Hypersensitivity

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Hypersensitivity
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Types of hypersensitivity reactions
Specialty Immunology

Hypersensitivity (also called hypersensitivity reaction or intolerance) is an abnormal physiological condition in which there is an undesirable and adverse immune response to antigen. [1] [2] It is an abnormality in the immune system that causes immune diseases including allergies and autoimmunity. It is caused by many types of particles and substances from the external environment or from within the body that are recognized by the immune cells as antigens. [3] The immune reactions are usually referred to as an over-reaction of the immune system and they are often damaging and uncomfortable. [4]

Contents

In 1963, Philip George Houthem Gell and Robin Coombs introduced a systematic classification of the different types of hypersensitivity based on the types of antigens and immune responses involved. According to this system, known as the Gell and Coombs classification [5] or Gell-Coombs's classification, [6] there are four types of hypersensitivity, namely, type I, which is an IgE mediated immediate reaction; type II, an antibody-mediated reaction mainly involving IgG or IgM; type III, an immune complex-mediated reaction involving IgG, complement system and phagocytes; type IV, a cytotoxic, cell-mediated, delayed hypersensitivity reaction involving T cells. [7]

The first three types are considered immediate hypersensitivity reactions because they occur within 24 hours. The fourth type is considered a delayed hypersensitivity reaction because it usually occurs more than 12 hours after exposure to the allergen, with a maximal reaction time between 48 and 72 hours. [8] Hypersensitivity is a common occurrence, it is estimated that about 15% of humans have at least one type during their lives, and has increased since the latter half of the 20th century. [9]

Gell and Coombs classification

The Gell and Coombs classification of hypersensitivity is the most widely used, and distinguishes four types of immune response which result in bystander tissue damage. [10]

Immunologic aspects of hypersensitivity reactions
TypeAlternative namesAntibodies or Cell MediatorsImmunologic ReactionExamples
I Fast response which occurs in minutes, rather than multiple hours or days. Free antigens cross link the IgE on mast cells and basophils which causes a release of vasoactive biomolecules. Testing can be done via skin test for specific IgE. [11]
II Antibody (IgM or IgG) binds to antigen on a target cell, which is actually a host cell that is perceived by the immune system as foreign, leading to cellular destruction via the MAC. Testing includes both the direct and indirect Coombs test. [12]
III Antibody (IgG) binds to soluble antigen, forming a circulating immune complex. This is often deposited in the vessel walls of the joints and kidney, initiating a local inflammatory reaction. [13]
IV Cells CTL's and T helper cells (specifically Th1 and Th17 cells) [14] are activated by an antigen presenting cell. When the antigen is presented again in the future, the memory Th1 cells will activate macrophages and cause an inflammatory response. This ultimately can lead to tissue damage. [15]

Type I hypersensitivity

Etiology

Type I hypersensitivity

Type I hypersensitivity occurs as a result of exposure to an antigen. The antigens are proteins with a molecular weight ranging from 10 to 40 kDa. [9] The response to the antigen occurs in two stages: the sensitization and the effect stage. In the "sensitization" stage, the host experiences an asymptomatic contact with the antigen. Subsequently, in the "effect" period, the pre-sensitized host is re-introduced to the antigen, which then leads to a type I anaphylactic or atopic immune response. [17]

Types of antigens involved

Type II hypersensitivity

Type II hypersensitivity reaction refers to an antibody-mediated immune reaction in which antibodies (IgG or IgM) are directed against cellular or extracellular matrix antigens with the resultant cellular destruction, functional loss, or damage to tissues. [9] The antigens may be for example glycoproteins on the cell membrane of erythrocytes that are key molecules that determine blood types. Depending on the chemical nature of the antigens, blood types have different levels of hypersensitivity; for instance, A and B are more antigenic than other antigens. [9]

Type II hypersensitivity

Damage can be accomplished via three different mechanisms: [9]

The pathophysiology of type II hypersensitivity reactions can be broadly classified into three types: [9]

The process involves a series of immune-mediated events that might take different forms. [18]

Type III hypersensitivity

Type III hypersensitivity

In type III hypersensitivity reaction, an abnormal immune response is mediated by the formation of antigen-antibody aggregates called "immune complexes". They can precipitate in various tissues such as skin, joints, vessels, or glomeruli, and trigger the classical complement pathway. Complement activation leads to the recruitment of inflammatory cells (monocytes and neutrophils) that release lysosomal enzymes and free radicals at the site of immune complexes, causing tissue damage. [7]

