Chapter 14- Allergy and the Immune Response to Parasites

Question 1

Hypersensitivity reactions

Answer 1

Immune responses to innocuous antigens that lead to symptomatic reactions on re-exposure. There are 4 types of hypersensitivity reactions

Question 2

Allergic reactions

Answer 2

The result of a secondary immune response to an allergen, causing a wide variety of unpleasant and sometimes life-threatening symptoms. Generally, “allergic reaction” is a term reserved for reactions involving IgE (type 1 hypersensitivity reactions)

Question 3

Allergens

Answer 3

Any antigen that elicits hypersensitivity or allergic reactions. Allergens are usually innocuous proteins that are not threatening to the body

Question 4

Atopy

Answer 4

The genetically determined tendency of some people to produce IgE-mediated hypersensitivity reactions (allergic reactions) against innocuous substances. These individuals have high blood levels of IgE and eosinophils. 40% of Europeans and North Americans of European origin are atopic. Multiple genes are involved, rather than just one like with primary immunodeficiencies. Polymorphisms tend to disturb the balance between TH1 and TH2 responses

Question 5

Epidemic of allergy

Answer 5

The increase in the incidence of allergy over the past 30 years in developed countries. The incidence of allergy has increased 2-3 fold, where 10-40% of individuals in developed countries are now allergic to one or more environmental antigens

Question 6

Common causes of hypersensitivity reactions (4)

Answer 6

1. Inhaled materials, like plant pollen and dust mite feces
2. Injected materials, like insect venom or drugs
3. Ingested materials, like peanuts or shellfish
4. Contacted materials, like plant oil or metal

Question 7

Type 1 hypersensitivity reactions

Answer 7

An immediate reaction. The allergen interacts with allergen-specific IgE bound to FcεRI of mast cells, basophils, and eosinophils. The cells are activated to degranulate and release inflammatory mediators. Reactions range in severity, from a runny nose to difficulty breathing and death. One example is the allergy to plant pollen. Only protein allergens provoke these responses

Question 8

Role of IgE

Answer 8

To cooperate with mast cells, basophils, and eosinophils in controlling infections by multicellular parasites

Question 9

TH2 arm of adaptive immunity

Answer 9

Provides a defense against helminth worms and other multicellular parasites. IgE is central to this arm of immunity

Question 10

Types of parasites

Answer 10

Helminths are the most important and widespread multicellular parasites. Tapeworms, hookworms, and roundworms live and reproduce in the intestine. Other parasites, like flukes, can live and reproduce in the blood, liver, or lungs. Helminths cause chronic and debilitating disease. They compete with the host for nutrients and damage the intestinal epithelium and blood vessels in order to feed

Question 11

Components of a typical adaptive immune response against helminths (4)

Answer 11

1. T cells- CD4 TH2 cells
2. Cytokines- IL-3, IL-4, IL-5, IL-9, IL-10, and IL-13
3. Antibodies- IgE, IgG1, and IgG4
4. Effector cells- expanded populations of eosinophils, basophils, and mast cells

Question 12

Why are parasites considered less antigenic?

Answer 12

Multicellular parasites and humans belong to the same taxonomic group (multicellular animals). Therefore, multicellular parasites are biologically and chemically more like humans than are the bacterial, fungal, viral, or protozoan pathogens. Parasites’ antigenic epitopes are mainly due to sequence differences in types of proteins that are present in both humans and parasites, making parasites are less antigenic

Question 13

Do parasites multiply in the human body?

Answer 13

Most multicellular parasites do not. They exploit the host during one stage of their life cycle

Question 14

Why can’t multicellular parasites be phagocytosed?

