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Hypersensitivity
Overreaction of the immune system to an antigen

Hypersensitivity, also known as hypersensitivity reaction or intolerance, is an abnormal immune response to an antigen causing immune diseases such as allergies and autoimmunity. The Gell and Coombs classification divides hypersensitivity into four types: type I (IgE-mediated immediate reaction), type II (antibody-mediated mainly involving IgG or IgM), type III (immune complex-mediated involving IgG and the complement system), and type IV (delayed, cell-mediated involving T cells). Types I–III are immediate reactions within 24 hours, while type IV is delayed, peaking 48–72 hours after exposure. Hypersensitivity affects about 15% of people worldwide and has been rising since the mid-20th century.

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Gell and Coombs classification

The Gell and Coombs classification of hypersensitivity is the most widely used, and distinguishes four types of immune response that result in bystander tissue damage.11

Immunologic aspects of hypersensitivity reactions
TypeAlternative namesAntibodies or Cell MediatorsImmunologic ReactionExamples
IFast 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.12
IIAntibody (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.13
IIIAntibody (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.14
IVCellsCTLs and T helper cells (specifically Th1 and Th17 cells)17 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.18

Type I hypersensitivity

Main article: Type I hypersensitivity

Etiology

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.20 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.21

Types of antigens involved

  • Food: nuts, eggs, soy, wheat, shellfish, etc.
  • Animal source: bees, wasp, cats, insects, rats, etc.
  • Environmental factors: dust mites, latex, pollen, mold, flowers smell, etc.
  • Atopic diseases: allergic asthma, allergic rhinitis, conjunctivitis, dermatitis, etc.
  • Medication-induced reactions: antibiotics22

Type II hypersensitivity

Main article: 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.23 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.24

Damage can be accomplished via three different mechanisms:25

  • Antibody binding to cell surface receptors and altering its activity
  • Activation of the complement pathway.
  • Antibody-dependent cellular cytotoxicity.

The pathophysiology of type II hypersensitivity reactions can be broadly classified into three types:26

  • Cell depletion or destruction without inflammation
  • Inflammation mediated by complement or Fc receptor
  • Cellular dysfunction by antibodies

The process involves a series of immune-mediated events that might take different forms.27

Type III hypersensitivity

Main article: 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.28

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.29

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.30

Type IV hypersensitivity

Main article: 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.31

Pathophysiology

A type IV hypersensitivity reaction is mediated by T cells that provoke an inflammatory reaction 32against 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.33

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.34

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.35

Treatment

Immediate hypersensitivity reactions

36The 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.37

  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.38

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.39

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. https://www.mattioli1885journals.com/index.php/actabiomedica/article/view/8168 ↩

  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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152468 ↩

  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. https://allergolyon.fr/wp-content/uploads/2020/08/0.4-Classification-of-hypersensitivity-reactions-2019.pdf ↩

  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. https://www.sciencedirect.com/science/article/abs/pii/S1286457914000914 ↩

  5. Silverstein, Arthur M. "Philip George Houthem Gell. 20 October 1914 – 3 May 2001 Elected FRS 1969". Biographical Memoirs of Fellows of the Royal Society. 49: 163–178. doi:10.1098/rsbm.2003.0010. ISSN 0080-4606. https://royalsocietypublishing.org/doi/10.1098/rsbm.2003.0010 ↩

  6. 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. https://www.sciencedirect.com/science/article/abs/pii/S0300483X00004005 ↩

  7. 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. https://www.cell.com/trends/immunology/fulltext/S1471-4906(03)00142-X?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS147149060300142X%3Fshowall%3Dtrue ↩

  8. Usman, Norina; Annamaraju, Pavan (2021), "Type III Hypersensitivity Reaction", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 32644548, retrieved 2021-07-05  This article incorporates text available under the CC BY 4.0 license. http://www.ncbi.nlm.nih.gov/books/NBK559122/ ↩

  9. Marwa, Khaled; Kondamudi, Noah P. (2021), "Type IV Hypersensitivity Reaction", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 32965899, retrieved 2021-07-05  This article incorporates text available under the CC BY 4.0 license. http://www.ncbi.nlm.nih.gov/books/NBK562228/ ↩