The most common diseases involving a type III hypersensitivity reaction are serum sickness, post-streptococcal glomerulonephritis, systemic lupus erythematosus, farmers' lung (hypersensitivity pneumonitis), and rheumatoid arthritis. [7]

The principal feature that separates type III reactions from other hypersensitivity reactions is that in type III reaction, the antigen-antibody complexes are pre-formed in the circulation before their deposition in tissues. [7]

Type IV hypersensitivity

Type IV hypersensitivity

Type IV hypersensitivity reactions are, to some extent, normal physiological events that help fight infections, and dysfunction in this system can predispose to multiple opportunistic infections. Adverse events can also occur due to these reactions when an undesirable interaction between the immune system and an allergen happens. [8]

Pathophysiology

A type IV hypersensitivity reaction is mediated by T cells that provoke an inflammatory reaction against exogenous or endogenous antigens. In certain situations, other cells, such as monocytes, eosinophils, and neutrophils, can be involved. After antigen exposure, an initial local immune and inflammatory response occurs that attracts leukocytes. The antigen engulfed by the macrophages and monocytes is presented to T cells, which then becomes sensitized and activated. These cells then release cytokines and chemokines, which can cause tissue damage and may result in illnesses. [8]

Examples of illnesses resulting from type IV hypersensitivity reactions include contact dermatitis and drug hypersensitivity. Type IV reactions are further subdivided into type IVa, IVb, IVc, and IVd based on the type of T cell (Th1, Th17, and CTLs) involved and the cytokines/chemokines produced. [8]

Delayed hypersensitivity plays a crucial role in our body's ability to fight various intracellular pathogens such as mycobacteria and fungi. They also play a principal role in tumor immunity and transplant rejection. Since patients with acquired immunodeficiency syndrome (AIDS) have a progressive decline in the number of CD4 cells, they also have a defective type four hypersensitivity reaction. [8]

Treatment

Immediate hypersensitivity reactions

The treatment of immediate hypersensitivity reactions includes the management of anaphylaxis with intramuscular adrenaline (epinephrine), oxygen, intravenous (IV) antihistamine, support blood pressure with IV fluids, avoid latex gloves and equipment in patients who are allergic, and surgical procedures such as tracheotomy if there is severe laryngeal edema. [9]

  1. Allergic bronchial asthma can be treated with any of the following: inhaled short- and long-acting bronchodilators (anticholinergics) along with inhaled corticosteroids, leukotriene antagonists, use of disodium cromoglycate, and environmental control. Experimentally, a low dose of methotrexate or cyclosporin and omalizumab (a monoclonal anti-IgE antibody) has been used.
  2. Treatment of autoimmune disorders (e.g., SLE) include one or a combination of NSAIDs and hydroxychloroquine, azathioprine, methotrexate, mycophenolate, cyclophosphamide, low dose IL-2, intravenous immunoglobulins, and belimumab.
  3. Omalizumab is a monoclonal antibody that interacts with the binding site of the high-affinity IgE receptor on mast cells. It is an engineered, humanized recombinant immunoglobulin. Moderate to severe allergic bronchial asthma can improve with omalizumab. [9]

Delayed hypersensitivity reactions

Treatment of type 4 HR involves the treatment of the eliciting cause.

  1. The most common drugs to treat tuberculosis include isoniazid, rifampin, ethambutol, and pyrazinamide. For drug-resistant TB, a combination of antibiotics such as amikacin, kanamycin, or capreomycin should be used.
  2. The most common drugs to treat leprosy include rifampicin and clofazimine in combination with dapsone for multibacillary leprosy. A single dose of antimicrobial combination to cure single lesion paucibacillary leprosy comprises ofloxacin, rifampicin, and minocycline.
  3. Praziquantel can be useful for treating infections caused by all Schistosoma species.
  4. Hydroxychloroquine and chloroquine can use in the therapy of sarcoidosis involving the skin, lungs, and the nervous system.
  5. The use of anti-TNF monoclonal antibodies such as adalimumab and certolizumab have been approved for Crohn disease. [19]

Related Research Articles

<span class="mw-page-title-main">Allergy</span> Immune system response to a substance that most people tolerate well

Allergies, also known as allergic diseases, are various conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic dermatitis, allergic asthma, and anaphylaxis. Symptoms may include red eyes, an itchy rash, sneezing, coughing, a runny nose, shortness of breath, or swelling. Note that food intolerances and food poisoning are separate conditions.

