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Home , Hypersensitivity, Serum sickness, Type IV hypersensitivity

Classification of reactions

Melanie C. Dispenza, M.D., Ph.D.

ABSTRACT As the primary defense against pathogens, the uses numerous strategies to ensure optimal protection for the host. When immune responses go awry, however, they can cause great damage. “Hypersensitivity” is a broad term used to describe an excessive and/or pathogenic immune response to either foreign or self . Gell and Coombs were the first to categorize hypersensitivity reactions into 4 types according to pathophysiology, but more recent insights into the mechanisms of these disorders have since modified the original classification system. This review describes the immune mechanisms involved in each of the modern Gell-Coombs categories. ( Proc 40:470–473, 2019; doi: 10.2500/aap.2019.40.4274)

n 1963, Gell and Coombs1 created the foundation for cells, and thus they cannot elicit immune responses by I classifying hypersensitivity reactions by dividing themselves. However, they may stimulate immune re- them into four distinct groups according to mecha- sponses in other ways. In the model, small nisms of tissue injury: type I (immediate or immuno- molecules (e.g., , molecular weight ϳ300 Dal- globulin E [IgE] mediated), type II (cytotoxic or IgG/ tons) covalently bind to soluble serum (e.g., IgM mediated), type III ( mediated), albumin) or cellular proteins to create new , and type IV (delayed type or T-cell mediated). This which can then be antigenic. Some drugs act as pro- classification system has since then been expanded to , meaning that they are inert in their native include subtypes of types II and IV, with the intent to form, but their metabolites can haptenize, as is the case better reflect the immunopathology of (Table with sulfamethoxazole.6 Finally, the p-i concept (phar- 1).2,3 In clinical practice, however, the hypersensitivity macologic interaction with immune receptors) pro- categories can overlap, and patients may display a poses that some drugs that lack hapten characteristics constellation of symptoms from multiple types of hy- may bind reversibly (noncovalently) to T-cell receptors persensitivity reactions at the same time. Syndromes or human leukocyte (HLA) molecules directly, that do not fit into the single Gell-Coombs classifica- possibly in a nonspecific or cross-reactive fashion.7 tion categories are often termed mixed drug reactions, This model may help to explain why some HLA alleles and, clinically, it may be more practical to classify these render patients prone to delayed hypersensitivity re- reactions by the organ systems affected. In addition, it actions due to certain medications. For example, an is increasingly recognized that many medications, e.g., estimated 55% of HLA-B*57:01 carriers will develop a , are capable of inducing many types of re- hypersensitivity reaction from abacavir.7 Thus, small- actions.4 molecular-weight compounds can cause all types of Antigens of all types and sizes may cause hypersen- hypersensitivity reactions.5 sitivity reactions. Large-molecular-weight antigens, whether self or foreign, can be processed and HYPERSENSITIVITY TYPES recognized directly by T-cell receptors or immunoglob- ulins. Many biologic drugs are recombinant Type I which can form immune complexes and/or bind to Fc Type I or immediate hypersensitivity is mediated by 5 receptors on leukocytes. In contrast, small low-molec- IgE specific for . An overview of allergens is Ͻ ular-weightDO compounds ( 1000 Daltons)NOT cannot be di- provided inCOPY this issue.8 Sensitization to allergens oc- rectly processed or presented by antigen-presenting curs when T-helper (Th) type 2 cells and their media- tors drive switching in B cells to produce IgE antibodies. A large portion of IgE remains bound to the From the Division of Allergy and , Department of Medicine, Northwest- high-affinity IgE Fc␧RI on the surface of mast ern University Feinberg School of Medicine, Chicago, Illinois Funded by the Ernest S. Bazley Grant to Northwestern Memorial Hospital and cells and . On re-exposure, cross- Northwestern University links specific IgE on these cells, which causes release of The author has no conflicts of interest to declare pertaining to this article mediators in two main phases. The early phase occurs Address correspondence to Melanie C. Dispenza, M.D., Ph.D., Division of Allergy and Clinical Immunology, Johns Hopkins School of Medicine, Allergy and Asthma within minutes and is caused by histamine, proteases Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224 (tryptase and chymase), lysosomal enzymes, and other E-mail address: [email protected] preformed mediators released immediately on mast Copyright © 2019, OceanSide Publications, Inc., U.S.A. cell and degranulation. In addition, mast cells