Answer 14

Multicellular parasites are simply too big to undergo phagocytosis. Therefore, the main strategy to fight off parasites is to eject them from the body. Mechanisms include coughing, sneezing, nose blowing, vomiting, diarrhea, scratching, and increasing mucus flow

Question 15

Role for TH2 cells in parasite defense

Answer 15

The immune response to parasites occur in mucosal tissues, and is conducted by TH2 cells that help B cells to switch to making IgE. Parasite-specific IgE binds to Fcε receptors on basophils, eosinophils, and mast cells. The cells are given a range of antigen-specific IgE that can recognize parasitic antigens. When the surface IgE is cross-linked by antigen, the cells release their granules, causing inflammatory reactions to eject the pathogens

Question 16

Cross-linking

Answer 16

When a pathogen’s protein or carbohydrate epitopes bind IgE and cross-links FcεR1 on the mast cell surface, it results in clustering that improves cell signaling. This clustering sends signals from the receptor to the nucleus so that inflammatory granules can be released. The cell can then secrete mediators that activate smooth muscle. The antigen must cross-link at least two IgE molecules.

Question 17

Arming of cells in the parasitic response

Answer 17

The binding of diverse, multiple-specificity IgE to basophils, eosinophils, and mast cells. When the surface IgE is cross-linked by antigen, the cells release their granules to create the explosive inflammatory reaction that ejects the parasites

Question 18

Goals of the TH2 immune response (2)

Answer 18

1. Eliminate parasites from the body
2. Cause minimal disruption to the structures and physiological functions of the tissues. This is in contrast to TH1, which disrupts infected tissues by causing inflammation so phagocytes can kill pathogens. The infected tissue is then vulnerable to secondary infections while it is repaired

Question 19

Hygiene hypothesis

Answer 19

The emergence of allergies during the past 150 years correlates with the sanitation of food and water, increased personal hygiene, and medical advances. Additionally, there is an inverse correlation between the incidence of parasitic infections and allergies. In the absence of parasitic infections, IgE has lost its natural target. Therefore, the TH2 arm of immunity is prone to attacking harmless environmental antigens. Vaccination campaigns and overuse of antibiotics may contribute, as children are exposed to less infections overall

Question 20

Development of allergies (type 1 hypersensitivity) requires

Answer 20

Primary exposure and sensitization to the allergen- a person has been exposed to the allergen and made IgE antibodies against it. A subsequent exposure to the antigen will result in an allergic reaction due to release of IgE (isotype switching to IgE) and degranulation of mast cells and basophils

Question 21

Localized vs systemic allergic reactions

Answer 21

A localized reaction targets a single organ or tissue (e.g., hives), while a systemic reaction is anaphylaxis

Question 22

What is the route of transmission of the most common allergens?

Answer 22

Airborne. These allergens are simply the most accessible

Question 23

Sensitization to inhaled allergens

Answer 23

Derp1 is an allergen found in the fecal pellets of dust mites. The allergen is able to enter through tight junctions in the mucosa. It is taken up by dendritic cells, and these cells travel to the secondary lymphoid tissues to interact with T cells. Some people are born with a predisposition to the allergy, in that their T cells may contain receptors that can recognize the Derp1 molecule. If activated in the appropriate environment, the T cell will differentiate into a TH2 cell, and can go on to activate B cells. The B cells produce IgM that is specific to Derp1 at first, but then undergo isotype switching to become IgE. When IgE is released by plasma cells, it can bind to the Fcε receptors on mast cells. Now, when a person is exposed to the allergen, it will bind to IgE on the Fcε receptors on mast cells. This causes rapid degranulation and allergic symptoms

Question 24

Where is IgE located in the tissues?

Answer 24

IgE is not a soluble molecule and is not found in the blood. It is found in tissues, bound to FcεR1. This receptor is constitutively expressed on mast cells and basophils

Question 25

FcεR1 receptor

Answer 25

This receptor is constitutively expressed in large quantities on mast cells and basophils. It allows mast cells to be decorated with a diversity of antigen receptors- IgE binds to the FcεR1 receptor, acting as an antigen receptor. Mast cells tend to be long lived, so they can circulate and respond to antigens if the antigens are encountered

Question 26

FcεR1 receptor in parasitic responses vs allergens

Answer 26

In a person who has been exposed to parasites, the parasite antigen is bound to IgE, which is bound to the FcεR1 receptor, and degranulation occurs. With allergy, the allergen is bound to IgE, which is bound to the FcεR1 receptor. When degranulation occurs, it involves uncomfortable and even life threatening symptoms

