Pichler WJ (ed): Drug . Basel, Karger, 2007, pp 168–189

Drug Hypersensitivity Reactions: Classification and Relationship to T-Cell Activation

Werner J. Pichler

Division of Allergology, Department for and Clinical /Allergology, Inselspital, University of Bern, Bern , Switzerland

A b s t r a c t gic reaction without detectable reactions of the The clinical characteristics of drug hypersensitivity reac- adaptive . tions are very heterogeneous as drugs can actually elicit all Drug hypersensitivity reactions can become types of immune reactions. The majority of allergic reac- tions involve either drug-specific IgE or T cells. Their stimu- manifest in a great variety of clinical symptoms lation leads to quite distinct immune responses, which are and diseases, some of which are quite severe and classified according to Gell and Coombs. Here, an extension even fatal [2, 3] . The most common allergic reac- of this subclassification, which considers the distinct T-cell tions occur in the skin and are observed in about functions and immunopathologies, is presented. These 2–3% of hospitalized patients [4, 5]. Any drug is subclassifications are clinically useful, as they require differ- assumed to be able to elicit hypersensitivity reac- ent treatment and diagnostic steps. Copyright © 2007 S. Karger AG, Basel tions. Antibiotics and antiepileptics are the drugs most frequently causing them. The risk of sensi- tization and the severity of clinical symptoms de- pend on the state of immune activation of the in- Introduction dividual, the dose and duration of treatment, fe- male sex and the immunogenetic predisposition Drug-induced adverse reactions are common (in particular HLA-B alleles), while a pharmaco- and normally classified as type A reactions, genetic predisposition has rarely been detected which represent predictable side effects due a [see chapters of Hung et al., pp 105–114, and No- pharmacological action of the drug or type B re- lan et al., pp 95–104]. actions, which are not predictable and comprise Epicutaneous application of a drug clearly in- idiosyncratic reactions due to some individual creases the risk of a sensitization compared to predisposition (e.g. an enzyme defect), and hy- oral or parental treatments. It may be due to persensitivity reactions [1] . Drug hypersensitivi- the high density of dendritic cells in the skin. ty reactions account for about one sixth of all ad- – defined as the genetic predisposition to verse drug reactions. They comprise allergic and mount an IgE response to inhaled or ingested in- so-called pseudoallergic reactions. The latter is nocuous – is normally not associated characterized by having the features of an aller- with a higher risk of drug hypersensitivity in

general. However, an atopic predisposition may with other, structurally-related drugs, natural prolong the persistence of drug-specific IgE in course and prognosis. It requires knowledge of the [6] , and an ongoing IgE-mediated al- underlying immune mechanisms, and of how lergic inflammation may aggravate the symp- these mechanisms result in different forms of toms of an IgE-mediated drug hypersensitivity clinical disease. On the other hand, one has to be reaction. aware that a classification is a simplification of complex events occurring in vivo. The immune system often combines different approaches to Classification of Drug Hypersensitivity defend against a real or – as is the case with Reactions – putative pathogen. On the other hand, in many hypersensitivity diseases a certain type Drug hypersensitivity reactions can cause many of immune reaction dominates the clinical pic- different diseases. To account for this heteroge- ture, even if the immune response is rather com- neity and to better explain the various clinical plex. pictures, Gell and Coombs [7] have classified In drug hypersensitivity, an additional level drug hypersensitivity as well as other immune re- of complexity derives from the p-i concept (phar- actions in four categories termed type I–IV reac- macological interaction with immune recep- tions: This classification relies on formation of tors), as drugs may act more like superantigens IgE , which bind to high-affinity IgE [discussed in the chapter by Gerber and Pichler, receptors on mast cells and basophilic leuko- pp 66–73]: cytes, on complement-fixing antibodies and on • The p-i concept postulates a bypassing of the T-cell reactions, which orchestrate different development of a normal immune response, as a forms of inflammations. One has to be aware that direct, pharmacological stimulation of memory these reactions are tightly connected, as for ex- and effector T cells is implied; ample the maturation of B cells to IgE- or IgG- • Therefore, it does not follow the normal rules producing plasma cells depends on the help of T of an immune response, which may already ex- cells. Moreover, this classification was devel- plain some as ‘bizarre’ classified clinical fea- opped in the 1960s, before any functional hetero- tures; geneity of T cells was known. In the meantime it • It could appear at the first encounter with has become clear that the immune system is not the drug, as no sensitization is required; only specific and has a kind of memory, but is • Those T cells which happen to be stimulated also well adapted to the type of challenge it faces, by drugs are assumed to actually have a peptide as for example the defense against intracellular specificity (to which they were primed); however, pathogens requires a different approach than the which peptides are recognized is unknown. defense against extracellular bacteria, etc. This It is unclear (a) whether the drug-induced discrimination seems to be regulated by different stimulation of peptide-specific T cells results in a types of T cells [8] . To better take into account different clinical picture, if the peptides, which this heterogeneity of T-cell functions, which are are recognized by the drug-stimulated T cells, are important to understand different forms of dis- present in the body; (b) whether the function of eases, the classification of Gell and Coombs has the stimulated T cells remains the same, if the T recently been revised [8] as discussed below. cell is stimulated by the drug or by its natural li- This modified and extended Gell and Coombs gand, a certain MHC-associated peptide, and (c) classification has an impact on classifying dis- whether the constant presence of the presumed ease severity, treatment, level of cross-reactivity natural ligand, the peptide, may contribute to the