470 November 2019, Vol. 40, No. 6 produce lipid mediators, including prostaglandin D2 cell. Second, IgG antibodies can induce damage via and leukotriene C4 from arachidonic acid and release -dependent cell-mediated cytotoxicity. IgG on them into circulation within 15 minutes of IgE cross- target cells binds to Fc gamma receptor IIb (Fc␥RIIb) on linking. natural killer cells and , which causes The late phase occurs 4 to 8 hours after allergen them to release granules that contain perforin and exposure and is caused by such as interleu- granzyme to directly kill cells. Finally, both IgG and kin (IL)-1, tumor factor (TNF)-␣, IL-4, IL-5, IgM can bind to Fc receptors on to activate IL-13, and colony-stimulating them and initiate phagocytosis. Type IIb reactions in- factor (GM-CSF) produced de novo by mast cells. The volve stimulating cells directly to create route and location of allergen exposure determine the pathogenic states. For example, in Graves , an- ensuing symptoms. Inhaled allergens may exacerbate tibodies to thyrotropin receptors stimulate the thyroid allergic or asthma by causing nasal congestion, gland to produce excessive amounts of thyroid hor- rhinorrhea, sneezing, and bronchospasm.9–11 Topical mone. Chronic idiopathic (spontaneous) urticaria may contact with allergens can cause urticaria. Also, expo- be categorized as a type IIb disorder (at least in some sure to allergen via the oral or intravenous route typi- patients), due to IgG antibodies directly binding to and cally produces systemic symptoms. is a stimulating Fc␧RI receptors on mast cells, which causes potentially life-threatening type I systemic allergic re- mast cell degranulation in the skin and, subsequently, sponse to allergens, such as foods, medications, or the development of urticaria. In this subset of patients, stinging insect venoms, and is characterized by urti- these autoantibodies are necessary but not sufficient caria, , bronchospasm, nausea, vomiting, for mast cell activation. diarrhea, , and, rarely, .4 It should be noted that some disorders are caused by Type III IgE-independent, nonspecific activation of mast cells, In type III responses, IgG and IgM antibodies bind to which could be considered to be a subset of type I antigens to form immune complexes. These complexes hypersensitivity reactions. These include systemic re- deposit in tissues and activate complement, which actions to substances such as iodinated contrast media, then causes organ damage. Common sites of com- biologic drugs, opiates, and others.4 Urticaria may also plex deposition include small arteries, renal glomer- be caused by mast cell activation by various stimuli12 uli, and synovial capsules of joints, thereby causing but may also be due to autoantibodies to the Fc␧RI , , and arthritis, respec- receptor, as discussed below. tively.13 Thus, the symptoms associated with type III reactions are determined by the site of immune com- Type II plex deposition and not by the source of the antigen. Antigens involved in type III responses can either be IgG and IgM antibodies are key components of host self, such as in autoimmune diseases including , defense, which bind to microbes and aid in their direct or foreign, as is the case in serum-sickness reactions killing via multiple mechanisms. Unfortunately, when caused by various medications, including proteins these antibodies bind to self antigens, they can direct (such as thymoglobulin) or small molecules (such as the cytotoxic response against the host itself and cause penicillin or ). potentially extensive damage. This is the basis of type II reactions, termed cytotoxic reactions, which are char- acterized by IgG and/or IgM antibodies against cell- Type IV surface antigens. These antigens are typically found Type IV hypersensitivity responses are collectively on circulating cells, such as red blood cells, plate- termed delayed reactions and involve T cells as the lets, , or on epithelial cells in mucosal sur- major effector cells. Sensitized T cells can cause dam- facesDO and basement membranes. NOTage directly, COPY as in the case of cytotoxic T cells, or helper Type II reactions are further divided into two sub- T cells may activate other leukocytes, such as macro- types: type IIa and type IIb. Type IIa refers to reactions phages, neutrophils, and , which may im- characterized by cytolytic destruction of targeted cells. part tissue injury through the production and release IgG/IgM binding to cell-surface components causes of reactive oxygen species, lysosomal enzymes, and cytotoxicity via three main mechanisms.13 The first is inflammatory cytokines. Relatively recent enumeration complement-dependent cytotoxicity, which is the pri- of T-cell subsets has allowed for further categorization, mary etiology in autoimmune hemolytic anemia and and type IV reactions are now divided into four sub- autoimmune thrombocytopenic purpura. Antigen-an- types according to the immune mechanisms and tibody complexes on the surface of cells activate the pathogenesis of each: types IVa, b, c, and d.3 The classic classic complement pathway, creating the membrane type IV reaction as first described by Gell and Coombs1 attack complex (C5-C9), which causes lysis of the target is now termed types IVa and is mediated by Th1 cells,