Question 27

FcεR2 receptor

Answer 27

A receptor that has a lower affinity for IgE than FcεR1 and is soluble. It is cleaved off of cells and can travel through the body. The soluble form can enter into germinal centers and may go on to promote further TH2 IgE responses. FcεR2 can bind both the BCR and B cell co-receptor in the germinal center, causing the B cell to differentiate into a plasma cell secreting large amounts of IgE. This receptor could be part of the reason why some people develop allergies and some don’t, or the reason why some people have multiple allergies

Question 28

Components of mast cells

Answer 28

Mast cells contain granules that are filled with mediators. They are found throughout the body, typically in mucosal sites (where airborne antigens make contact) and in connective tissue. Mediators include histamines and proteases. There are also other mediators like chemokines and cytokines

Question 29

Histamines

Answer 29

Cause vessel permeability inflammation, mucus, smooth muscle contraction (wheezing, airway constriction)

Question 30

Proteases

Answer 30

Break down the extracellular matrix in order to promote WBC trafficking from the circulation to the site of allergen exposure. Includes tryptase and chymotryptase

Question 31

Eosinophils

Answer 31

Eosinophils are resident in tissues and activated in a similar manner to mast cells. They produce a wide range of highly toxic mediators that can damage parasites and host tissue. TH2 cytokines (like IL-4) induce the production of eosinophils from the bone marrow and exacerbate the allergic response

Question 32

Basophils

Answer 32

Recruited to secondary lymphoid tissues and play a role in promoting TH2 responses. When an allergen is presented to a naive T cell, basophils can be there secreting IL-4 so the T cell will produce GATA3 and become a TH2 cell. Basophils also express CD40L to drive B cell differentiation

Question 33

Mediators of allergic responses

Answer 33

1. Histamine
2. Leukotrienes
3. Prostaglandins

Question 34

Histamine

Answer 34

A derivative of histidine that exerts effects through cells that express histamine receptors. Histamine exerts is effects through the contraction of smooth muscle and blood vessels. The contraction of smooth muscle leads to the airway constriction that can occur during an allergic reaction. There is also an increased secretion of mucus by epithelial cells

Question 35

Leukotrienes

Answer 35

Molecules that are synthesized from fatty acids (arachidonic acid). They act similarly to histamine but are 100 times more potent. They act in the later stages of the allergic response

Question 36

Prostaglandin

Answer 36

Increases permeability and acts as a chemoattractant to bring neutrophils from the circulation to the sites of allergen exposure. Aspirin blocks the synthesis of prostaglandins

Question 37

Properties of inhaled allergens (6)

Answer 37

1. They tend to be proteins- T cells only respond to peptides
2. Most tend to be proteases- they break down the extracellular matrix to get deeper into the tissue and be taken up by antigen presenting cells
3. Low molecular mass- allows the molecules to diffuse through mucus
4. High solubility- the allergen readily elutes from the particle
5. High stability- allows the allergen to survive in the outside environment
6. Has peptides presented by MHC class 2- needed for T cell activation

Question 38

Similarities between allergens and parasitic antigens

Answer 38

Allergens often resemble parasitic antigens- if a person already has T cells that respond to a parasitic antigen, they may respond to a similar allergen

Question 39

Which genetic components can predispose someone to developing an allergy?

