Immune response in human pathology:
hypersensitivity and autoimmunity
Jacques Descotes and Thierry Vial
Introduction
The immune system is a complex network of regula-
tory and effector cells and molecules whose primary
function is discrimination of self from non-self to
maintain the homeostasis of the body. Closely inter-
acting processes ensure coordinated immune
responses.The renewal, activation and differentiation
of specialized (immunocompetent) cells are
required to achieve a normal level of immunocompe-
tence under the control of many mechanisms with
either a redundant or conflicting outcome. It is note-
worthy, however, that immune responses are not
always beneficial. Thus, inadvertent immunological
reactivity against innocent ANTIGENS can lead to HYPER-
SENSITIVITY reactions while immune responses against
self constituents of the host result in autoimmune dis-
eases or reactions. Although the mechanism(s) lead-
ing to either type of adverse immune responses can
be inhibited, at least to some extent, by pharmacolog-
ical manipulation, pharmaceutical drugs as well as
environmental or industrial chemicals can trigger
HYPERSENSITIVITYand autoimmune reactions [1].
Hypersensitivity
Nearly every chemical in our medical, domestic,
occupational or natural environment can induce
HYPERSENSITIVITY reactions.
Epidemiology of hypersensitivity reactions to
drugs
Although HYPERSENSITIVITY is widely held as a major
cause of immunotoxic events,there are very few data
on the actual incidence of HYPERSENSITIVITY reactions
A8
in human beings. Most published data consist of
case reports and epidemiological studies are rela-
tively rare. It has been suggested that approximately
one-third of all drug-induced adverse effects might
have an IMMUNOALLERGIC or PSEUDOALLERGIC origin [2].
More conservative estimates, e.g., 6–10%, have also
been proposed and current limitations or uncertain-
ties in the medical diagnosis of drug allergies [3]
probably account for these differences. For instance,
severe anaphylactic or anaphylactoid reactions may
develop in about 1 in 5,000 exposures to antibiotics
or radiocontrast media [4], or 1 in 10,000 drug treat-
ments [5]. The same lack of data precludes any reli-
able estimate of the incidence of HYPERSENSITIVITY
reactions in relation to occupational or environmen-
tal exposure, as well as to food allergies.
Clinical manifestations of drug-induced
hypersensitivity reactions
HYPERSENSITIVITY reactions can affect nearly every
organ or tissue of the body, but one organ or tissue is
often a predominant target [6].
Anaphylactic shock
Anaphylactic shock is one of the most severe HYPER-
SENSITIVITY reactions with an estimated death rate of
about 1% [7]. ANAPHYLAXIS unexpectedly develops
within 1–20 minutes after the last contact with the
drug and almost always within the first two hours,
depending on the route of administration. Patients
usually complain of itching, and then rapidly devel-
op urticaria and angioedema, tachycardia, hypoten-
sion progressing to cardiovascular collapse or shock
in the most severe cases, and marked respiratory dif-
ficulties with cyanosis. Anaphylactic shock is a major
118 Immune response in human pathology: hypersensitivity and autoimmunity
FIGURE 1
Erythematous skin rash due to amoxicillin.
medical emergency. Initial supportive measures tend
to maintain or restore normal respiratory and circu-
latory functions. The key treatment is epinephrine
(adrenaline) injected either subcutaneously or intra-
muscularly.
Skin reactions
Skin reactions are the most frequent immune-medi-
ated adverse effects of drugs [8, 9]. Relatively rare
reactions involve specific IgE ANTIBODIES, e.g.,
urticaria and angioedema, or circulating immune
complexes, e.g., vasculitis, but the majority of
immune-mediated cutaneous manifestations caused
by drugs are presumably due to T cell-mediated
mechanisms. The clinical presentation is extremely
varied. Morbilliform or exanthematous rash may
occur in up to 2% of all treated patients (Fig. 1).The
onset varies within 1–2 weeks after the start of treat-
ment. A T cell-mediated cytotoxic mechanism is
most likely [10]. Contact dermatitis is a frequent
complication of occupational and environmental
exposures, but it can also develop following topical
drug applications [11]. It is characterized by pruritic
vesicles on an erythematous background (Fig. 2).
Allergic contact dermatitis is a T LYMPHOCYTE-mediat-
ed reaction that should be differentiated from irritant
contact dermatitis caused by non antigen-specific
FIGURE 2
Contact dermatitis.
mechanism(s).Stevens-Johnson syndrome (SJS) and
toxic epidermal necrolysis (TEN) are the most severe
and potentially life-threatening cutaneous complica-
tions of drug treatments [12]. They affect approxi-
mately 0.5-2 in 1 million persons per year [13]. Typi-
cally, the first clinical symptoms, i.e., flu-like reaction
of variable severity and mucous membrane involve-
ment, appear 7 to 21 days after the start of treatment.
Skin lesions extend within 2 to 3 days with purpuric
macules and bullae leading to erosion of the epider-
mis (Fig. 3). Painful erosions of the mucous mem-
branes account for dysphagia, conjunctivitis, kerati-
tis,diarrhea and/or respiratory distress.The prognosis
and management are similar to those of severely
burnt patients.The mortality rate is about 5% for SJS
and 30% for TEN.
The drug HYPERSENSITIVITY syndrome or DRESS –
Drug Rash with Eosinophilia and Systemic
Symptoms – is characterized by fever and rash, but
50% of patients also present with lymphadenopathy,
arthritis or hepatitis,and less frequently kidney,heart,
lung, thyroid, or brain involvement (Hyper)eosino-
philia is noted in 90% of cases [14].
Immunoallergic cytopenias
Cytopenias generally manifest as antibody-mediated
destruction of one or several blood cell lines. Even
 Hypersensitivity 119