<span class="mw-page-title-main">T helper cell</span> Type of immune cell

The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4+ cells are mature Th cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4+ cells determines susceptibility to a broad class of autoimmune diseases.

<span class="mw-page-title-main">Mast cell</span> Cell found in connective tissue

A mast cell is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a part of the immune and neuroimmune systems. Mast cells were discovered by Paul Ehrlich in 1877. Although best known for their role in allergy and anaphylaxis, mast cells play an important protective role as well, being intimately involved in wound healing, angiogenesis, immune tolerance, defense against pathogens, and vascular permeability in brain tumors.

<span class="mw-page-title-main">Immunoglobulin E</span> Immunoglobulin E (IgE) Antibody

Immunoglobulin E (IgE) is a type of antibody that has been found only in mammals. IgE is synthesised by plasma cells. Monomers of IgE consist of two heavy chains and two light chains, with the ε chain containing four Ig-like constant domains (Cε1–Cε4). IgE is thought to be an important part of the immune response against infection by certain parasitic worms, including Schistosoma mansoni, Trichinella spiralis, and Fasciola hepatica. IgE is also utilized during immune defense against certain protozoan parasites such as Plasmodium falciparum. IgE may have evolved as a defense to protect against venoms.

Haptens are small molecules that elicit an immune response only when attached to a large carrier such as a protein; the carrier may be one that also does not elicit an immune response by itself. The mechanisms of absence of immune response may vary and involve complex immunological interactions, but can include absent or insufficient co-stimulatory signals from antigen-presenting cells.

<span class="mw-page-title-main">Food allergy</span> Hypersensitivity reaction to a food

A food allergy is an abnormal immune response to food. The symptoms of the allergic reaction may range from mild to severe. They may include itchiness, swelling of the tongue, vomiting, diarrhea, hives, trouble breathing, or low blood pressure. This typically occurs within minutes to several hours of exposure. When the symptoms are severe, it is known as anaphylaxis. A food intolerance and food poisoning are separate conditions, not due to an immune response.

<span class="mw-page-title-main">Type I hypersensitivity</span> Type of allergic reaction

Type I hypersensitivity, in the Gell and Coombs classification of allergic reactions, is an allergic reaction provoked by re-exposure to a specific type of antigen referred to as an allergen. Type I is distinct from type II, type III and type IV hypersensitivities. The relevance of the Gell and Coombs classification of allergic reactions has been questioned in the modern-day understanding of allergy, and it has limited utility in clinical practice.

Omalizumab, sold under the brand name Xolair, is an injectable medication to treat severe persistent allergic forms of asthma, nasal polyps, urticaria (hives), and immunoglobulin E-mediated food allergy.

<span class="mw-page-title-main">Hemolytic disease of the newborn</span> Fetal and neonatal alloimmune blood condition

Hemolytic disease of the newborn, also known as hemolytic disease of the fetus and newborn, HDN, HDFN, or erythroblastosis fetalis, is an alloimmune condition that develops in a fetus at or around birth, when the IgG molecules produced by the mother pass through the placenta. Among these antibodies are some which attack antigens on the red blood cells in the fetal circulation, breaking down and destroying the cells. The fetus can develop reticulocytosis and anemia. The intensity of this fetal disease ranges from mild to very severe, and fetal death from heart failure can occur. When the disease is moderate or severe, many erythroblasts are present in the fetal blood, earning these forms of the disease the name erythroblastosis fetalis.

The direct and indirect Coombs tests, also known as antiglobulin test (AGT), are blood tests used in immunohematology. The direct Coombs test detects antibodies that are stuck to the surface of the red blood cells. Since these antibodies sometimes destroy red blood cells they can cause anemia; this test can help clarify the condition. The indirect Coombs test detects antibodies that are floating freely in the blood. These antibodies could act against certain red blood cells; the test can be carried out to diagnose reactions to a blood transfusion.

<span class="mw-page-title-main">Atopy</span> Predisposition towards allergy

Atopy is the tendency to produce an exaggerated immunoglobulin E (IgE) immune response to otherwise harmless substances in the environment. Allergic diseases are clinical manifestations of such inappropriate, atopic responses.

