophil activity. - Hyposensitization/allergy "vaccines": Repeated low-dose exposures may induce an increase in regulatory T cells and their cytokines. May also induce competitive IgG subtypes that may compete with IgE for ag-binding or co-cluster FceRI with inhibitory FcgRII receptors.

Question 26

Allergy have a very big genetic component, but also the environment plays a role. Name three environmental predisposing factors and three protective factors.

Answer 26

Predisposing: - High air pollution - Low gut microbiome diversity (especially in early years) - Low fiber diet --> allergy way more common in westernized societies. Protective: - Farm environment - High gut microbiome diversity - high fiber diet. --> allergy less common in developing countries.

Question 27

There is no "allergy gene", allergy is extremely polygenic and differ from person to person, and the type of genes that have been associated with allergies have very diverse functions. Give examples of two functions that can lead to a higher predisposition to allergy when mutated.

Answer 27

Out of the genes involved in epithelial barrier integrity, allowing the initial entry of allergens. Many are known to be associated with developing type 1 hypersensitivity. Also many genes for innate pathogen sensing responses (TLR7 and many other TLRs and CD14 (LPS binding receptor on macrophages) for example) are associated with allergy. There are also some polymorphisms that can lead to lower risk of developing asthma for example, so it's very complex!

Question 28

Early life is very important in allergy, it often starts there. There are several hypotheses to why the risk of developing allergy is higher in westernized countries. Explain the hygiene hypothesis.

Answer 28

The hygiene hypothesis is based on the finding that the susceptibility to allergy is higher in industrialized countries where the exposure to microbes is little, and reduced in environments where there is early exposure to microbes (many "developing" countries). This hypothesis proposes that exposure to some pathogens during infancy and childhood benefits individuals by stimulating immune responses other than the type 2 responses that induce IgE responses and allergies. The skewing of responses away from Th2 responses appears to occur as children become exposed to childhood infections, reflecting either the induction of T 1 responses or the suppression of Th2 responses by Treg cells. In Westernized countries, where microbial infections are reduced as a result of sanitation, vaccinations, antibiotics, and less exposure to farm animals, a child’s immune system may be less likely to undergo the exposure to infections that would otherwise reorient it away from Th2 responses, leading to higher risk of strong Th2 responses later. There are strong indications that the microbiome has a major influence, there is also the microbial deprivation hypothesis (e.g. C-section depriving the baby of microbiome exposure and the dysbiosis hypothesis.

Question 29

What is the "allergic march"?

Answer 29

Allergy often starts in early life and the symptoms change with age, eczema is most common in very young children, while rhinitis/hay fever is more common in adults. The progression from eczema to later developing food allergies, allergic rhinitis and asthma is called the "allergic march".

Question 30

In Eva's studies, they have looked into two treatments which have shown to be preventative in developing allergies, which?

Answer 30

- They found that bacteria that produce short chain fatty acids are overrepresented in non-asthma group. Treatment with that kind of bacteria or supplemented SCFAs in the future? Promising. - In study with increasing exposure to peanuts in children with peanut allergy they found that it gave rise to tolerance in 72% of all the children! Food exposure in early life could be preventative.

Question 31

Why do we think allergy has evolved?

Answer 31

IgE-mediated type I hypersensitivity reactions may have evolved because of their protective roles against helminth worm parasites and insect and animal venoms.

Question 32

Explain type II hypersensitivity in short.

Answer 32

Type II Hypersensitivity is also referred to as antibody-mediated hypersensitivity. Type II hypersensitivity reactions involve antibody-mediated destruction of cells by IgG and IgM immunoglobulins. there are three mechanisms for antibody-mediated destruction: complement activation, ADCC (in which cytotoxic cells bearing Fc receptors bind to the Fc region of antibodies on target cells and promote killing of the cells) and opsonization.

Question 33

There are three types of type II hypersensitivity, which?

Answer 33

There are three types of type II hypersensitivity reactions: - (Drug-induced) hemolytic anemia: - Transfusion reactions - Hemolytic disease of the newborn (erythroblastosis fetalis)

Question 34

Explain how drug induced hemolytic anemia works.