Allergy and Asthma Proceedings 471 Table 1 Modern classification of hypersensitivity reactions* Classification Immunologic Mechanisms Clinical Examples Type I Mast cell-mediated reactions IgE-dependent (anaphylactic) Anaphylaxis, angioedema, urticaria, asthma, IgE-independent (nonimmunologic or Reactions to iodinated contrast reagents and anaphylactoid) some biologics IIa Antibody-mediated cytotoxic reactions (IgG/IgM Immune cytopenias antibodies); complement often involved IIb Antibody-mediated cell-stimulating reactions Graves disease, chronic idiopathic (spontaneous) urticaria III Immune complex-mediated complement , drug-induced lupus, activation vasculitis IVa Th1 cell–mediated activation , contact (with type IVc), tuberculin test reactions IVb Th2 cell–mediated eosinophilic Maculopapular exanthems, DRESS syndrome, persistent asthma, allergic rhinitis IVc Cytotoxic –mediated reactions SJS and/or TEN, bullous exanthems IVd T cell–mediated neutrophilic inflammation AGEP, Behçet’s disease IgE ϭ ; Th ϭ T-helper cell; DRESS ϭ Drug Reaction with Eosinophilia and Systemic Symptoms; SJS ϭ Stevens-Johnson syndrome; TEN ϭ toxic epidermal necrolysis; AGEP ϭ acute generalized exanthematous pustulosis. *Adapted from Ref. 14.

which activate macrophages to secrete cytokines such IMMUNOLOGY ␥ ␣ as interferon and TNF- . A prototypical example of • Type I reactions are mediated by allergen-specific this type is , which can occur to IgE bound to the high-affinity Fc␧RI receptor on various substances, including poison ivy, oak, and su- mast cells and basophils. On allergen cross-linking mac (members of the Toxicodendron genus). Type IVb of these receptors, mediators (e.g. histamine) are reactions involve the production of IL-4, IL-5, and released, which result in urticaria, angioedema, IL-13 by Th2 cells to induce eosinophilic inflammation and/or anaphylaxis. and IgE production from B cells. For example, in pa- • Type II reactions are characterized by IgG/IgM tients with Drug Reaction with Eosinophilia and Sys- binding to self antigens on the surface of cells, temic Symptoms (DRESS syndrome) drug-sensitized which can cause tissue damage by activating Th2 cells promote eosinophilic survival, activation, and phagocytosis, complement-directed cytotoxicity, tissue migration to cause multiorgan injury. In addi- and/or antibody-dependent cell-mediated cyto- tion, type IVb reactions may be involved in the late- toxicity. phase inflammation of atopic disorders, such as • Type III reactions are mediated by immune com- asthma or allergic rhinitis. Type IVc is primarily me- plexes of IgG/IgM and antigens, which deposit into diatedDO by cytotoxic CD8ϩ T cells,NOT which directly kill tissues toCOPY cause direct organ damage. targeted cells by using a number of mediators, includ- • Type IV reactions are delayed responses that are ing perforin, granulysin, and granzyme B. Type IVc mediated by T cells and are further divided into four reactions seem to be the underlying mechanism of subtypes. tissue damage in Stevens-Johnson syndrome and toxic epidermal necrolysis, in which activated CD8ϩ T cells CLINICAL PEARLS induce apoptosis and/or necrosis of keratinocytes. • Some medications (such as penicillins) can cause all Type IVd responses cause tissue damage when T- types of hypersensitivity reactions. cell–derived CXCL-8 (also known as IL-8) recruits • There are no known therapies that can effectively neutrophils into tissues to create sterile neutrophilic prevent IgE-mediated reactions. Medications such inflammation, as is the case with acute generalized as H1 and only miti- exanthematous pustulosis. gate the effects of some (but not all) mediators.