Drug Hypersensitivity Reactions: Classification and Relationship to T-Cell Activation 169 persistence of drug-allergic reactions over years Table 1. IgE-mediated drug allergies in spite of strict avoidance of the drug. Up to 50% of patients with IgE-induced These questions are open and explain why the to certain drugs have no history of previous drug naming of type B reactions as ‘bizarre’ reactions exposure! is actually not so far fetched. Anaphylaxis occurs rapidly (<20 min), seldom later Asphyxia is probably the main cause of lethal anaphylaxis -Mediated Drug Hypersensitivity Reactions Cardiac arrest can be the sole symptom of an anaphylaxis (in particular in perioperative anaphylaxis) The hapten-like features of a drug allow the mod- In certain cases, desensitization procedures are possible ification of soluble and cell-bound proteins. For and may allow reuse of the drug example, a molecule could bind cova- lently to a lysine within a serum , but also to cell-bound proteins [see figure 2 in chapter of Torres et al., pp 190–203]. The ‘normal’ reaction dins, TNF- , etc.) are released, which cause the of the immune system to such modified proteins immediate symptoms and may start and facili- is the development of a humoral immune re- tate late allergic reactions. sponse, consisting of many distinct antibodies IgE-mediated reactions to drugs are usually with hapten specificity. Consequently, if a coor- thought to depend on the prior development of dinated humoral immune response develops an immune response to a hapten/carrier com- (based on T-cell help), one may conclude that the plex: B cells need to mature into IgE-secreting eliciting drug has hapten-like features forming plasma cells, and T cells help in this process by hapten-carrier complexes or is itself a protein interacting with B cells (i.e. CD40-CD40L in- bearing ‘foreign’ determinants [e.g. a chimeric teraction) and by releasing IL-4/IL-13, which antibody, see figure 1 in chapter of Pichler and are switch factors for IgE synthesis. This sensi- Campi, pp 151–165]. Indeed, as shown in table 1 , tization phase is asymptomatic and may have the majority of drugs able to elicit IgE-mediated occurred during an earlier drug treatment. allergies are known to be haptens, or they contain Upon renewed contact with the drug, a hapten- foreign antigenic structures ( fig. 1) [9] . carrier complex is formed again, which then cross-links preformed drug-specific IgE on Type I (IgE-Mediated) Allergies mast cells. The drug itself is normally too small The IgE system is geared to react to small amounts to cross-link two adjacent IgE molecules, and of . It achieves this extraordinary sensi- needs to bind to proteins to cross-link [see chap- tivity by the ubiquitous presence of mast cells ter of Torres et al., pp 190–203]. However, it is to armed with high-affinity Fc-IgE receptors (Fc- be noted that in ca. 50% of patients with imme- IgE-RI), to which allergen/drug-specific IgE is diate reactions, no prior contact with the drug bound. Very small amounts of a drug are appar- can be elucidated [see con tribution of Chris- ently sufficient to interact and stimulate these re- tiansen, pp 233–241] and that 80% of the pa- ceptor-bound IgE molecules, as occasionally even tients with lethal anaphylaxis had no prior con- skin tests with drugs can elicit systemic reactions tact with the drug [10] . This indicates that ei- [see contribution of Barbaud, pp 366–379]. Upon ther (a) a silent sensitization to a cross-reactive cross-linking the Fc-IgE-RI, various mediators compound had occurred, or (b) preformed IgE (histamine, tryptase, leukotrienes, prostaglan- existed which happened to react with the small