though drugs are the most likely cause,the incidence

is low and probably not more than 1 in 1–300,000
treated patients [15]. Patients with agranulocytosis
are either asymptomatic and the diagnosis is then
made after a routine blood examination, or they
develop clinical symptoms of infection, in particular
sore throat. In this latter case, neutropenia is often
below 100/mm3. Hemolytic anemias are due either
to direct or antibody-mediated toxicity to the mem-
brane of erythrocytes. Depending whether AUTOANTI-
BODIES are involved or not, immune-mediated
hemolytic anemias are either autoimmune or
immunoallergic. However, the distinction may be dif-
ficult to make as both AUTOANTIBODIES and drug-
dependent ANTIBODIES can be produced by the same
drug [16]. Most IMMUNOALLERGIC hemolytic anemias
are acute or subacute. Clinical symptoms develop
within hours following drug intake and include
abdominal and dorsal pain,headache,malaise,fever,
nausea and vomiting. Shock and acute renal failure
are noted in 30–50% of cases.
Two main mechanisms can be involved. The
causative drug, e.g., a third-generation cephalosporin
[17], can nonspecifically bind to ERYTHROCYTES and
reacts with circulating specific ANTIBODIES. Otherwise, FIGURE 3
the drug bound to a plasma protein can form an Toxic epidermal necrolysis.
antigenic complex with the resulting production of
IgM or IgG against the drug-protein complex that can
be passively fixed to erythrocytes.The reintroduction
of even a tiny amount of the drug can trigger an anti- reaction in most instances.An unpredictable adverse
gen-ANTIBODY reaction leading to intravascular immune response against the liver with cytolytic,
hemolysis by activation of the complement cascade. cholestatic or mixed clinical and biological features,
Drug-induced IMMUNOALLERGIC thrombocytopenias however, can be involved [19].The causative mecha-
are uncommon with the notable exception of those nism is not known in most cases and the association
induced by heparin [18]. Most patients with heparin- of liver injury with fever, rash and eosinophilia, typi-
induced immune thrombocytopenia have detect- cally within 1 to 8 weeks after starting drug treat-
able ANTIBODIES against the platelet glycoproteins ment, is often held as suggestive of an IMMUNOALLER-
Ib/IX and IIb/IIIa. Clinically, thrombocytopenia leads GIC reaction. Drugs are the leading cause of acute
to bleeding when platelet counts are less than interstitial nephritis, which accounts for 1–3% of all
10–30,000/mm3. cases of acute renal failure [20].The clinical presen-
tation is nonoliguric renal dysfunction associated
Other clinical manifestations with fever, rash and/or eosinophilia in up to 50% of
patients. Drugs can cause acute interstitial or
Other clinical manifestations of drug-induced HYPER- eosinophilic pneumonia, and HYPERSENSITIVITY pneu-
SENSITIVITY reactions include hepatitis, nephritis and monitis [21]. Clinical manifestations including fever,
pneumonitis. Severe drug-induced hepatitis is rela- cough, eosinophilia, and elevated serum IgE levels
tively infrequent and considered as an IDIOSYNCRATIC vary depending on the offending drug.
120 Immune response in human pathology: hypersensitivity and autoimmunity
Mechanisms of drug-induced hypersensitivity
reactions
Immune-mediated HYPERSENSITIVITY reactions are the
consequence of the exquisite capacity of the
immune system to recognize structural elements of
non-self molecules or antigens, and to mount specif-
ic responses due to the involvement of immunologi-
cal memory.
Sensitization
An absolute prerequisite for any antigen-specific
HYPERSENSITIVITY reaction to develop is that sensitiza-
tion occurred prior to the eliciting contact. Impor-
tantly, it is normally impossible to demonstrate