Answer 34

Some drugs can adsorb nonspecifically to proteins on red blood cell membranes. These drug-protein complexes are then "misread" as foreign and may stimulate antibody production --> Antibodies then bind to RBCs when the drug is present, stimulating complement-mediated destruction, leading to anemia (blodbrist) which causes oxygen deprivation and can have anything from small to severe symptoms.

Question 35

Transfusion reactions are an example of type II hypersensitivity, explain what happens when given the wrong blood type.

Answer 35

The different blood group (ABO) antigens (agglutinins, ABH) are carbohydrates expressed on the surface of red blood cells. Adults possess antibodies to the agglutinins they do NOT have (A/B - H is expressed by all blood groups) after exposure to similar antigens on microorganisms, which have triggered antibody responses (B cells recognizing own agglutinins are negatively selected). If you receive a transfusion of the “wrong” type of blood, your (IgM) antibodies will quickly attach to the donor blood cells (within hours) and trigger complement proteins. IgM is VERY good at fixing complement, so the foreign red blood cells will be destroyed and the buildup of the degraded RBCs e.g. excess hemoglobin is metabolized to bilirubin can build to toxic levels. Note: Antibodies to other blood-group antigens such as Rh factor are usually of the IgG class, and produces delayed (2-6 days) and less severe reactions as IgG is less effective than IgM in activating complement.

Question 36

Briefly explain the causes of hemolytic disease of the newborn (erythroblastosis fetalis).

Answer 36

If a Rh negative mother has an Rh positive baby, the mother will start to produce IgM antibodies (and memory) towards Rh after the pregnancy (the mother is exposed to the blood of the baby in labor - not before as their circulations are separate). This has no effect on the first baby. But, if the mother gets pregnant with an Rh positive baby again, small amounts of Rh can enter the mother and cause her to start producing IgG against Rh, which can travel over the placenta and into the fetus. In the fetus, the anti-Rh IgG binds to the red blood cells and fix complement, cause the destruction of RBCs and lead to hemolytic disease of the newborn (erythroblastosis fetalis). Symptoms can vary from mental retardation to organ failure and death.

Question 37

How do we prevent hemolytic disease of the newborn?

Answer 37

The prevention treatment is to treat the Rh negatinve mother with anti-Rh antibodies after the first pregnancy to make sure the mother don't develop memory cells secreting anti-Rh antibodies. Very effective, and prevents hemolytic disease of the newborn in the following pregnancy.

Question 38

Explain type III hypersensitivity in short.

Answer 38

Type III hypersensitivity is also called immune complex-mediated hypersensitivity. Immune complexes are a natural result following an immune reaction, and normally, they facilitate antigen clearance by phagocytic and red blood cells. If immune complexes aren’t cleared effectively, they may deposit in tissues and lead to tissue damaging type III hypersensitivity reactions. The deposition of immune complexes in the blood vessels or tissues initiates reactions that result in the recruitment of complement components and neutrophils may trigger release of inflammatory mediators (e.g. proteases) and vasoactive mediators to the site, with resultant tissue injury.

Question 39

What determines the severity of type III hypersensitivity reactions?

Answer 39

The magnitude of the type III hypersensitivity reaction depends on the levels and size of immune complexes, their distribution within the body, and the ability of the phagocyte system to clear the complexes and thus minimize the tissue damage. Failure to clear immune complexes may also result from peculiarities of the antigen itself, or disorders in phagocytic machinery.

Question 40

What are some common symptoms to type III hypersensitivity

Answer 40

Symptoms to immune complex-mediated hypersensitivity include; fever, rashes, joint pain, lymph node enlargement, and protein in the urine. - Common in autoimmune manifestations - Vasculitis if in blood vessel (inflammation) - Glomerulonephritis if in kidney (inflammation of the tiny filters in the kidneys (glomeruli)) - Arthritis if in joints

Question 41

A common type III hypersensitivity reaction is Arthus reactions, explain what happens.