Autoimmune hemolytic anemia (AIHA) occurs when antibodies directed against the person's own red blood cells (RBCs) cause them to burst (lyse), leading to an insufficient number of oxygen-carrying red blood cells in the circulation. The lifetime of the RBCs is reduced from the normal 100–120 days to just a few days in serious cases. The intracellular components of the RBCs are released into the circulating blood and into tissues, leading to some of the characteristic symptoms of this condition. The antibodies are usually directed against high-incidence antigens, therefore they also commonly act on allogenic RBCs. AIHA is a relatively rare condition, with an incidence of 5–10 cases per 1 million persons per year in the warm-antibody type and 0.45 to 1.9 cases per 1 million persons per year in the cold antibody type. Autoimmune hemolysis might be a precursor of later onset systemic lupus erythematosus.

<span class="mw-page-title-main">Immune complex</span> Molecule formed binding antigens to antibodies

An immune complex, sometimes called an antigen-antibody complex or antigen-bound antibody, is a molecule formed from the binding of multiple antigens to antibodies. The bound antigen and antibody act as a unitary object, effectively an antigen of its own with a specific epitope. 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-coated immune complexes and transport them to phagocytes, mostly in liver and spleen, and return to the general circulation.

Immune tolerance, also known as immunological tolerance or immunotolerance, refers to the immune system's state of unresponsiveness to substances or tissues that would otherwise trigger an immune response. It arises from prior exposure to a specific antigen and contrasts the immune system's conventional role in eliminating foreign antigens. Depending on the site of induction, tolerance is categorized as either central tolerance, occurring in the thymus and bone marrow, or peripheral tolerance, taking place in other tissues and lymph nodes. Although the mechanisms establishing central and peripheral tolerance differ, their outcomes are analogous, ensuring immune system modulation.

A drug allergy is an allergy to a drug, most commonly a medication, and is a form of adverse drug reaction. Medical attention should be sought immediately if an allergic reaction is suspected.

Type II hypersensitivity, in the Gell and Coombs classification of allergic reactions, is an antibody mediated process in which IgG and IgM antibodies are directed against antigens on cells or extracellular material. This subsequently leads to cell lysis, tissue damage or loss of function through mechanisms such as

  1. complement activation via the classical complement pathway
  2. Antibody-dependent cellular cytotoxicity or
  3. anti-receptor activity.
<span class="mw-page-title-main">Type III hypersensitivity</span> Type of allergic reaction

Type III hypersensitivity, in the Gell and Coombs classification of allergic reactions, occurs when there is accumulation of immune complexes that have not been adequately cleared by innate immune cells, giving rise to an inflammatory response and attraction of leukocytes. There are three steps that lead to this response. The first step is immune complex formation, which involves the binding of antigens to antibodies to form mobile immune complexes. The second step is immune complex deposition, during which the complexes leave the plasma and are deposited into tissues. Finally, the third step is the inflammatory reaction, during which the classical pathway is activated and macrophages and neutrophils are recruited to the affected tissues. Such reactions may progress to immune complex diseases.

The following outline is provided as an overview of and topical guide to immunology:

Type IV hypersensitivity, in the Gell and Coombs classification of allergic reactions, often called delayed-type hypersensitivity, is a type of hypersensitivity reaction that can take a day or more to develop. Unlike the other types, it is not humoral but rather is a type of cell-mediated response. This response involves the interaction of T cells, monocytes, and macrophages.