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Penicillin G O Hapten (penicillin G) Clinic: ‘Everything’ H H Binding to 1 and 2: binding to cell-bound and Hapten C N b CH S 3 1: soluble proteins soluble proteins r H2 or IgE or IgG to hapten-protein: HC 3 1 N 2: membrane-bound proteins anaphylaxis, hemolytic , 2 O a aNO or thrombocytopenia 3: the MHC-peptide complexes 3: MHC class I and II O (I und II) directly binding (a) via modification: T-cell reaction -lactam ring-forming penicilloyl with exanthem, hepatitis, Processing 3 (PPL-PLL) or (b) via thiaolidin interstitial lung disease, contact structure dermatitis, AGEP, TEN... 3 a Metabolism-dependent hapten Clinic: ‘Everything’ Prohapten formation Potentially immunogenic for B (e.g. sulfamethoxazole, SMX) and T cells; ONro HN 2 ONro Uptake of the non-hapten drug Immunogenicity and clinical SMX in cells able to metabolize it, manifestation might be generation of a hapten (SMX-NO), restricted to the liver (hepatitis!) R HN R HN )ON-( XMS )ON-( R NH which can bind to intracellular or kidney (interstitial nephritis!), SO OS OS proteins: presentation of where metabolism occurs O S O processed modified peptides and HN N binding to extracellular soluble r O proteins ( both T- and B-cell HOHN NO S-N responses might develop): the H metabolism may also induce CH 3 co-stimulatory molecules on b -presenting cells

p-i concept SMX p-i concept Clinic: Only T cells HN The drug happens to fit into some An exclusive T-cell response 2 1 TCR (1) with sufficient affinity to might develop with exanthems, CHM cause a signal. This drug-TCR hepatitis, etc. XMS alc s Is interaction is supplemented by Whether B cells (by drug MHC interaction (2); the T cells binding to Ig) can similarily be react and proliferate. No stimulated, remains unclear O OS T llec metabolism of drugs required. The HN reacting T cells are probably N CHM 2 preactivated and have an additional O lc IIssa peptide specificty

c 3CH

Fig. 1. Hapten and prohapten concept and the non-co- chemically reactive compound (e.g. from sulfamethoxa- valent drug presentation to T cells. a Haptens: Drugs are zole (SMX) to the chemically reactive form SMX-NO). The haptens if they can bind covalently to molecules, be they resulting intake may lead to modification of cell-bound soluble or cell bound (e.g. penicillin G). They can even or soluble proteins by the chemically reactive metabo- bind directly to the immunogenic major histocompati- lite, similar to a real hapten. c The p-i concept (pharma- bility complex (MHC)/peptide complex on antigen-pre- cological interaction with immune receptors): Drugs are senting cells (APC), either to the embedded peptide or often designed to fit into certain proteins/enzymes to to the MHC molecule itself. Thus, the chemical reactivity block their function. Some drugs may happen to bind of haptens leads to the formation of many distinct anti- also into some of the available T-cell receptors. Under genic epitopes, which can elicit both humoral and cel- certain conditions (see text), this drug–T-cell in- lular immune responses. Some examples of a B- or T-cell- teraction may lead to an immune response of the mediated immune response are listed on the right side. with a ‘fitting’ T-cell receptor. For a full T-cell stimulation b Prohaptens: Other drugs are ‘prohaptens’, requiring by such an inert drug, an interaction of the T-cell recep- metabolic activation to become haptens (= chemically tor with the MHC molecule is required. This type of drug reactive). The metabolism leads to the formation of a stimulation results in an exclusive T-cell stimulation.

