Immunity Disorders: Hypersensitivity

Type I (Anaphylactic) Reactions

Type I (or immediate/anaphylactic) hypersensitivity can be caused by the body’s response to a foreign substance.

Learning Objectives

Describe Type I hypersensitivity reactions

Key Takeaways

Key Points

  • Common triggers for anaphylaxis include venom from insect bites or stings, foods, and medication.
  • People with atopic diseases such as asthma, eczema, or allergic rhinitis have a high risk of anaphylaxis from food, latex, and radiocontrast agents.
  • Anaphylaxis is a severe allergic reaction that starts suddenly and affects many body systems due to the release of inflammatory mediators and cytokines from mast cells and basophils.

Key Terms

  • anaphylaxis: A severe and rapid systemic allergic reaction to an allergen, causing a constriction of the trachea, preventing breathing; anaphylactic shock.
  • hives: Itchy, swollen, red areas of the skin which can appear quickly in response to an allergen or due to other conditions.
  • mast cells: A mast cell is a resident cell of several types of tissues and contains many granules rich in histamine and heparin. Mat cells play a role in allergy, anaphylaxis, wound healing and defense against pathogens.

Type I hypersensitivity is also known as immediate or anaphylactic hypersensitivity. Anaphylaxis typically produces many different symptoms over minutes or hours. Symptoms typically include raised bumps on the skin (; hives), itchiness, red face or skin (flushing), or swollen lips.

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Hives and flushing on the back of a person with anaphylaxis: Hives and flushing on the back of a person with anaphylaxis

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Anaphylaxis: A representation of the signs and symptoms of anaphylaxis that result from an allergic reaction.

Anaphylaxis can be caused by the body’s response to almost any foreign substance. Common triggers include venom from insect bites or stings, foods, and medication. Foods are the most common trigger in children and young adults. Medications and insect bites and stings are more common triggers in older adults. Less common causes include physical factors, biological agents (such as semen), latex, hormonal changes, food additives (e.g. monosodium glutamate (MSG) and food coloring), and medications that are applied to the skin (topical medications). Exercise or temperature (either hot or cold) may also trigger anaphylaxis by causing tissue cells known as mast cells to release chemicals that start the allergic reaction.

Anaphylaxis caused by exercise is often also linked to eating certain foods. If anaphylaxis occurs while a person is receiving anesthesia, the most common causes are certain medications that are given to produce paralysis (neuromuscular blocking agents), antibiotics, and latex. Many foods can trigger anaphylaxis, even when the food is eaten for the first time. In Western cultures, the most common causes are eating or being in contact with peanuts, wheat, tree nuts, shellfish, fish, milk, and eggs.

People with atopic diseases such as asthma, eczema, or allergic rhinitis have a high risk of anaphylaxis from food, latex, and radiocontrast agents. These people do not have a higher risk from injectable medications or stings. People who have disorders caused by too many mast cells in their tissues (mastocytosis) or who are wealthier are at increased risk. The longer the time since the last exposure to an agent that caused anaphylaxis, the lower the risk of a new reaction.

Anaphylaxis is a severe allergic reaction that starts suddenly and affects many body systems. It results from the release of inflammatory mediators and cytokines from mast cells and basophils. This release is typically associated with an immune system reaction, but may also be caused by damage to cells that are not related to an immune reaction. When anaphylaxis is caused by an immune response, immunoglobulin E (IgE) binds to the foreign material that starts the allergic reaction (the antigen ). The combination of IgE bound to the antigen activates FcεRI receptors on mast cells and basophils. The mast cells and basophils react by releasing inflammatory mediators such as histamine. These mediators increase the contraction of bronchial smooth muscles, cause blood vessels to widen (vasodilation), increase the leakage of fluid from blood vessels, and depress the actions of the heart muscle. There is also an immunologic mechanism that does not rely on IgE, but it is not known if this occurs in humans. When anaphylaxis is not caused by in immune response, the reaction is due to an agent that directly damages mast cells and basophils, causing them to release histamine and other substances that are usually associated with an allergic reaction (degranulation). Agents that can damage these cells include contrast medium for X-rays, opioids, temperature (hot or cold), and vibration.

Diagnosis and Treatment of Allergy

Allergy testing can help confirm or rule out allergies, reducing adverse reactions and limiting unnecessary avoidance and medications.