Answer 39

Many genes contribute. The proteins affected may include the coding sequence MHC class 2, which would enhance the presentation of antigen derived peptides. The IL-4 promoter may be influenced, causing altered IL-4 expression. The TCR alpha chain may be impacted as well, enhancing T cell recognition of allergen derived peptides

Question 40

Predisposition to allergy in children of atopic mothers

Answer 40

A child is at increased risk for allergy if their mother is atopic. Maternal IgE is present in amniotic fluid, so it may gain access to the fetal mucosal tissues. Then, IgE-antigen complexes could bind to fetal macrophages and fetal B cell FcεR2 to present allergen to CD4 T cells. After birth, the infant could make IgE against allergens. From an evolutionary perspective, this could protect a child against endemic parasites

Question 41

Allergy skin test

Answer 41

An immediate type 1 response can occur, called a “wheal and flare” response. This is characterized by raise skin and redness lasting around 30 minutes, due to inflammation at the injection site. The inflammation is caused by IgE degranulation. Some individuals may experience a late phase reaction, 6-8 hours later. There is widespread swelling due to chemokines and cytokines

Question 42

Asthmatic response to an inhaled allergen

Answer 42

When an inhaled allergen causes immediate constriction of the airways and coughing. People recover from the immune response within 30 minutes. However, the late phase 6-8 hours later is the most damaging. It recruits eosinophils and TH2 CD4 T cells to the airways, causing chronic inflammation

Question 43

Physical effects of mast cell degranulation (3)

Answer 43

Response depends on which tissue comes into contact with the antigen
1. GI tract- increased fluid secretion and peristalsis. There is expulsion of the GI tract contents through diarrhea or vomiting
2. Airways- decreased diameter and increased mucus secretion to trap the allergen. There is expulsion of airway contents through coughing, sneezing, and expulsion of phlegm
3. Blood vessels- increased blood flow and permeability. Causes edema and inflammation due to increased flow of antigens in the lymph to lymph nodes

Question 44

Systemic anaphylaxis

Answer 44

When allergens entering the bloodstream cause systemic mast cell activation- can occur with insect venom, injected drugs, and ingested allergens. Rapid degranulation causes a widespread increase in vascular permeability and muscle contraction. There is a rapid drop in blood pressure (shock) and death by asphyxiation if untreated. Can be treated with epinephrine

Question 45

Effects of epinephrine (Epi-pen)

Answer 45

Used to treat anaphylaxis. It acts to reduce permeability, prevent fluid loss, lower swelling, and normalize blood pressure

Question 46

Allergic rhinitis (hay fever)

Answer 46

When allergens activate mucosal mast cells in the nasal passages. Symptoms include localized swelling, mucus, and irritation due to histamine release. Can also cause allergic conjunctivitis

Question 47

Asthma

Answer 47

If an allergen is inhaled deeper into the respiratory tract, it can cause activation of mast cells in the lower airways. Patients can experience rapid shortness of breath and wheezing. Chronic inflammation can occur as well.

Question 48

Allergic asthma acute response

Answer 48

Involves allergen-induced cross-linking of complexes of IgE and FcεR1 on mast cells. The mast cells are immediately activated and secrete inflammatory mediators, which causes contraction of the bronchial smooth muscle. There is also increased epithelial secretion of mucus. Airway obstruction can result

Question 49

Allergic asthma chronic response

Answer 49

Eosinophils and T cells are recruited to the airways, where they can reside for a long period of time. Products such as cytokines are released that exacerbate inflammation. Can result in people having a “hyper-active airway”, where irritants (exercise, cold weather) and infections can cause cytokine secretion, leading to eosinophil degranulation even if the allergen is not present Results in inflammation and irreversible damage to airways

Question 50

Mast cells in connective tissue

Answer 50

Mast cells can be found in the connective tissue just below the epidermis. If an allergen is introduced subcutaneously, it can interact with mast cells, which degranulate locally. Causes raised, itchy swellings called hives (urticaria) which resembles “wheal and flare”

Question 51

Mast cells in deeper tissue

Answer 51

More mast cells are engaged here, causing angioedema- diffuse swelling, the allergen is carried to the skin by the blood

Question 52

Eczema

Answer 52

A prolonged allergic response, causing a chronic itching and skin rash. Thought to result from the loss of the skin’s barrier function due to chronic inflammation damaging the skin. When the skin breaks down, allergens can access deeper tissues more readily