Drug Hypersensitivity Reactions: Classification and Relationship to T-Cell Activation 171 molecular compound, or (c) that the reaction ther just due to a shift of volume into the extra- was pseudoallergic (see below). vascular space or – and more severely – if a These reactions were erroneously considered cardiac arrhythmia develops. The full syndrome to be dose-in dependent, as sometimes very small is anaphylactic , which is lethal in ca. 1–2% amounts can already cause severe reactions. But of all anaphylaxis cases and the more dangerous further diminishing the dose – as is done in de- the more rapid it appears! Risk factors for a severe sensitization procedures – illustrates that also course are high dose, preexisting (undertreated) these reactions are clearly dose-dependent. and older age, as myocardial infarction IgE-mediated reactions can cause mild to or cerebral hypoxia and brain damage can lead to very severe, even lethal, diseases. In sensitized death days after the acute event. In perioperative individuals the reaction can start within seconds anaphylaxis, the symptoms may affect initially after contact with the parentally applied drug, only one organ system (e.g. the cardiovascular and minutes after oral drug uptake. Symptoms system with arrhythmia), and skin symptoms ap- reach from simple local itch, local wheal-and- pear later. Anaphylaxis is a severe event, and sur- flare reaction upon parenteral drug application, vivors do not rarely have some cognitive or intel- to acute bronchospasm and generalized urticaria lectual impairment. Table 2 summarizes the and edema, preferentially periorbital, perioral or main drugs causing anaphylaxis. genital. More severe and complex reactions are Most IgE-mediated reactions to drugs are less called anaphylaxis, whereby in most cases with severe – and often only an urticaria, angioedema anaphylaxis some circulatory events with col- or a local wheal may develop. However, any IgE- lapse and (transient) unconsciousness are ob- mediated drug can be potentially life- served together with a generalized redness, itch threatening, as the mild symptoms might be due or urticaria. to a relatively low dose, and each treatment might Anaphylactic shock occurs often within 15 also boost the drug-specific IgE response. min, and asphyxia due to laryngeal edema often between 15 and 60 min. Starting symptoms may (Non-Immune-Mediated be a palmar, plantar, genital or axillar itch, which Hypersensitivity) should be seen as an alarm sign, as it often her- An unsolved problem are so-called ‘pseudoaller- alds a possibly severe, anaphylactic reaction, fol- gic’ reactions (non-immune-mediated hypersen- lowing rapidly within minutes ( fig. 2 ): the skin sitivities), which in fact are as frequent as true becomes red (diffuse erythema), often first at the IgE-mediated reactions. Detection of a specific trunk, later over the whole body. In the next immune mechanism is negative. The majority of 30–60 min an urticaria may appear, together these reactions imitate the clinical features of with swelling of the periorbital, perioral and milder immediate reactions (erythema, urticar- sometimes genital area. Asphyxia may account ia), but some reactions cause anaphylaxis and can for 60% of anapylaxis-related deaths [11] : laryn- be lethal. For non-steroidal anti-inflammatory geal swelling may be suspected if the voice be- drug (NSAID)-induced pseudoallergic reactions, comes hoarse, the patients have difficulty speak- it seems that they tend to arise less rapidly (often ing and swallowing as the tongue is swollen. Pa- 115 min) than true IgE-mediated allergies and tients may also complain about chest tightness they may require higher drug doses than for true and dyspnea – signs of acute bronchospasm. IgE-mediated reactions. Elevated tryptase levels Some patients develop gastrointestinal symp- in the acute stage underline the role of mast cell toms (nausea, cramps, vomiting and fecal incon- degranulation, at least in some of these reac- tinence). The pressure may collapse – ei- tions.

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Multiorgan involvement Skin + Respiratory tract + GI tract Anaphylaxis Anaphylactic shock

Severity

Symptoms

Death

Generalized itch

+ Bronchospasm

+ Laryngeal edema

Generalized urticaria

Local wheal-and-flare

Skin, respiratory and GI

symptoms and collapse

(Often facial) local edema

Skin symptoms and collapse

Arrhythmia, cerebral hypoxia,

generalized urticaria, collapse

bronchospasm, laryngeal edema,

Fig. 2. Anaphylaxis is a complex and severe allergic re- volemia, due to a shift of intravascular volume to extra- action affecting multiple organs. It can be seen as the vascular space (less dangerous), or due to arrhythmia. summary of different, severe allergic manifestations in Its most severe form is anaphylactic shock, which can various organs. In many, but not all cases, the cardiovas- result in death in 1–2% of affected persons (for details, cular system is involved either as result of relative hypo- see text).