Learning Objectives

Describe how the skin prick test and the allergy blood test work to assess the presence of allergen specific antibodies in an individual

Key Takeaways

Key Points

  • To assess the presence of allergen -specific IgE antibodies, you can use one of two methods: a skin-prick test or an allergy blood test.
  • Challenge testing is when small amounts of a suspected allergen are introduced to the body orally, through inhalation, or via other routes.
  • Patch testing is used to help ascertain the cause of skin contact allergy (contact dermatitis).
  • Traditional treatment and management of allergies consisted of simply avoiding the allergen in question.
  • Several antagonistic drugs are used to block the action of allergic mediators or to prevent activation of cells and degranulation processes.

Key Terms

  • allergen: a substance that causes an allergic reaction
  • antihistamine: a drug or substance that counteracts the effects of a histamine. Commonly used to alleviate the symptoms of hay fever and other allergies
  • skin prick test: Skin-prick testing is also known as “puncture testing” and “prick testing” because of the series of tiny punctures or pricks made in the patient’s skin. Small amounts of suspected allergens or their extracts (pollen, grass, mite proteins, peanut extract, etc.) are introduced to sites on the skin marked with pen or dye.

Allergy testing can help confirm or rule out allergies, reducing adverse reactions and limiting unnecessary avoidance and medications. Correct diagnosis, counseling, and avoidance advice based on valid allergy test results will help reduce the incidence of symptoms and medications and will improve quality of life. Earlier and more accurate diagnoses save costs due to a reduction in consultations, referrals to secondary care, misdiagnoses, and emergency admissions.

For assessing the presence of allergen-specific IgE antibodies, you can use two different methods: a skin prick test or an allergy blood test. Both methods are recommended by the NIH guidelines, are equally cost-effective, and have similar diagnostic value in terms of sensitivity and specificity. A healthcare provider can use the test results to identify the specific allergic triggers that may be contributing to symptoms.

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Allergy Skin Testing: Skin testing on an arm.

Allergies undergo dynamic changes over time. Regular allergy testing for relevant allergens provides information on if and how patient management can be changed in order to improve health and quality of life. Annual testing is often the practice for determining whether allergies to milk, eggs, soy, and wheat have been outgrown. The testing interval is extended to two to three years for allergies to peanuts, tree nuts, fish, and crustacean shellfish. Results of followup testing can guide decision-making regarding whether and when it is safe to introduce or re-introduce allergenic food into the diet.

Skin testing is also known as “puncture testing” and “prick testing” because of the series of tiny punctures or pricks made in the patient’s skin. Small amounts of suspected allergens or their extracts are introduced to sites on the skin marked with pen or dye (the dye should be carefully selected, lest it cause an allergic response itself). Sometimes, the allergens are injected “intradermally” into the patient’s skin with a needle and syringe. Common areas for testing include the inside forearm and the back. If the patient is allergic to the substance, then a visible inflammatory reaction will usually occur within 30 minutes. This response will range from a slight reddening of the skin to a full-blown hive (called “wheal and flare”) similar to a mosquito bite in more sensitive patients. Interpretation of the results of the skin-prick test is normally done by allergists on a scale of severity, with +/- meaning borderline reactivity and 4+ indicating a severe reaction.

In contrast, an allergy blood test is quick and simple and can be performed irrespective of age, skin condition, medication, symptom, disease activity, and pregnancy. In addition, multiple allergens can be detected with a single blood sample. Allergy blood tests are very safe, since the patient is not exposed to any allergens during the testing procedure. The test measures the concentration of specific IgE antibodies in the blood.

Challenge testing is when small amounts of a suspected allergen are introduced to the body orally, through inhalation, or via other routes. Challenge tests are utilized most often with foods or medicines. If the patient experiences significant improvement while avoiding a suspected allergen, she may then be “challenged” by reintroducing it to see if symptoms can be reproduced.

Patch testing is used to help ascertain the cause of skin contact allergy (contact dermatitis). Adhesive patches, usually treated with a number of different commonly allergenic chemicals or skin sensitizers, are applied to the back. The skin is then examined for possible local reactions at least twice, usually 48 hours after application and then again two or three days later.