whether a prior contact was actually sensitizing.
Identifying a prior and supposedly sensitizing con-
tact is more or less easy.This can be straightforward
when a patient who developed an adverse reaction
was being treated with the suspected offending
drug.At least 5–7 days of treatment are necessary to
potentially result in sensitization. The majority of
immune-mediated HYPERSENSITIVITY reactions do
develop within the first month of treatment, but a
longer period of time is nevertheless possible. No
difficulty either is expected in patients previously
treated with the same drug. An immune-mediated
HYPERSENSITIVITY reaction can develop within min-
utes to several days depending on the route of
administration and the underlying mechanism. A
prior contact may be far less easy to detect when it
is due to exposure via the food chain, or involves a
closely related molecule leading to cross-allergenic-
ity. Finally, it is important to bear in mind that even
though a prior contact is absolutely required, a clin-
ical reaction often does not develop after a subse-
quent contact.
Broadly speaking, a molecule can be sensitizing
when this is a foreign and large molecule. The
majority of drugs are foreign molecules.There is no
formally established minimal requirement regard-
ing the size of foreign molecules to be immuno-
genic (sensitizing). A molecular weight of at least
1,000 or more conservatively 5,000 has been pro-
posed. However, the structural complexity, degree of
polymerization and biodegradability also play a
major role. The vast majority of drugs are too small
to act as direct immunogens. It is widely assumed
that low-molecular-weight molecules must there-
fore play the role of haptens to induce sensitization
[22]. Haptens are small molecules that strongly
bind to carrier macromolecules so that the formed
hapten-carrier complex can mount a specific
immune response. Sufficient chemical reactivity is
absolutely required for low-molecular-weight mole-
cules to become haptens. As most molecules
intended for therapeutic use are devoid of any sig-
nificant chemical reactivity, metabolites are thought
to be involved. However, highly reactive metabolites
have very short half-lives so that they often cannot
be identified.The consequence is that evidence for
the role of metabolites in drug-induced HYPERSENSI-
TIVITY reactions is often indirect and therefore large-
ly assumptive.
Risk factors
Even potent sensitizing drugs, such as penicillin G,
induce HYPERSENSITIVITY reactions in only quite a
small percentage of treated patients. The involve-
ment of risk factors may account for this finding.Risk
factors may be related either to the patient or the
drug. Age, gender, atopy and genetic predisposition
are the main risk factors related to the patient.Young
adults develop more frequent HYPERSENSITIVITY reac-
tions to drugs for unknown reasons. An epidemiolog-
ical study of severe anaphylactic and anaphylactoid
reactions in hospitalized patients found 927 reac-
tions per 1 million in patients less than 20 years of
age, 221–276 in patients between 20 and 59 years of
age, and only 154 in patients over 60 [23].Young girls
and women seem to develop only slightly more
HYPERSENSITIVITY reactions induced by drugs than
boys and men. Atopy is characterized by excessive
production of IgE associated or not with one or sev-
eral diseases, such as reaginic asthma, hay fever and
constitutional dermatitis. Due to variable definitions
over time, conflicting results have been published,
but the most recent data support the role of atopy as
a risk factor. Multi-generation family and twin studies
have demonstrated a genetic component in a num-
ber of allergic diseases, in particular IgE-mediated