‘Pseudoallergic’ reactions can be elicited by tinct chemical and pharmacological features. many drugs, but some drugs seem to elicit them Neither IgE nor T-cell reactions can be demon- more often (table 2). Some drugs might elicit strated, the reactions are recurrent, but provoca- both pseudoallergic and also presumably real al- tion tests are often negative, suggesting that ad- lergic reactions, as positive prick skin tests can be ditional cofactors might be needed to develop detected in very severe reactions (contrast media, clinical symptoms. A few patients may have con- neuromuscular-blocking agents). In vitro, these stantly elevated tryptase levels as a sign of a mas- drugs do not release mediators from basophils. tocytosis . Such patients sometimes report about A certain group of people seems to show a multiple anaphylactic reactions to various trig- higher susceptibility to react in this way, as they gers (food, drugs, hymenoptera stings, etc.). Some develop similar, mostly mild symptoms to a quite milder reactions can be suppressed by pretreat- heterogeneous panel of drugs, with clearly dis- ment with , but it is unclear wheth-

Drug Hypersensitivity Reactions: Classification and Relationship to T-Cell Activation 173 Table 2. Drugs causing IgE-mediated or pseudoallergic reactions

Drugs involved in IgE-mediated allergies1 Drugs causing ‘pseudoallergic’ reactions1

Foreign proteins (chimeric antibodies) (Radio)contrast media Immunglobulin preparations (IgE anti-IgA) Plasma expanders -Lactam antibiotics NSAIDs: acetylsalicylic acid, diclofenac, Penicillin mefanamic acid, , … Pyrazolones Pyrazolones Quinolones Quinolones Neuromuscular-blocking agents2 Neuromuscular-blocking agents

1 Not complete; only main groups mentioned. 2 The main causes of perioperative anaphylaxis are neuromuscular-blocking agents, followed by antibiotics (mainly i.v. ) and latex. Skin tests may be positive even if the drug was given the first time.

er pretreatment with antihistamines and cortico- clear as originally thought, since a clear hapten- steroids can prevent more severe reactions, e.g. to specific immune reaction can often not be docu- contrast media [12]. The most common form of mented [13, 14] . One differentiates between: such reactions is related to NSAIDs and is dis- (a) Development of complement-fixing anti- cussed in detail in the contributon by Sczecklik bodies (IgG1, IgG3, rarely IgM) to the hapten- et al. [pp 340–349]. carrier complex, mostly after longer duration of high-dose treatment. It is rather rare and best IgG-Mediated Reactions (Cytotoxic Mechanism, documented for high-dose penicillin and cepha- Type II) losporin treatments. Some antibody reactivity Type II and III reactions rely on the formation of may be directed to the carrier molecule itself complement-fixing IgG antibodies (IgG1, IgG3). (= autoantibodies). This autoimmune form is less Occasionally, IgM is involved. They are similar, abrupt, but longer lasting (weeks instead of days) as both depend on the formation of immune after cessation of the drug. complexes and interaction with complement and (b) Non-specific adherence with autoantibody Fc-IgG receptor (Fc-IgGI, IIa & IIIa) bearing cells inductions can occur when a drug or metabolite (on macrophages, NK cells, , plate- is somehow adsorbed to the erythrocyte or lets), but the target structures and physiological thrombocyte membrane, creating a new antigen- consequences are different: ic complex in combination with the cell mem- In type II reactions, the antibody can be di- brane. For example, quinine-induced immune rected to cell structures on the membrane (rare- thrombocytopenia is caused by a remarkable ly) or activation occurs on the class of IgG and/or IgM immunoglobulins that cell surface: both events can lead to cell destruc- react with selected epitopes on membrane tion or sequestration. Affected target cells in- glycoproteins, usually GPIIb/IIIa (fibrinogen re- clude erythrocytes, leukocytes, and ceptor) or GPIb/IX (von Willebrand factor recep- probably hematopoietic precursor cells in the tor) only when the drug is present in its soluble bone marrow [see also chapter of Aster, pp 306– form [13] . Well-documented cases are due to qui- 320]. The mechanism of type II reaction is not as nine, or antibiotics. The