Traditional treatment and management of allergies consisted of simply avoiding the allergen in question. However, while avoidance of allergens may reduce symptoms and avoid life-threatening anaphylaxis, it is difficult to do for those with allergies to pollen or other airborne allergens. Several antagonistic drugs are used to block the action of allergic mediators or to prevent activation of cells and degranulation processes. These include antihistamines, glucocorticoids, epinephrine (adrenaline), theophylline, and cromolyn sodium.

Desensitization or hyposensitization is a treatment in which the patient is gradually vaccinated with progressively larger doses of the allergen in question. This can either reduce the severity or eliminate hypersensitivity altogether. It relies on the progressive skewing of IgG antibody production to block excessive IgE production seen in atopys. In effect, the person builds up immunity to increasing amounts of the allergen. Studies have demonstrated the long-term efficacy and the preventive effect of immunotherapy in reducing the development of new allergies. A second form of immunotherapy involves the intravenous injection of monoclonal anti-IgE antibodies. These bind to free- and B cell-associated IgE, signaling their destruction.

Type II (Cytotoxic) Reactions

In type II (cytotoxic) hypersensitivity, the antibodies produced by the immune response bind to antigens on the patient’s own cell surfaces.

Learning Objectives

Describe Type II hypersensitivity reactions

Key Takeaways

Key Points

  • The antigens recognized in this way may either be intrinsic (“self” antigen, innately part of the patient’s cells) or extrinsic (adsorbed onto the cells during exposure to some foreign antigen, possibly as part of infection with a pathogen).
  • Mediators of acute inflammation are generated at the site where a foreign antigen is recognized and membrane attack complexes cause cell lysis and death.
  • In antibody -dependent cell-mediated cytotoxicity (ADCC), cells exhibiting the foreign antigen are tagged with antibodies ( IgG or IgM) and they are then recognised by natural killer (NK) cells and macrophages which in turn kill these tagged cells.

Key Terms

  • macrophages: A type of white blood cell that targets foreign material, including bacteria and viruses.
  • dendritic cells: Dendritic cells are immune cells that function to process antigen material and present it on the surface of other cells of the immune system. They act as messengers between innate and adaptive immunity.
  • cytotoxic hypersensitivity: In type II hypersensitivity, the antibodies produced by the immune response bind to antigens on the patient’s own cell surfaces.

In type II hypersensitivity (or cytotoxic hypersensitivity), the antibodies produced by the immune response bind to antigens on the patient’s own cell surfaces. The antigens recognized in this way may either be intrinsic (“self” antigen, innately part of the patient’s cells) or extrinsic (adsorbed onto the cells during exposure to some foreign antigen, possibly as part of infection with a pathogen). These cells are recognized by macrophages or dendritic cells, which act as antigen-presenting cells. This causes a B cell response, wherein antibodies are produced against the foreign antigen.

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Complement death: A complement protein attacking an invader.

An example of type II hypersensitivity is the reaction to penicillin wherein the drug can bind to red blood cells, causing them to be recognized as different; B cell proliferation will take place and antibodies to the drug are produced. IgG and IgM antibodies bind to these antigens to form complexes that activate the classical pathway of complement activation to eliminate cells presenting foreign antigens (which are usually, but not in this case, pathogens). That is, mediators of acute inflammation are generated at the site and membrane attack complexes cause cell lysis and death. The reaction takes hours to a day. The membrane attack complex (MAC; ) is typically formed on the surface of pathogenic bacterial cells as a result of the activation of the alternative pathway and the classical pathway of the complement system, and it is one of the effector proteins of the immune system. The membrane-attack complex (MAC) forms transmembrane channels. These channels disrupt the phospholipid bilayer of target cells, leading to cell lysis and death.

Another form of type II hypersensitivity is called antibody-dependent cell-mediated cytotoxicity (ADCC). Here, cells exhibiting the foreign antigen are tagged with antibodies (IgG or IgM). These tagged cells are then recognised by natural killer (NK) cells and macrophages (recognised via IgG bound (via the Fc region) to the effector cell surface receptor, CD16 (FcγRIII)), which in turn kill these tagged cells.

Autoimmune diseases resemble type II-IV hypersensitivity reactions. They differ from hypersensitivity reactions in that the antigens driving the immune process are self-antigens rather than non-self as in hypersensitivity reactions. Below are some examples of Type II hypersensitivity-like autoimmunity.

Type III (Immune Complex) Reactions

Type III hypersensitivity occurs when there is little antibody and an excess of antigen, leading to the formation of small immune complexes.

