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Home , Hypersensitivity, Poison ivy, Serum sickness

Chapter 28

Classification of reactions

Ashraf Uzzaman, M.D., and Seong H. Cho, M.D.

ABSTRACT The original Gell and Coomb’s classification categorizes hypersensitivity reactions into four subtypes according to the type of immune response and the effector mechanism responsible for cell and tissue injury: type I, immediate or IgE mediated; type II, cytotoxic or IgG/IgM mediated; type III, IgG/IgM mediated; and type IV, delayed-type hypersensitivity or T-cell mediated. The classification has been improved so that type IIa is the former type II and type IIb is -mediated cell stimulating (Graves and the “autoimmune” type of chronic idiopathic urticaria). Type IV has four major categories: ϩ type IVa is CD4 Th1 lymphocyte mediated with activation of macrophages (granuloma formation and type I diabetes mellitus); ϩ type IVb is CD4 Th2 lymphocyte mediated with eosinophilic involvement (persistent and allergic ); type IVc ϩ is cytotoxic CD8 T lymphocyte with involvement of perforin-granzme B in apoptosis (Stevens-Johnson syndrome and toxic epidermal necrolysis); type IVd is T-lymphocyte–driven neutrophilic (pustular psoriasis and acute generalized exanthematous pustulosis). Some have multiple types of immunologic hypersensitivity. ( Asthma Proc 33:S96–S99, 2012; doi: 10.2500/aap.2012.33.3561)

lthough, the is primarily used to TYPE I—IMMEDIATE OR IgE-MEDIATED A protect against microbes such as bacteria, vi- REACTIONS ruses, and fungi, unexpected excesses of the immune IgE are produced in response to parasitic response may lead to disease states. The excessive im- infections and, along with activation, pri- mune responses are usually referred to as hypersensi- marily serve protective functions and help eradicate tivity reactions. The original Gell and Coomb’s classi- the parasites. Atopic individuals may form - fication categorizes hypersensitivity reactions into four specific IgE antibodies in response to ,3 such subtypes according to the type of immune response as present in the environment, in foods,4 and in drugs.5 and the effector mechanism responsible for cell and The IgE antibodies thus formed attach to high-affinity tissue injury: type I, immediate or IgE mediated; type IgE receptors (Fc␧RI), which are present on mast cell II, cytotoxic or IgG/IgM mediated; type III, IgG/IgM and surfaces. On reexposure, the allergen is immune complex mediated; and type IV, delayed-type recognized by IgE antibodies bound to mast cells and hypersensitivity or T-cell mediated.1 In clinical prac- and leads to triggering of these cells result- tice, however, patients often display a constellation of ing in an immediate hypersensitivity reaction. The im- symptoms that usually overlap several of these mech- mediate hypersensitivity reaction usually consists of anisms. For example, individuals who are allergic to two phases; an immediate response that occurs within may exhibit symptoms that suggest a type I minutes and is caused by histamine, prostaglandin D2, or IgE-mediated reaction such as ; they leukotriene D4, and kinins (and tryptase) and a delayed may also exhibit a such as a disease that reaction that occurs after 4–8 hours and is effected by suggestsDO a type III or an IgG/IgM NOT immune complex– suchCOPY as IL-1, tumor necrosis factor, IL-4, IL-5, mediated reaction (Table 1).2 IL-13, and various colony-stimulating factors such as colony-stimulating factor.6 In addition to mast cells and basophils, and may also be involved in producing the From the Division of Allergy–, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois complete spectrum of the immediate hypersensitivity Funded by the Ernest S. Bazley Grant to Northwestern Memorial Hospital and reaction. Northwestern University Examples of immediate hypersensitivity reactions The authors have no conflicts of interest to declare pertaining to this article 7 Address correspondence and reprint requests to Seong Cho, M.D., Number 14108, 676 are anaphylaxis, which is characterized by dilatation North St. Clair Street, Chicago, IL 60611 of the vessels and constriction of the airways and E-mail address: [email protected] may occur in response to allergens present in foods— Copyright © 2012, OceanSide Publications, Inc., U.S.A. nuts and milk; bronchial asthma,8 which may be