diseases. As drug-induced HYPERSENSITIVITY reactions
involving IgE are relatively uncommon, limited evi-
dence supports the role of genetic predisposition.
However, as already mentioned, metabolites are
widely thought to play a critical role in sensitization
to drugs so that the genetic polymorphism of meta-
bolic pathways involved in drug biotransformation is
likely to affect the incidence of drug-induced HYPER-
SENSITIVITY reactions.
Major risk factors related to the drug include the
chemical structure, route of administration, and
treatment schedule.The role of specific elements of
the chemical structure is suspected, but much
remains to be done to define reliable structure-
immunogenicity relationships [24]. Every route of
administration can result in sensitization, but the
topical route has a greater potential.The oral route
normally leads to tolerance and the mechanism of
tolerance breakdown is ill-understood. In sensitized
patients, the intravenous route is associated with
more rapidly developing and more severe reac-
tions. Finally, intermittent treatment regimens facili-
tate sensitization.
Pathophysiological mechanisms of
drug-induced hypersensitivity reactions
In the early 1960s, Gell and Coombs proposed a clas-
sification of IMMUNOALLERGIC reactions, later extend-
ed to drugs. This antique classification is still widely
used, although it can be misleading as not all mech-
anisms are covered, several mechanisms can be
involved concomitantly, or distinct mechanisms can
be involved in different patients treated with the
same drug despite clinically similar reactions [25,
26]. Despite major flaws, this classification into 4
types can serve as an introduction to the pathophys-
iology of drug-induced HYPERSENSITIVITY reactions.
Type I-IV reactions. Type I reactions are immediate
HYPERSENSITIVITY (anaphylactic) reactions. Causative
ANTIGENS (allergens) induce the production of
reaginic ANTIBODIES, namely IgE and to a lesser extent
IgG4 in man. IgE bind to high affinity receptors
(FcεRI or CD64) on the membrane of mast cells and
basophils. After a subsequent contact, the reaction
between a divalent drug allergen and specific IgE
Hypersensitivity 121
triggers the DEGRANULATION of mast cells and
basophils, which results in the immediate release of
preformed mediators including HISTAMINE, neutral
proteases (e.g., tryptase), and heparin, that are stored
in cytoplasmic granules. Another consequence of
DEGRANULATION is de novo synthesis of mediators
from membrane phospholipids, including PROSTA-
GLANDINS and LEUKOTRIENES, and their delayed release
(Fig. 4).
Type II reactions are cytotoxicity reactions due to
IgM or, less often, IgG. Typically, when the sensitizing
drug bound to the surface of blood cells encounters
circulating ANTIBODIES, the resulting COMPLEMENT acti-
vation provokes the destruction of blood cells as is
seen in IMMUNOALLERGIC hemolytic anemias and
thrombocytopenias.
Type III reactions are caused by circulating
immune complexes that are formed when the anti-
gen is in greater quantity in the serum than IgM or
IgG ANTIBODIES. Depending on their size, immune
complexes deposit in capillary vessels and activate
the COMPLEMENT SYSTEM, platelets, MACROPHAGES and
neutrophils.Activated cells release a variety of medi-
ators and free radicals, which damage the endothe-
lial cells. If the antigen is present predominantly at
one site, localized damage is seen as in the Arthus
reaction. Immune complex deposition is one possi-
ble mechanism of cutaneous vasculitis. When the
immune complexes are present in the circulation,
they may cause serum sickness with fever, arthral-
gias, cutaneous eruption and proteinuria within 9 to
11 days after the injection of heterologous serum or
monoclonal ANTIBODIES. No immune complexes cir-
culating in the blood or deposited in the glomeruli
are seen after treatment with low-molecular-weight
drugs. The term serum sickness-like disease should
be used to avoid confusion.
Type IV or delayed HYPERSENSITIVITY reactions
include allergic contact dermatitis and photoallergy.
Contact dermatitis can be either non-immune-medi-
ated (i.e., irritant contact dermatitis) or immune-
mediated (i.e., allergic contact dermatitis). Allergic
contact dermatitis is characterized by the infiltration
of T LYMPHOCYTES into the dermis and epidermis.
After penetrating into the skin, low-molecular-weight
drugs or their metabolites can play the role of hap-
tens that bind to or complex with various cells,
122 Immune response in human pathology: hypersensitivity and autoimmunity