Learning Objectives

Describe Type III hypersensitivity reactions

Key Takeaways

Key Points

  • It is characterized by solvent antigens that are not bound to cell surfaces (which is the case in type II hypersensitivity) but bind antibodies to form immune complexes of different sizes.
  • Large complexes can be cleared by macrophages but small immune complexes cannot be cleared and they insert themselves into small blood vessels, joints, and glomeruli, causing symptoms.
  • The cause of damage is as a result of the action of cleaved complement anaphylotoxins C3a and C5a, which, mediate the onset of the inflammatory response and eventual tissue damage.

Key Terms

  • glomerulonephritis: A form of nephritis characterized by inflammation of the glomeruli
  • immune complex: An immune complex is formed from the integral binding of an antibody to a soluble antigen. The bound antigen acting as a specific epitope, bound to an antibody is referred to as a singular immune complex.
  • Arthus reaction: The Arthus reaction is a type of local type III hypersensitivity reaction which involves the deposition of antigen/antibody complexes mainly in the vascular walls, serosa (pleura, pericardium, synovium) and glomeruli.

Type III hypersensitivity occurs when there is little antibody and an excess of antigen, leading to small immune complexes being formed that do not fix complement and are not cleared from the circulation. It is characterized by solvent antigens that are not bound to cell surfaces (which is the case in type II hypersensitivity). When these antigens bind antibodies, immune complexes of different sizes form. Large complexes can be cleared by macrophages but macrophages have difficulty in the disposal of small immune complexes. These immune complexes insert themselves into small blood vessels, joints, and glomeruli, causing symptoms. Unlike the free variant, small immune complex bound to sites of deposition (like blood vessel walls) are far more capable of interacting with complement. These medium-sized complexes, formed in the slight excess of antigen, are viewed as being highly pathogenic.

Such depositions in tissues often induce an inflammatory response, and can cause damage wherever they precipitate. The cause of damage is as a result of the action of cleaved complement anaphylotoxins C3a and C5a, which, respectively, mediate the induction of granule release from mast cells (from which histamine can cause urticaria), and recruitment of inflammatory cells into the tissue (mainly those with lysosomal action, leading to tissue damage through frustrated phagocytosis by polymorphonuclear neutrophils and macrophages).

Immune complex glomerulonephritis, as seen in Henoch-Schönlein purpura is an example of IgA involvement in a nephropathy. The reaction can take hours, days, or even weeks to develop, depending on whether or not there is immunlogic memory of the precipitating antigen. Typically, clinical features emerge a week following initial antigen challenge, when the deposited immune complexes can precipitate an inflammatory response. Because of the nature of the antibody aggregation, tissues that are associated with blood filtration at considerable osmotic and hydrostatic gradient (e.g. sites of urinary and synovial fluid formation, kidney glomeruli and joint tissues respectively) bear the brunt of the damage. Hence, vasculitis, glomerulonephritis and arthritis are commonly-associated conditions as a result of type III hypersensitivity responses. As observed under methods of histopathology, acute necrotizing vasculitis within the affected tissues is observed concomitant to neutrophilic infiltration, along with notable eosinophilic deposition (fibrinoid necrosis).

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Henoch-Schönlein nephritis IgA immunostaining: Immune Complex Glomerulonephritis, as seen in Henoch-Schönlein purpura; this is an example of IgA involvement in a nephropathy.

Often, immunofluorescence microscopy can be used to visualize the immune complexes. Skin response to a hypersensitivity of this type is referred to as an Arthus reaction, and is characterized by local erythema and some induration. Platelet aggregation, especially in microvasculature, can cause localized clot formation, leading to blotchy hemorrhages. This typifies the response to injection of foreign antigen sufficient to lead to the condition of serum sickness. An immune complex is formed from the integral binding of an antibody to a soluble antigen. The bound antigen acting as a specific epitope, bound to an antibody, is referred to as a singular immune complex. After an antigen-antibody reaction, the immune complexes can be subject to any of a number of responses, including complement deposition, opsonization, phagocytosis, or processing by proteases.

Red blood cells carrying CR1-receptors on their surface may bind C3b-decorated immune complexes and transport them to phagocytes, mostly in liver and spleen, and return back to the general circulation. Immune complexes may themselves cause disease when they are deposited in organs, e.g. in certain forms of vasculitis. This is the third form of hypersensitivity in the Gell-Coombs classification, called Type III hypersensitivity. Immune complex deposition is a prominent feature of several autoimmune diseases, including systemic lupus erythematosus, cryoglobulinemia, rheumatoid arthritis, scleroderma and Sjögren’s syndrome.