S96 May–June 2012, Vol. 33, No. 3 Delivered by Ingenta to: Guest User IP: 179.61.200.128 On: Thu, 14 Jul 2016 14:46:49 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm Table 1 Classification of hypersensitivity reactions Classification Immunoreactants Clinical Presentation Type I Mast cell mediated, IgE dependent Anaphylaxis, urticaria, , asthma, and (anaphylactic, and IgE independent) Type IIa Antibody-mediated cytotoxic reactions Immune cytopenias (IgG and IgM antibodies complement often involved) Type IIb Antibody-mediated cell-stimulating Graves disease and chronic idiopathic urticaria reactions Type III Immune complex–mediated reactions Serum sickness and complement involved Type IVa Th1 cell-mediated reactions macrophage and contact (with activation IVc) Type IVb Th2 cell–mediated reactions eosinophilic Persistent asthma and allergic rhinitis inflammation Type IVc Cytotoxic -mediated Stevens-Johnson syndrome and TEN (perforin/granzyme B involved) Type IVd T-cell-mediated neutrophilic inflammation AGEP and Behcet disease Source: Adapted from Ref. 2. AGEP ϭ acute generalized exanthematous pustulosis; TEN ϭ toxic epidermal keratinocytes. caused by repeated immediate hypersensitivity and nism of immune response is antibody-dependent cell- late-phase reactions in the lung tissue; and skin mani- mediated cytotoxicity, which occurs when eosinophils festations such as urticaria,9 which is a wheal and flare bind to IgE-bound helminths and release their granule (erythema) reaction. components. Type II reactions can also be divided into two different subtypes. Type IIa reactions are charac- TYPE II—CYTOTOXIC OR IgG/IgM-MEDIATED terized by cytolytic reactions produced by antibodies REACTIONS causing autoimmune hemolytic anemia, whereas Immune responses that usually afford protection type IIb reactions are characterized by cell-stimulat- against infections and eradication of malignant cells ing antibodies in patients with Graves disease (a may sometimes cause damage to tissues. The im- long-acting thyroid stimulator, thyroid-stimulating mune responses commonly involve IgG and IgM antibodies) or antibodies to the and, to a lesser extent, IgA antibodies. The antibod- high-affinity mast cell receptor (Fc␧RI␣) or IgE in 9 ies usually are directed against cell surface chronic idiopathic urticaria. such as those present on red blood cells, neutrophils, and ; those present on epithelial cells of TYPE III—IgG/IgM IMMUNE COMPLEX glandular and mucosal surfaces; or against those MEDIATED present on tissues such as basement membranes. In type II immune response, the mechanism of tissue Three underlying mechanisms commonly account injury involves the formation of IgG or IgM antibodies for the tissue damage.10 First, antibodies may di- to self or foreign antigens and then the formation of rectly coat or opsonize cells or they may activate the complexes. The complexes deposit and activate the complementDO system, which leadsNOT to the production complement COPY pathway, with concomitant fall in serum of activated complement components that may then complement levels. The activated complement compo- coat or opsonize the cells. These opsonized cells are nents recruit and activate neutrophils, which results in phagocytosed and are destroyed by that inflammation and tissue injury. The constellation of express receptors for antibodies and complement symptoms is determined by the site of immune com- . The underlying mechanism in autoimmune plex deposition and not by the source of the . hemolytic anemia and autoimmune thrombocytope- The antigen–antibody complexes are usually deposited nic purpura is an example. Second, antibodies de- in small arteries, renal glomeruli, and synovial of joints posited in tissues subsequently recruit neutrophils and the symptoms usually are vasculitis, nephritis, and and macrophages, which leads to tissue injury and arthritis, respectively.10 One example is serum sick- inflammation. This is the mechanism of injury in anti- ness-like disease, which may be acute or may have a body-mediated . The third mecha- prolonged or chronic course. This prototypical immune