Type I: Immediate hypersensitivity Type II: Cytotoxicity reaction

IgM, IgG
Antigen
IgE Complement

Mediator release NK cell

Red blood cell

IgE bind FcγRI receptors on mast cells and
basophils. Cross-linking of IgE by the antigen
results in degranulation with the release of
stored (e.g., histamine), then neo-synthesized
mediators (e.g., prostaglandins, leukotrienes).
IgM or IgG antibodies directed against
antigens on the hosts cells are associated
with cytotoxicity by K and NK cells (ADCC)
or complement-mediated lysis.

Type III: Immune complex reaction Type IV: Delayed-type hypersensitivity

Platelets CD4 or
CD8
CMH TCR LT Cytotoxicity
APC
Complement CD3

Neutrophil Cytokines

CIC Mo/M
Endothelial
cell

Immune complexes (CIC) are deposited in Antigen-sensitized cells release cytokines

the walls of small capillaries. Local damage
to endothelial cells occurs as a consequence
of complement activation and phagocyte
attraction to the site of deposition.
following a subsequent contact with the same
antigen. Cytokines induce an inflammatory
response and activate monocytes/macrophages
(Mo/M) to release mediators. T lymphocytes
can also be directly cytotoxic.

FIGURE 4
Mechanisms of type I–IV hypersensitivity reactions according to Gell and Coombs classification.

including Langerhans cells and keratinocytes.
Langerhans cells process and present the antigen to
T LYMPHOCYTES, which leads to the clonal prolifera-
tion of sensitized LYMPHOCYTES and to a clinically
patent inflammatory reaction.
Delayed hypersensitivity reactions have been pro-
posed to be divided into four distinct sub-categories
[27]: type IV-a reactions involve a TH1 RESPONSE and
closely correspond to the Gell and Coombs type IV
reactions.Type IV-b reactions involve a TH2 RESPONSE