  10. 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  This article incorporates text available under the CC BY 4.0 license. http://www.ncbi.nlm.nih.gov/books/NBK513315/ ↩

  11. "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. https://doi.org/10.1080%2F22201009.2008.10872174 ↩

  12. 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. http://escholarship.org/uc/item/2fw0g1xx ↩

  13. Delayed Hypersensitivity Reactions at eMedicine https://emedicine.medscape.com/article/136118-overview ↩

  14. 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. 978-0-323-29635-9 ↩

  15. 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. http://escholarship.org/uc/item/2fw0g1xx ↩

  16. Delayed Hypersensitivity Reactions at eMedicine https://emedicine.medscape.com/article/136118-overview ↩

  17. Abbas, Abul K. (6 May 2021). Cellular and Molecular Immunology. Elsevier. p. 444. ISBN 978-0-323-75748-5. 978-0-323-75748-5 ↩

  18. Le, Tau. First Aid for the USMLE Step 1 2013, p. 203-204 ↩

  19. 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. 978-1-4160-2973-1 ↩

  20. 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  This article incorporates text available under the CC BY 4.0 license. http://www.ncbi.nlm.nih.gov/books/NBK513315/ ↩

  21. Abbas, Malak; Moussa, Mohamed; Akel, Hassan (2021), "Type I Hypersensitivity Reaction", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 32809396, retrieved 2021-07-04  This article incorporates text available under the CC BY 4.0 license. http://www.ncbi.nlm.nih.gov/books/NBK560561/ ↩

  22. Abbas, Malak; Moussa, Mohamed; Akel, Hassan (2021), "Type I Hypersensitivity Reaction", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 32809396, retrieved 2021-07-04  This article incorporates text available under the CC BY 4.0 license. http://www.ncbi.nlm.nih.gov/books/NBK560561/ ↩

  23. 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  This article incorporates text available under the CC BY 4.0 license. http://www.ncbi.nlm.nih.gov/books/NBK513315/ ↩

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  25. 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  This article incorporates text available under the CC BY 4.0 license. http://www.ncbi.nlm.nih.gov/books/NBK513315/ ↩

  26. 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  This article incorporates text available under the CC BY 4.0 license. http://www.ncbi.nlm.nih.gov/books/NBK513315/ ↩

  27. Bajwa, Shammas F.; Mohammed, Reem Hamdy A. (2021), "Type II Hypersensitivity Reaction", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 33085411, retrieved 2021-07-05  This article incorporates text available under the CC BY 4.0 license. http://www.ncbi.nlm.nih.gov/books/NBK563264/ ↩

  28. Usman, Norina; Annamaraju, Pavan (2021), "Type III Hypersensitivity Reaction", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 32644548, retrieved 2021-07-05  This article incorporates text available under the CC BY 4.0 license. http://www.ncbi.nlm.nih.gov/books/NBK559122/ ↩

  29. Usman, Norina; Annamaraju, Pavan (2021), "Type III Hypersensitivity Reaction", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 32644548, retrieved 2021-07-05  This article incorporates text available under the CC BY 4.0 license. http://www.ncbi.nlm.nih.gov/books/NBK559122/ ↩

  30. Usman, Norina; Annamaraju, Pavan (2021), "Type III Hypersensitivity Reaction", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 32644548, retrieved 2021-07-05  This article incorporates text available under the CC BY 4.0 license. http://www.ncbi.nlm.nih.gov/books/NBK559122/ ↩

  31. Marwa, Khaled; Kondamudi, Noah P. (2021), "Type IV Hypersensitivity Reaction", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 32965899, retrieved 2021-07-05  This article incorporates text available under the CC BY 4.0 license. http://www.ncbi.nlm.nih.gov/books/NBK562228/ ↩

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  34. Marwa, Khaled; Kondamudi, Noah P. (2021), "Type IV Hypersensitivity Reaction", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 32965899, retrieved 2021-07-05  This article incorporates text available under the CC BY 4.0 license. http://www.ncbi.nlm.nih.gov/books/NBK562228/ ↩

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  38. 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  This article incorporates text available under the CC BY 4.0 license. http://www.ncbi.nlm.nih.gov/books/NBK513315/ ↩

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