Allergy and Asthma Proceedings S97 Delivered by Ingenta to: Guest User IP: 179.61.200.128 On: Thu, 14 Jul 2016 14:46:49 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm ϩ complex–mediated disease, however, was first observed where activated CD8 T cells induce apoptosis or in individuals with infections. These individ- necrosis of keratinocytes. Type IVd reactions are uals were being treated with sera containing antibodies to neutrophilic inflammation via T lymphocytes. Sterile diphtheria antitoxin (passive immunization) from horses neutrophilic inflammation of the skin in acute gen- that had been immunized with the diphtheria toxin. A eralized exanthematous pustulosis is a typical exam- number of autoimmune diseases may also be caused by ple. Acute generalized exanthematous pustulosis is tissue deposition of antigen–antibody complexes. Sys- characterized by appearance of superficial pustules temic erythematosus is an in after drug ingestion or infection. In this disease, which a large number of antibodies to DNA and nucleo- T-cell–derived CXCL-8 recruits neutrophils to the proteins are produced, which complex with antigens and lesion and granulocyte monocyte colony-stimulating then deposit in the tissues and lead to an inflammatory factor from T cells prevents apoptosis of the re- response. cruited neutrophils. In addition, IL-17 and IL-22 stimulate production of IL-8, which supports the accumulation of neutrophils in lesions. Behcet dis- TYPE IV—DELAYED-TYPE HYPERSENSITIVITY ease and pustular psoriasis are other examples of OR T-CELL MEDIATED type IVd reactions. Type IV reactions involve sensitized T cells. The type IV reaction that Gell and Coombs described, also called delayed-type hypersensitivity, is medi- IMMUNOLOGY ϩ ated by CD4 T helper cells and is a Th1 type of • Type I reactions are effected by mediators released 2 response. This response is currently called type IVa. from mast cells and basophils. The tissue injury is primarily caused by lysosomal • Type II reactions result from formation of antibodies enzymes, reactive oxygen intermediates, nitric oxide, that are usually directed against cellular or matrix and proinflammatory cytokines that are secreted by antigens and lead to localized disease. activated macrophages. The secretion of cytokines • Type III reactions result from the deposition of an- and growth factors often lead to tissue fibrosis. A tigen-antibody complexes that activate the comple- delayed hypersensitivity response may be involved ment pathway and then recruit and activate neutro- in the pathogenesis of a number of diseases. Exam- phils and result in tissue injury. ples include, type I diabetes, in which destruction of • Type IV reactions are mediated by T lymphocytes; insulin-producing islet cells may be affected by lym- there are four subtypes. Some conditions involve phocytes and macrophages; , an more than one subtype. autoimmune disorder affecting the central nervous system, in which T cells react against myelin anti- gens; and , in which a T-cell– CLINICAL PEARLS mediated inflammation is suspected. • Penicillin can cause all types of reactions; type I, Enumeration of the T-cell subsets has allowed fur- anaphylaxis and urticaria; type II, hemolytic ane- ther categorization of the type IV immune responses. mia; type III, serum sickness-like reaction; and This categorization into four subtypes—type IVa, type IV, delayed type drug or contact derma- IVb, IVc, and IVd—is based on the distinct titis. 11 profile, types of cells involved, and pathogenesis. • An anaphylactic reaction to radiocontrast media is An example of type IVa response is contact derma- non-IgE–mediated hypersensitivity reaction and titis due to poison ivy Rhus antigen. This reaction can be prevented by pretreatment with corticoste- involves Th1 type T cells that activate macrophages roid and , whereas IgE-mediated by secreting large amounts of cytokines such as in- anaphylaxis is not blocked by pre- terferon-DO␥ and tumor necrosis NOT factor-␣. Type IVb treatment. COPY ϩ reactions follow a Th2 type immune response. CD4 Th2 cells produce IL-4, IL-5, and IL-13, which pro- REFERENCES mote IgE production from B cells, deactivation of 1. Coombs RRA, and Gell PGH. Classification of allergic reactions macrophage, and mast cell and eosinophil responses. responsible for clinical hypersensitity and disease. In Clinical Type IVb reactions may be involved in the late-phase Aspect of Immunology, 3rd ed. Gell PGH, Coombs RRA, and allergic of the bronchi or nasal mu- Lachman PJ (Eds). Oxford, U.K.: Blackwell Scientific Publica- cosa (i.e., asthma and allergic rhinitis). Type IVc tions, 575–596, 1975. ϩ reactions are mainly mediated by cytotoxic CD8 T 2. 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S98 May–June 2012, Vol. 33, No. 3 Delivered by Ingenta to: Guest User IP: 179.61.200.128 On: Thu, 14 Jul 2016 14:46:49 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm delphia, PA: Wolters Kluwer, Lippincott, Williams & Wilkins, 7. Greenberger PA, and Ditto AM. Anaphylaxis. Allergy Asthma 238–275, 2009. Proc 33:S80–S83, 2012. 3. Shah R, and Grammer LC. An overview of allergens. Allergy 8. Koterba AP, and Saltoun CA. Asthma classification. Allergy Asthma Proc 33:S2–S5, 2012. Asthma Proc 33:S28–S31, 2012. 4. Robison RG, and Pongracic JA. . Allergy Asthma 9. Carr TF, and Saltoun CA. Urticaria and angioedema. Allergy Proc 33:S77–S79, 2012. Asthma Proc 33:S70–S72, 2012. 5. Greenberger PA. Drug allergy. Allergy Asthma Proc. 33:S103– 10. Chinen J, Fleisher TA, and Shearer WT. The Immune system: S107, 2012. An overview. In Middleton’s Allergy Principles & Practice, 7th 6. Abbas AK, Lichtman AH, and Pillai S. Immediate hypersensi- ed. Adkinson NF Jr, Bochner BS, Busse WW, et al. (Eds). Phil- tivity. In Cellular and Molecular Immunology, 6th ed. Abbas adelphia, PA: Mosby, 3–17, 2009. AK, Lichtman AH, and Pillai S (Eds). Philadelphia, PA: Saun- 11. Pichler WJ. Delayed drug hypersensitivity reactions. Ann Intern ders, 441–461, 2007. Med 139:683–693, 2003. e

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