in which the cytokine IL-5 is suspected to play a key
role as in the drug HYPERSENSITIVITY syndrome
(DRESS) and drug-induced exanthemas. Type IV-c
reactions are caused by cytotoxic T LYMPHOCYTES
and type IV-d reactions involving IL-8 lead to neu-
trophilic inflammation. This extended classification
offers the advantage to stick more closely to the
wide spectrum of drug-induced HYPERSENSITIVITY
reactions, but it remains to be established whether it
is fully applicable to non-cutaneous drug-induced
reactions involving T LYMPHOCYTE-mediated mecha-
nisms.
Pseudo-allergic reactions. An immune-mediated
mechanism does not account for all HYPERSENSITIVITY
reactions induced by drugs. Clinical manifestations
mimicking genuine IgE-mediated reactions have
been consistently described in patients exposed for
the first time to the same offending drug, hence the
proposed term of pseudo-allergy [28]. Several mech-
anisms have been identified.
HISTAMINE can be released by mast cells and
basophils independently of any IgE-mediated
mechanism. A cytotoxic or osmotic effect may be
involved in direct (non-antigen-specific) HISTAMINE
release.Clinical signs and symptoms mimic more or
less closely a histaminic reaction with flush,redness
of the skin, headache, cough and abdominal pain.
The red man syndrome induced by vancomycin is
one typical example [29]. Complement activation
can be caused by immunological as well as nonim-
munological triggers, such as the pharmaceutical
solvent Cremophor EL and hydrosoluble radiologi-
cal contrast media [30]. C3a and C5a are potent by-
products – the ANAPHYLATOXINS – released during
complement activation, which induce leukocyte
chemotaxis, increased vascular permeability, con-
traction of bronchial smooth muscle, HISTAMINE
release, generation of LEUKOTRIENES, and IL-1 produc-
tion. Aspirin as well as most NSAIDs can cause
acute intolerance reactions [31]. They develop
within 1 hour after drug ingestion as an acute asth-
ma attack, often associated with rhinorrhea and
conjunctival irritation. Aspirin and the majority of
NSAIDs are more potent inhibitors of the COX-1 iso-
form of the enzyme CYCLOOXYGENASE (COX) than of
the COX-2 isoform. Any NSAID with marked COX-1
Autoimmunity 123
inhibiting activity can precipitate asthma attacks,
presumably by increasing the availability of arachi-
donic acid and/or the release of LEUKOTRIENES by the
enzyme 5-lipooxygenase. That COX-2 inhibitors
appear to be safe in patients with a history of
aspirin intolerance supports this hypothesis. Finally,
angioedema associated with angiotensin-convert-
ing enzyme inhibitors probably results from the
decreased degradation of bradykinin, which
increases vascular permeability, contracts smooth
muscles and elicits pain [32].
Autoimmunity
Although autoimmunity is still largely a mystery,
autoimmune diseases are relatively common in the
general population. Estimates vary widely, but over 1
million new cases may develop every 5 years in the
USA [33]. A wide range of xenobiotics have been
reported to induce autoimmune diseases [34], but
the incidence of drug-induced autoimmunity is
seemingly low [35]. It is noteworthy that one given
drug can typically induce only one type of autoim-
mune disease (reaction), e.g., hydralazine and
pseudolupus, or α-methyldopa and autoimmune
hemolytic anemia. In contrast, treatments with an
immunostimulatory drug, such as the therapeutic
CYTOKINES rIL-2 and INTERFERONS-α,are associated with
a wide range of more frequent autoimmune diseases
that cannot be distinguished from spontaneous dis-
eases [36].
Clinical manifestations of autoimmunity
Autoimmune diseases are clinically very diverse
and, in many instances, the diagnosis is based on the
presence of several clinical signs and symptoms
among a predefined set.The clinical presentation of
drug-induced autoimmune reactions is more or less
variable with respect to the spontaneous disease so
that the presence of AUTOANTIBODIES in the sera of
patients is a prerequisite. Spontaneous as well as
drug-induced autoimmune diseases are divided into
systemic and organ-specific.
124 Immune response in human pathology: hypersensitivity and autoimmunity
Systemic autoimmune diseases
Systemic lupus erythematosus (SLE) is estimated to
affect 2–10 in 10,000 individuals. The causes of SLE