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References

  1. ↑ Andreozzi, Laura; Giannetti, Arianna; Cipriani, Francesca; Caffarelli, Carlo; Mastrorilli, Carla; Ricci, Giampaolo (2019). "Hypersensitivity reactions to food and drug additives: problem or myth?". Acta Bio-Medica. 90 (3–S): 80–90. doi:10.23750/abm.v90i3-S.8168. ISSN   2531-6745. PMC   6502174 . PMID   30830065.
  2. ↑ Gargano, Domenico; Appanna, Ramapraba; Santonicola, Antonella; De Bartolomeis, Fabio; Stellato, Cristiana; Cianferoni, Antonella; Casolaro, Vincenzo; Iovino, Paola (2021). "Food Allergy and Intolerance: A Narrative Review on Nutritional Concerns". Nutrients. 13 (5): 1638. doi: 10.3390/nu13051638 . ISSN   2072-6643. PMC   8152468 . PMID   34068047.
  3. ↑ Dispenza, Melanie C. (2019). "Classification of hypersensitivity reactions" (PDF). Allergy and Asthma Proceedings. 40 (6): 470–473. doi:10.2500/aap.2019.40.4274. ISSN   1539-6304. PMID   31690397. S2CID   207891282.
  4. ↑ Tian, Bao-Ping; Zhou, Hong-Bin; Xia, Li-Xia; Shen, Hua-Hao; Ying, Songmin (2014). "Balance of apoptotic cell death and survival in allergic diseases". Microbes and Infection. 16 (10): 811–821. doi: 10.1016/j.micinf.2014.07.004 . ISSN   1769-714X. PMID   25111826.
  5. ↑ Descotes, J.; Choquet-Kastylevsky, G. (2001-02-02). "Gell and Coombs's classification: is it still valid?". Toxicology. 158 (1–2): 43–49. doi:10.1016/s0300-483x(00)00400-5. ISSN   0300-483X. PMID   11164991.
  6. ↑ Rajan, T. V. (2003). "The Gell-Coombs classification of hypersensitivity reactions: a re-interpretation". Trends in Immunology. 24 (7): 376–379. doi:10.1016/s1471-4906(03)00142-x. ISSN   1471-4906. PMID   12860528.
  7. 1 2 3 4 Usman, Norina; Annamaraju, Pavan (2021), "Type III Hypersensitivity Reaction", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID   32644548 , retrieved 2021-07-05 Creative Commons by small.svg  This article incorporates text available under the CC BY 4.0 license.
  8. 1 2 3 4 5 Marwa, Khaled; Kondamudi, Noah P. (2021), "Type IV Hypersensitivity Reaction", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID   32965899 , retrieved 2021-07-05 Creative Commons by small.svg  This article incorporates text available under the CC BY 4.0 license.
  9. 1 2 3 4 5 6 7 8 Justiz Vaillant, Angel A.; Vashisht, Rishik; Zito, Patrick M. (2021), "Immediate Hypersensitivity Reactions", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID   30020687 , retrieved 2021-07-05 Creative Commons by small.svg  This article incorporates text available under the CC BY 4.0 license.
  10. ↑ "Davidson's Principles and Practice of Medicine, IE Edition, 20th Ed: Medicine—Clinical Medicine". Journal of Endocrinology, Metabolism and Diabetes of South Africa. 13 (2): 75. July 2008. doi: 10.1080/22201009.2008.10872174 . ISSN   1608-9677. S2CID   220276722.
  11. 1 2 Black, C. A. (1999). "Delayed type hypersensitivity: Current theories with an historic perspective". Dermatology Online Journal. 5 (1): 7. doi:10.5070/D32FW0G1XX. PMID   10673450.
  12. 1 2 Delayed Hypersensitivity Reactions at eMedicine
  13. ↑ Kumar, Vinay; Abbas, Abul K.; Aster, Jon C., eds. (2014). "Hypersensitivity: Immunologicaly Mediated Tissue Injury". Robbins & Cotran Pathologic Basis of Disease (9th ed.). Elsevier Health Sciences. pp. 200–11. ISBN   978-0-323-29635-9.
  14. ↑ Abbas, Abul K. (6 May 2021). Cellular and Molecular Immunology. Elsevier. p. 444. ISBN   978-0-323-75748-5.
  15. ↑ Le, Tau. First Aid for the USMLE Step 1 2013, p. 203-204
  16. ↑ Mitchell, Richard Sheppard; Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson (2007). "Table 5-1". Robbins Basic Pathology (8th ed.). Philadelphia: Saunders. ISBN   978-1-4160-2973-1.
  17. 1 2 Abbas, Malak; Moussa, Mohamed; Akel, Hassan (2021), "Type I Hypersensitivity Reaction", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID   32809396 , retrieved 2021-07-04 Creative Commons by small.svg  This article incorporates text available under the CC BY 4.0 license.
  18. ↑ Bajwa, Shammas F.; Mohammed, Reem Hamdy A. (2021), "Type II Hypersensitivity Reaction", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID   33085411 , retrieved 2021-07-05 Creative Commons by small.svg  This article incorporates text available under the CC BY 4.0 license.
  19. ↑ Justiz Vaillant, Angel A.; Zulfiqar, Hassam; Ramphul, Kamleshun (2021), "Delayed Hypersensitivity Reactions", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID   30085565 , retrieved 2021-07-05 Creative Commons by small.svg  This article incorporates text available under the CC BY 4.0 license.
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