Type IV (Delayed Cell-Mediated) Reactions

Type IV hypersensitivity reactions are cell-mediated and take 2 to 3 days to develop.

Learning Objectives

Describe Type IV cell-mediated reactions and explain why they take two to three days to develop

Key Takeaways

Key Points

  • Cell-mediated immunity is an immune response that does not involve antibodies but rather involves the activation of phagocytes, natural killer cells (NK), antigen -specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen.
  • In type IV hypersensitivity reactions, CD4+ helper T cells recognize antigen in a complex with Class 2 major histocompatibility complex on macrophages (the antigen-presenting cells).
  • A classic example of delayed type IV hypersensitivity is the Mantoux tuberculin test in which skin induration indicates exposure to tuberculosis.

Key Terms

  • cellular immunity: Cellular immunity protects the body by: activating antigen-specific cytotoxic T-lymphocytes, activating macrophages and natural killer cells and stimulating cytokine secretion to stimulate other cells involved in adaptive immune responses and innate immune responses.
  • type IV hypersensitivity: A cell-mediated immune response that takes two to three days to develop.

Cell-mediated immunity is an immune response that does not involve antibodies, but rather involves the activation of phagocytes, natural killer cells (NK), antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen. Historically, the immune system was separated into two branches: humoral immunity, for which the protective function of immunization could be found in the humor (cell-free bodily fluid or serum) and cellular immunity, for which the protective function of immunization was associated with cells. CD4 cells or helper T cells provide protection against different pathogens. Cytotoxic T cells cause death by apoptosis without using cytokines. Therefore in cell mediated immunity cytokines are not always present.

Cellular immunity protects the body by:

1. activating antigen-specific cytotoxic T-lymphocytes that are able to induce apoptosis in body cells displaying epitopes of foreign antigen on their surface, such as virus-infected cells, cells with intracellular bacteria, and cancer cells displaying tumor antigens

2. activating macrophages and natural killer cells, enabling them to destroy pathogens

3. stimulating cells to secrete a variety of cytokines that influence the function of other cells involved in adaptive immune responses and innate immune responses

Cell-mediated immunity is directed primarily at microbes that survive in phagocytes and microbes that infect non-phagocytic cells. It is most effective in removing virus-infected cells, but also participates in defending against fungi, protozoans, cancers, and intracellular bacteria. It also plays a major role in transplant rejection.

Type IV hypersensitivity is often called delayed type hypersensitivity as the reaction takes two to three days to develop. Unlike the other types, it is not antibody mediated but rather is a type of cell-mediated response. CD4+ helper T cells recognize antigen in a complex with Class 2 major histocompatibility complex. The antigen-presenting cells in this case are macrophages that secrete IL-12, which stimulates the proliferation of further CD4+ Th1 cells. CD4+ T cells secrete IL-2 and interferon gamma, further inducing the release of other Th1 cytokines, thus mediating the immune response. Activated CD8+ T cells destroy target cells on contact, whereas activated macrophages produce hydrolytic enzymes and, on presentation with certain intracellular pathogens, transform into multinucleated giant cells.

A classic example of delayed type IV hypersensitivity is the Mantoux tuberculin test in which skin induration indicates exposure to tuberculosis. Other examples include: temporal arteritis, Hashimoto’s thyroiditis, symptoms of leprosy, symptoms of tuberculosis, coeliac disease, graft-versus-host disease and chronic transplant rejection.

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Mantoux test: The reaction is read by measuring the diameter of induration (palpable raised, hardened area) across the forearm (perpendicular to the long axis) in millimeters. If there is no induration, the result should be recorded as “0 mm”. Erythema (redness) should not be measured. If a person has had a history of a positive tuberculin skin test, or had a recent tuberculin skin test (within one year), another skin test should be used.

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Mantoux tuberculin test: The Mantoux test (also known as the Mantoux screening test, tuberculin sensitivity test, Pirquet test, or PPD test for purified protein derivative) is a diagnostic tool for tuberculosis. A standard dose of tuberculin is injected intradermally (between the layers of dermis) and read 48 to 72 hours later.