472 November 2019, Vol. 40, No. 6 • Anaphylactic reactions to some substances, such as 7. Pichler WJ, Adam J, Watkins S, Wuillemin N, Yun J, Yerly D. iodinated contrast media, are not IgE mediated and Drug hypersensitivity: how drugs stimulate t cells via pharma- can be prevented for most patients by pretreatment cological interaction with immune receptors. Int Arch Allergy Immunol. 2015; 168:13–24. with corticosteroids and H1 antihistamines. 8. Lei DK, Grammer LC. An overview of allergens. Allergy Asthma Proc. 2019; 40:362–365. REFERENCES 9. Agnihotri NT, McGrath KG. Allergic and non-allergic rhinitis. 1. Gell PGH, Coombs RRA. The classification of allergic reactions Allergy Asthma Proc. 2019; 40:376–379. underlying disease. In: Coombs, R.R.A., Gells, P.G.H. (Eds.), 10. Devonshire AL, Kumar R. Pediatric asthma: Principles and Clinical Aspects of Immunology, Blackwell, Oxford. 1963. treatment. Allergy Asthma Proc. 2019; 40:389–392. 2. Pichler WJ. Immune mechanism of drug hypersensitivity. Im- 11. Agnihotri NT, Saltoun C. Acute severe asthma (status asthmati- munol Allergy Clin North Am. 2004; 24:373–397, v–vi. cus). Allergy Asthma Proc. 2019; 40:406–409. 3. Pichler WJ. Delayed drug hypersensitivity reactions. Ann Intern 12. Guo C, Saltoun S. Urticaria and angioedema. Allergy Asthma Med. 2003; 139:683–693. Proc. 2019; 40:437–440. 4. Lieberman P, Nicklas RA, Randolph C, Oppenheimer J, Bern- 13. Celik GE, Pichler WJ, Adkinson NF Jr. . In: Adkin- stein D, Bernstein J, et al. Anaphylaxis–a practice parameter son NF Jr, Bochner BS, Burks AW, et al, eds. Middleton’s update 2015. Ann Allergy Asthma Immunol. 2015; 115:341–384. Allergy: Principles and Practice. 8th ed. Philadelphia, PA: 5. Murphy KM, Weaver C, editors. Janeway’s immunobiology. 9th Elsevier Saunders; 2014. ed. New York: Garland Science, Taylor and Francis; 2017. 14. Ditto AM. Drug allergy. Patterson’s allergic diseases. 8th ed. In: 6. Schnyder B, Brockow K. Pathogenesis of drug allergy–current Grammer LC, Greenberger PA, editors. Philadelphia, PA: Lip- concepts and recent insights. Clin Exp Allergy. 2015; 45:1376–1383. pincott, Williams & Wilkins, 2018; 308–354. e

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