Question 53

Mechanism of penicillin

Answer 53

Penicillin mimics the substrate that is necessary for bacterial cell wall synthesis (transpeptidase). Penicillin’s beta-lactam ring binds to transpeptidase and inactivates it. The beta lactam ring can also form covalent conjugates with cellular proteins to form new epitopes. RBCs are the cells most commonly modified by penicillin

Question 54

Penicillin allergy

Answer 54

Macrophages phagocytose penicillin-modified RBCs and present the penicillin-modified antigens to CD4 T cells. In the right context of cytokines, CD4 cells become TH2 cells, which stimulate antigen-specific B cells to make IgE. The IgE specific for the penicillin-modified epitope binds to mast cells. The next time a person is exposed to penicillin, it can cause an anaphylactic reaction

Question 55

IgE-mediated food allergies

Answer 55

These allergies are a response to an allergen from a food product. Food intolerances (metabolic defects like lactose intolerance) are not the same thing as allergies. 1-4% of Americans have food allergies, and 25% of food allergies are due to peanuts. Can cause mild symptoms like diarrhea and vomiting, so can cause anaphylaxis

Question 56

Local reactions to food allergens

Answer 56

When ingested, the allergen crosses through the gut lumen and interacts with mast cells in the lamina propria. The local reaction is caused by the histamine released by mast cells, which acts on the intestinal epithelium, blood vessels, and smooth muscle. Symptoms include cramping, vomiting, and diarrhea

Question 57

Systemic reactions to food allergens

Answer 57

Caused by the allergen entering the blood. Symptoms include lip swelling and urticaria, may lead to constriction of the airways in severe cases

Question 58

Omalizumab

Answer 58

A monoclonal anti-IgE antibody used to treat IgE allergic diseases. It binds to the IgE molecule, which prevents it from binding to the mast cell Fcε receptor. Prevents a reaction from taking place

Question 59

Antihistamines

Answer 59

Inhibit the effects of inflammatory mediators on specific receptors, or inhibit synthesis of specific mediators. Beta agonists, leukotriene receptor blockers, and lipoxygenase inhibitors have similar mechanisms

Question 60

Corticosteroids

Answer 60

Have general anti-inflammatory effects, used to mitigate chronic inflammatory reactions

Question 61

Desensitization therapy

Answer 61

Carried out through small injections of the specific antigen in gradually increasing doses. Used for respiratory allergens such as asthma, hay fever, indoor allergies, and insect stings. Its use for food allergies has been avoided due to concern regarding anaphylaxis. These injections are done subcutaneously so the response is localized to the skin

Question 62

Phases of desensitization therapy (2)

Answer 62

1. Build-up phase- shots 1-3 times per week with increasing doses of allergen, lasts 3-6 months
2. Maintenance phase- once the effective dose is reached, shots are done every 2-4 weeks, and this continues for 3-5 years

Question 63

Goal of desensitization

Answer 63

To reduce the severity of allergy symptoms, to reduce the chances of developing new allergies (if a person is predisposed), or to reduce the need for certain medications, like histamines

Question 64

How does desensitization therapy work?

Answer 64

By giving an individual repeated doses of the allergen, we are causing a shift in the T cell response. The T cells that encounter the allergen are signaled to differentiate into cell types other than TH2. There is a shift from creating TH2 cells to creating regulatory T cells, which secrete IL-10 and TGF-beta. The regulatory T cells can then act on the allergen-specific T cells to block their activation. The cytokines can also change the type of antibody the B cells are producing- IgG instead of IgE. These antibodies still have specificity for the antigen, but they bind to the antigen and remove it rather than binding to mast cells

Question 65

Food allergy desensitization

Answer 65

In 2016, there was a clinical trial using a skin patch containing the peanut protein. The individuals used a new patch daily for a year, and had developed a tolerance to peanuts by the end of the trial. An oral immunotherapy trial was conducted in 2018, using capsules of purified peanut flour daily for a year long period. Two thirds of participants responded. This therapy is not a cure, but allows people to tolerate higher doses of the allergen