Answer 41

Arthus reactions are localized type III hypersensitivity reactions. If an animal or human subject is injected intradermally with an antigen to which large amounts of circulating antibodies exist (or have been recently introduced by intravenous injections), antigen will diffuse into the walls of local blood vessels and large immune complexes will precipitate close to the injection site. This initiates an inflammatory reaction that peaks approximately 4 to 10 hours post-injection and is known as an Arthus reaction, that is characterized by swelling and localized bleeding at injection site. This can cause cause local and sometimes severe inflammation of blood vessels in the skin and other tissues. This can occur after a localized type 1 reaction of an insect bite/sting for example, or may develop in lungs after inhalation of antigen, for example farmer’s lung from inhalation of moldy hay.

Question 42

Explain type IV hypersensitivity in short.

Answer 42

Type IV hypersensitivity, commonly referred to as delayed-type hypersensitivity (DTH), is the only hypersensitivity category that is purely cell mediated rather than antibody mediated. DTH is initiated by T cells, which takes time to develop and get activated, that's why it's delayed, and mediated by macrophages (as opposed to neutrophils or eosinophils) as the primary cellular component of the infiltrate that surrounds the site of inflammation. The response is the same as to intracellular pathogens a Th1 response, but against the "wrong" thing, contact antigens, like hair dyes, poison ivy/oak, nickel salts etc. Some responses can be severe and require hospitalization.

Question 43

Explain the mechanism of a delayed-type (type IV) hypersensitivity (DTH) described after contact with peptides from intracellular bacteria.

Answer 43

In the sensitization phase, T cells get intracellular bacteria antigens presented, eg by DCs, macrophages or langerhans cells, and gets activated and differentiate into Th1 cells with polarizing cytokine signalling from APCs. The effector phase is initiated by a second exposure to the antigen. The sensitized Th1 cells are stimulated to secrete cytokines like IFN-γ, TNF-α, and TNF-β which recruit and activate macrophages to clear the bacteria from infected cells, BUT, the bacteria are hard to get rid off, which can lead to a prolonged immune response. The infected cells can form a granuloma if severe and the infection is not properly cleared. The activated macrophages will then try to kill the framed pathogen, but instead just harms the surrounding tissue. The granulomatous response can damage blood vessels and lead to extensive tissue necrosis. With contact antigens, we can set this pathway in motion which lead to formation of granulomas in the skin, contact dermatitis.

Question 44

Describe a common manifestation on a type IV hypersensitivity response.

Answer 44

A common manifestation on a type IV hypersensitivity response is contact dermatitis, common in response to poison ivy. When poison ivy comes in contact with the skin, the toxin urushiol binds to skin cells and gets taken up by APCs that induce the formation of Th1 cells, or Th17. These sensitized effector cells can go back to the skin and release chemokines that recruit leukocytes to the site and cytokines, such as IFN-γ and TNF-α, that activate macrophages to release inflammatory cytokines, lytic enzymes, and reactive oxygen species (ROS) that cause tissue damage. At present, the best way to avoid a DTH response is to avoid the causative antigen. Once hypersensitivity has developed, topical or oral corticosteroids can be used to suppress the destructive immune response.

Question 45

Name one thing that can induce all four of the hypersensitivity types.

Answer 45

Penicillin can actually induce all four types of hypersensitivities under the correct circumstances for each. The worst, anaphylaxis, is luckily very rare.

Question 46

What is chronic inflammation?

Answer 46

Chronic inflammation is a pathological condition characterized by persistent, increased expression of inflammatory cytokines. It can have both Infectious and non-infectious causes. One example, unfortunately increasing in incidence, is type 2 diabetes. DAMPs released by damaged tissue induce the secretion of inflammatory cytokines and other mediators, and can lead to chronic inflammation if tissue damage persists. Also, the causes to chronic inflammation contribute to more inflammation, so it's a downward spiral. Recent studies also suggest that chronic inflammation exacerbates heart disease, kidney disease, Alzheimer’s, autoimmunity, and cancer.

Question 47

Give two examples each of infectious vs non-infectious causes to chronic inflammation.

Answer 47

Infections causes to chronic inflammation include for example unresolved infections and dysbiosis in the intestine. Non-infectious causes to chronic inflammation include autoimmune responses, allergy, organ transplants and cancer.