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antibodies are clearly not hapten-specific, and it A special, intermediate form between type II remains enigmatic how a soluble drug can pro- and III reactions is heparin-induced thrombocy- mote binding of an otherwise innocuous anti- topenia : Platelets contain low-affinity (Fc-IgG- body to a membrane glycoprotein to cause plate- RIIa) Fc receptors that are capable of binding im- let destruction. mune complexes, leading to platelet activation The antibody-coated cells will be sequestrated [15] . Heparin is a high molecular weight, sulfat- to the reticuloendothelial system in liver and ed, linear polysaccharide that inhibits blood co- spleen by Fc or complement receptor binding. agulation by activating regulatory proteins such More rarely, intravascular destruction may occur as antithrombin III. About 50% of patients anti- by complement-mediated lysis. coagulated with heparin for at least 7 days pro- has been attributed to pen- duce antibodies that recognize complexes con- icillin and its derivatives, cephalosporins, le- sisting of heparin and platelet factor 4, a CXC vodopa, , quinidine and some anti- chemokine normally stored in platelet -gran- inflammatory drugs. Today, cephalosporins are ules. When a patient with such an antibody is giv- the main cause. The clinical symptoms of hemo- en heparin, heparin/PF4 complexes are formed lytic anemia are insidious and may be restricted that react with antibodies to form immune com- to symptoms of anemia (fatigue, paleness, short- plexes, which bind to the platelet Fc-IgG-RIIa re- ness of breath, tachycardia) and jaundice with ceptors, leading to platelet activation, additional dark urine. The laboratory investigation may re- PF4 release and eventually, platelet destruction. veal reduced erythrocyte and hemoglobin levels, Thrombocytopenia occurs in about 5% of pa- increased reticulocytes, a positive direct and – if tients given heparin and is rarely severe enough the drug is present during the test – indirect to cause bleeding. However, about 10% of the af- . Indirect bilirubin levels are elevat- fected patients experience paradoxical thrombo- ed, haptoglobulin decreased. In urine, hemoglo- sis which can be life-threatening. bin and hemosiderin are increased. These thrombopenic reactions due to heparin Thrombocytopenia is a relatively common side have to be differentiated from other heparin- or effect of drug treatment: Acute, sometimes severe heparinoid-induced immune reactions. They and life-threatening thrombocytopenia is a rec- may be due to a T-cell-mediated allergy with ex- ognized complication of treatment with quinine, anthematous or eczematous skin reactions, and quinidine, sulfonamide antibiotics and many very rarely anaphylaxis due to heparin-specific other medications. It is a not so rare complication IgE has been described [16] . In delayed reactions of treatment with biologicals. Drug-induced im- due to subcutaneous applications, intravenous mune thrombocytopenia usually develops after administration of heparin or subcutaneous ap- 5–8 days of exposure to the sensitizing medica- plications of structurally different anticoagulants tion, or after a single exposure in a patient ex- like for example fondaparinux of hirudin may be posed previously to the same drug. Patients with tolerated. this condition often present with widespread pe- techial hemorrhages in the skin and buccal mu- IgG-Mediated Reactions (Immune Complex cosa, sometimes accompanied by urinary tract or Deposition, Type III) gastrointestinal bleeding. Intracranial hemor- Formation of immune complexes is a common rhage is rare, but examples have been reported. event in the frame of a normal immune response After discontinuation of the provocative medica- and does not normally cause symptoms. Immune tion, platelet counts usually return to normal complexes may also be formed during drug treat- within 3–5 days. ment: either if the drug forms a hapten-carrier