are not known, but endocrine, genetic and environ-
mental factors are likely to be involved. The lupus
syndrome or pseudolupus is the most common drug-
induced autoimmune reaction [37],and hydralazine
and procainamide are by far the most frequent caus-
es. AUTOANTIBODIES have been detected in the sera of
up to 25% of patients treated with hydralazine and
50% of those treated with procainamide.However,no
clinical signs were associated with AUTOANTIBODIES in
the majority of patients.Other drugs seldom reported
to induce lupus syndromes include several anti-
epileptic drugs,most β-blockers,chlorpromazine and
isoniazid. In recent years, minocycline appeared as a
leading cause.
Drug-induced lupus syndromes normally bear
few clinical and biological similarities to SLE.In con-
trast to SLE, lupus syndromes are as frequent in men
as in women.The most typical clinical signs include
arthritis in over 80% of patients,fever,weight loss,and
muscular weakness with myalgias. Cutaneous mani-
festations are often uncharacteristic. Renal involve-
ment is inconsistent and usually mild. No neurologi-
cal signs are noted. One major distinction is the high
incidence of pleural effusion seen in up to 40% of
patients and pericardial effusion which can result in
cardiac tamponade. No biological abnormalities are
typical of a drug-induced lupus syndrome. Anti-
nuclear ANTIBODIES are always present. Anti-ds (dou-
ble-stranded) or native DNA ANTIBODIES are found in
50–70% of patients with SLE, but in less than 5% of
those with the lupus syndrome. In contrast, ANTIBOD-
IES to denatured DNA are relatively common in the
lupus syndrome. No AUTOANTIBODIES have so far been
identified as markers of drug-induced lupus syn-
dromes. In contrast to SLE, lupus syndromes have a
favorable outcome after cessation of the offending
drug.
Scleroderma or systemic sclerosis is a relatively
rare disease characterized by a more or less diffuse
infiltration of the dermis and viscera by collagen
with vascular abnormalities including vasospasm
and microvascular occlusion. The pathogenesis of
scleroderma is not elucidated. There is an overpro-
duction of collagen by fibroblasts. T LYMPHOCYTES are
thought to play a pivotal role. Only very few drugs
have been reported to induce scleroderma-like dis-
eases. The most severe was the oculo-muco-cuta-
neous syndrome induced by the beta-blocker prac-
tolol, with kerato-conjunctivitis, lesions of the con-
junctivae with loss of sight, psoriasis-like eruption,
and pleural and/or pericardial effusion [38].
Organ-specific autoimmune diseases
In contrast to systemic autoimmune reactions
induced by drugs, organ-specific reactions are char-
acterized by a homogeneous ANTIBODY response
against a unique target and clinical symptoms close-
ly mimicking those of the spontaneous autoimmune
disease.
Guillain-Barré syndrome usually presents with
progressive lower extremity weakness potentially
leading to autonomic dysfunction.The mortality rate
is 3–5%. A possible link between Guillain-Barré syn-
drome and vaccination has been suspected [39].
Multiple sclerosis is a multifocal demyelinating dis-
ease of the central nervous system that may take a
relapsing or progressive course. Early symptoms con-
sist of paresthesias, gait disorders, visual loss and
diplopia. Relapses evolve within days and resolve
gradually, but incompletely. Multiple sclerosis is char-
acterized by perivascular cuffing of CD4+ T LYMPHO-
CYTES and myelin destruction.Vaccines, in particular
hepatitis B vaccine, have been suspected to induce
or facilitate the development of multiple sclerosis,
but so far no fully confirmative epidemiological evi-
dence has been published. Myasthenia is character-
ized by a loss of muscular strength due to impaired
neuromuscular transmission. There is a predilection
for certain cranial nerves and virtually all patients
complain of ocular symptoms. 80–90% of patients
with the generalized disease have IgG AUTOANTIBOD-
IES against the nicotinic receptors of acetylcholine in
the neuromuscular motor plates.This condition must
be differentiated from myasthenia-like syndromes
due to a pharmacodynamic interference between
the causative drug and acetylcholine. Penicillamine
is the most frequent cause of drug-induced myasthe-
nia [40].Whatever the causative drug, the underlying
mechanism is not known.