Question 66

Type 2 hypersensitivity

Answer 66

This is non-IgE allergic disease. IgG antibodies bind to antigens on the patient’s own cells. This antigen-antibody complexes lead to activation of the classical complement pathway. These reactions include transfusion reactions to different blood types, autoimmune hemolytic anemia, myasthenia gravis, and others. IgG could also activate NK cells to undergo ADCC, as during transplant rejection

Question 67

Type 3 hypersensitivity

Answer 67

Involves the deposition of immune complexes in tissues like the blood vessels and kidneys. Formation is dependent on the amount of antigen (there needs to be a certain ratio of antibody to antigen) as well as antibody affinity. Once deposition occurs, complement is activated and phagocytes are recruited, causing an exacerbated inflammatory response. Examples- serum, arthus reaction, sickness, Systemic lupus erythematosus

Question 68

Serum sickness

Answer 68

An immune response to injection of a human with animal antisera (for passive immunization). The response occurs 7-10 days after injection and involves chills, fever, rash, and joint pain. Patients also exhibit inflammation of the glomeruli of the kidneys since this is the major site where complexes deposit

Question 69

What causes serum sickness?

Answer 69

Anaphylatoxins C3a and C5a cause mast cell degranulation and the influx of inflammatory cells to tissues

Question 70

Arthus reaction

Answer 70

Observed after intradermal injection of antigen. Antibodies bind to the allergen and form a complex, which binds to deposit at the injection site and in surrounding tissue. Can cause local vasculitis due to deposition of IgG-based immune complexes in the dermal blood vessels. Severe cases may involve thrombosis. Infrequently reported following diphtheria and tetanus toxoid vaccinations

Question 71

Which immune components are involved in the arthus reaction?

Answer 71

Involves some mast cells- mast cells degranulate when the immune complexes binding mast cell FcγR3. Also involves the production of anaphylatoxins C3a and C5a, which carry out neutrophil recruitment.

Question 72

Delayed-type hypersensitivity (type 4)

Answer 72

Mediated by antigen-specific TH1 effector CD8 and CD4 T cells. A sensitization process is still required, where dendritic cells carry antigen to the regional lymph nodes in order to activate T cells. The T cells become memory T cells, which produce cytokines that induce inflammation and recruitment of phagocytes in the dermis if a person is exposed to the allergen again. The response typically takes 48-72 hours, as seen with the Mantoux TB test

Question 73

Allergic contact dermatitis

Answer 73

May occur due to poison ivy, insect bites, or metals like nickel. The allergen penetrates the skin and is taken up by dendritic cells, then presented to T cells in secondary lymphoid tissues. The T cells are activated and travel back to the skin site. If they are exposed to the molecule again, they release different chemokines and cytokines, causing a localized inflammatory response

Question 74

Celiac disease

Answer 74

A type 4 immune (allergic) response directed against gluten (the protein present in wheat, oats, and barley). The response against gluten causes severe inflammation of the small intestine, which leads to destruction of the villi (impacts nutrient absorption). Patients experience malabsorption and diarrhea. 95% of patients express HLA-DQ2 (associated with the MHC class 2 gene)

Question 75

Increasing prevalence of celiac disease

Answer 75

Over the past 60 years, there has been a 4x increase in cases of celiac disease. Could be due to the increased use of gluten in doughs or to better diagnosis

Question 76

Celiac disease immunopathology

Answer 76

This a CD4 T cell mediated disease. The response is specific for alpha-gliadin, which is a breakdown product of gluten. In the lumen of the intestine, an enzyme called tissue transglutaminase (tTG) deaminates alpha-gliadin, which helps the peptides to bind to HLA-DQ2. CD4 T cells with receptors that are specific for this molecule are activated to produce IFN-γ, which results in intestinal inflammation. IL-15, produced by intestinal epithelial cells in response to IFN-γ, activates dendritic cells and causes further inflammation and damage

Question 77

Diagnosis of Celiac disease

Answer 77

Activation of T cells allows for activation of B cells, which produce anti-gliadin antibodies. These antibodies do not mediate the disease, but they are used diagnostically. The antibodies are found in the serum of all patients with Celiac disease