Drug Hypersensitivity Reactions: Classification and Relationship to T-Cell Activation 175 complex and thus gives rise to an immune reac- Vasculitis may be localized mainly to the skin tion, or if the drug is a (partly) foreign protein, as ‘’ – purplish, red spots, usu- which elicits an immune reaction itself (e.g. a chi- ally found on the legs [see figure 5 on hypersen- meric antibody). Such immune complexes will sitivity vasculitis in chapter of Bircher, pp 352– normally be rapidly cleared, either by Fc-IgG-RI 365]. In children, it is often referred to as Henoch- or CR1 binding on reticuloendothelial cells. No Schönlein purpura , sometimes appearing togeth- symptoms arise, but the efficiency of treatment er with an arthritis. Lesions may coalesce to form decreases. plaques and they may ulcerate in some instances. Why under certain circumstances an immune The internal organs most commonly affected are complex disease develops is not clear: very high the gastrointestinal tract, kidneys and joints. The immune complex levels, a relative deficiency of prognosis is good when no internal involvement some complement components, and thus lower is present. The disorder may be acute or chronic. capacity to eliminate immune complexes or an Histology can reveal IgA-containing immune aberrant Fc-IgG-R function might be considered. complexes, and the histology of kidney lesions is Recently, a low copy number of Fc-IgG-RIII genes in fact identical to IgA nephropathy, a main cause could be associated with another immune com- of chronic renal failure. plex disease, namely [17] . Thus, reduced removal of immune complexes may lead to inappropriate deposition of immune T-Cell-Mediated, Delayed Drug Hypersensitivity complexes and recruitment of inflammatory Reactions cells, in particular PMNs due to immune com- plex binding to Fc-IgG-R on PMN. In addition, Subclassification of Type IV Reactions anaphylatoxins C3a and C5a, generated due to lo- The old Gell and Coombs classification was es- cal complement activation, may attract PMNs. tablished before a detailed analysis of T-cell sub- The clinical symptoms of a type III reaction sets and functions was available. In the mean- may be hypersensitivity, small vessel vasculitis time, immunological research has revealed that and/or . Serum sickness was first the three antibody-dependent types of reactions described with the use of heterologous or foreign require an involvement of helper T cells. More- serum for passive immunizations: Antibodies are over, T cells can orchestrate different forms of in- generated within 4–10 days, which react with the flammations. Therefore, T-cell-meditated type antigen, forming soluble circulating immune IV reactions were further subclassified in IVa- complexes. Complement (C1q)-containing im- IVd reactions as proposed in figure 3 [8] . This mune complexes are deposited in the postcapil- subclassification considers the distinct cytokine lary venules and are attracting neutrophilic leu- production by T cells and thus incorporates the kocytes by interacting with their Fc-IgG-RIII well-accepted Th1/Th2 distinction of T cells; it [18] , which thereby release proteolytic enzymes includes the cytotoxic activity of both CD4 and that can mediate tissue damage. CD8 T cells (IVc), and it emphasizes the partici- Currently, non-protein drugs are the most pation of different effector cells like monocytes common cause of serum sickness. Hypersensitiv- (IVa), eosinophils (IVb), or neutrophils (IVd), ity vasculitis reportedly has an incidence of 10– which are the cells causing the inflammation and 30 cases per million people per year. Most reports tissue damage ( fig. 4 ): concern , followed by trimethoprim-sul- Type IVa reactions correspond to Th1-type famethoxazole, cephalexin, amoxicillin, NSAIDs immune reactions: Th1-type T cells activate mac- and diuretics. rophages by secreting large amounts of interfer-

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correlate might be an eosinophil-rich maculo- papular exanthem, but also infestations with nematodes, or an allergic inflammation of the bronchi or nasal mucosa (asthma and ). Type IVc: T cells can also act as effector cells themselves: they emigrate to the tissue and can kill tissue cells like hepatocytes or keratinocytes in a perforin/granzyme B- and FasL-dependent manner ( fig. 5 ) [19, 20] . Such reactions occur in most drug-induced delayed hypersensitivity re- actions, mostly together with other type IV reac- tions (monocyte, eosinophil or PMN recruitment and activation). Cytotoxic T cells thus play a role in maculopapular or bullous skin diseases as well as in neutrophilic inflammations (acute general- Fig. 3. Urticaria with itching wheals (pseudoallergic re- action). ized exanthematous pustulosis – AGEP), and in contact dermatitis. Type IVc reactions appear to be dominant in bullous skin reactions, where ac- tivated CD8+ T cells kill keratinocytes [8, 19, 20], on (IFN)- , drive the production of complement- but may also be the dominant cell type in hepati- fixing antibody isotypes involved in type II and tis or nephritis. III reactions (IgG1, IgG3), and are co-stimulatory Type IVd: Rather neglected was the possibility for pro-inflammatory responses (TNF, IL-12) that T cells could coordinate (sterile) neutrophil- and CD8+ T-cell responses. The T cells promote ic inflammations as well. Typical examples would these reactions by IFN- secretion and possibly be sterile neutrophilic inflammations of the skin, other cytokines (TNF- , IL-18, etc.). An in vivo in particular AGEP. In this disease, CXCL8- and correlate would on the one hand be a monocyte GM-CSF-producing T cells recruit neutrophilic activation, for example in skin tests to tuberculin leukocytes via CXCL8 release and prevent their or even granuloma formation as seen in sarcoid- apoptosis via GM-CSF release [21] . Besides AGEP, osis. On the other hand, these Th1 cells are known such T-cell reactions are also found in Behçet’s to help in the activation of CD8 cells, which might disease and pustular psoriasis [22] . explain the common combination of IVa and IVc Tolerance mechanism: Most patients can take reactions (e.g. in contact dermatitis). drugs without developing immune-mediated Type IVb corresponds to the Th2-type im- side effects. One could argue that they lack pre- mune response. Th2 T cells secrete the cytokines cursor cells able to interact with the drug, but the IL-4, IL-13 and IL-5, which promote B-cell pro- great heterogeneity of the immune response to duction of IgE and IgG4, macrophage deactiva- drugs [8] , a high precursor frequency in sensi- tion and mast cell and eosinophil responses. The tized patients [23] and the finding that 2–4% of high production of the Th2 cytokine IL-5 leads to the normal population, but that 30 to 150% of an eosinophilic inflammation, which is the char- HIV-infected patients may react with sulfa- acteristic inflammatory cell type in many drug methoxazole, suggests that not a lack of precursor hypersensitivity reactions [8] . In addition, there cells but other factors like the underlying im- is a link to type I reactions, as Th2 cells boost IgE mune status (preactivation of memory T cells) production by IL-4/IL-13 secretion. An in vivo and ‘regulatory’ mechanisms may be important.

Drug Hypersensitivity Reactions: Classification and Relationship to T-Cell Activation 177 detartsehcrollec-T dna )III–I( ydobitnA )III–I( dna detartsehcrollec-T )d–a VI(snoitcaerytivitisnesrepyh )d–a

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Fig. 4. Revised Gell and Coombs classification of drug leads to a local vascular inflammation. Type IVa corre- reactions. Drugs can elicit all types of immune reactions. sponds to Th1 reactions with high IFN- /TNF- secre- In fact, all reactions are T-cell regulated, but the effector tion and involves monocyte/macrophage activation. Of- function rely mainly on antibody-mediated effector ten, one can also see a CD8 cell recruitment (type IVc re- functions (type I–III) or more T-cell/cytokine-dependent action). Type IVb reactions correspond to eosinophilic functions (type IVa–IVd) [8] . Type I reactions are IgE-me- inflammation and to a Th2 response with high IL-4/IL-5/ diated. Cross-linking IgE molecules on high-affinity IgE IL-13 secretion; they are often associated with an IgE-me- receptors (Fc-IgE-RI) on mast cells and basophilic leuko- diated type I reaction. Type IVc: the cytotoxic reactions cytes lead to degranulation and release of mediators, (both by CD4 and CD8 cells) rely on cytotoxic T cells which cause a variety of symptoms (vasodilatation, in- themselves as effector cells (type IVc). They seem to oc- creased permeability, bronchoconstriction, itch, etc.). cur in all drug-related delayed hypersensitivity reac- Type II reactions are IgG-mediated, and cause cell de- tions. Type IVd correspond to a T-cell-dependent, sterile struction due to complement activation or interaction neutrophilic inflammatory reaction. It is clearly distinct with Fc-IgG receptor-bearing killer cells. Type III reac- from the rapid influx of PMN in bacterial infections. It tions are also IgG-mediated: complement deposition seems to be related to high CXCL8/GM-CSF production and activation in small vessels and recruitment of neu- by T cells (and tissue cells). trophilic granulocytes via Fc-IgG receptor interaction

178 Pichler