Thyroiditis is due to a specific autoimmune
response involving T cells and autoANTIBODIES.Thyro-
peroxidase is the main autoantigen, but thyroglobu-
lin or the thyrotropin receptor can also be the targets
of the autoimmune process [41]. Most often, autoim-
mune thyroiditis presents as a slowly progressing
atrophy of the thyroid gland. Treatments with rIL-2
and the IFNs are associated with a higher incidence
of autoimmune thyroiditis [36].
More than 80% of patients with autoimmune hep-
atitis have hypergammaglobulinemia. The presence
of autoANTIBODIES, such as antinuclear ANTIBODIES,
ANTIBODIES against smooth muscle and liver-kidney
microsomal ANTIBODIES,is common,but their diagnos-
tic value is debatable. Several drugs have been re-
ported to cause hepatitis associated with highly spe-
cific AUTOANTIBODIES in the sera of affected patients
as discussed below [42].
Mechanisms of drug-induced autoimmunity
Overall, our current understanding of the mecha-
nisms involved in drug-induced autoimmunity is
very limited.
Cytokine overproduction
Treatments with recombinant CYTOKINES typically
induce marked cytokine overproduction [43]. One
hypothesis to account for the observed changes in
patients treated with recombinant CYTOKINES is an
abnormal expression of MHC class II molecules
induced by IFN-γ and amplified by IL-1 and TNF-α.
Under the influence of IFN-γ, thyroid cells may
express MHC class II molecules and act as ANTIGEN-
PRESENTING CELLS with the production of antithyroid
AUTOANTIBODIES as a consequence.
Formation of neo-antigens
Drugs or their metabolites can bind to cellular con-
stituents with the ensuing formation of neo-autoanti-
gens.This mechanism has been conclusively shown in
(autoimmune) hepatitis induced by several drugs [42].
Following biotransformation in the liver, metabolites
are formed that bind to CYP isoforms, such as CYP450
Autoimmunity 125
1A2 (dihydralazine), CYP450 4E1 (halothane) or
CYP450 2C9 (tienilic acid). Structural changes in these
hepatocyte constituents trigger a specific immune
response that subsequently leads to liver damage.
Molecular mimicry
Basically molecular mimicry means that part of a
given protein closely resembles a part of another pro-
tein.When a foreign protein penetrates the body, the
immune system mounts a specific ANTIBODY response
and when the foreign protein closely resembles a self
protein of the body, AUTOANTIBODIES are formed that
can be pathogenic [43]. Molecular mimicry is the
causative mechanism of cardiac changes in rheu-
matic fever due to cross-reactivity between strepto-
coccal and cardiac myosin. The involvement of
molecular mimicry in drug-induced autoimmunity is
only assumptive, but a cause for concern during the
development of new vaccines or biotechnology-
derived therapeutic products.
T cell involvement
Because of their pivotal role in immune responses,T
cells are a major focus of current research on auto-
immunity [44]. Recognition of closely similar epi-
topes shared by self and non-self molecules can trig-
ger autoimmune responses due to molecular mimic-
ry or more subtle mechanisms. Activation of T cells
could also be due to drugs mimicking co-stimulato-
ry molecules or MHC class II ANTIGENS that are exquis-
itely involved in the functioning of the IMMUNOLOGI-
CAL SYNAPSE.
Conclusion
HYPERSENSITIVITY and autoimmune reactions are
potentially severe immunotoxic consequences of
drug treatments. Their clinical features are relatively
well known, but much remains to be done to obtain
a clear understanding of the underlying mecha-
nisms. This is, however, a crucial step for designing
relevant tools that are so much needed [45–47] in
order to predict the potential of new drugs for induc-
ing such adverse reactions.
126 Immune response in human pathology: hypersensitivity and autoimmunity
Summary
The immune system is a complex network and
inadvertent immunological reactivity can result in
HYPERSENSITIVITY or autoimmunity. Nearly every
chemical can induce HYPERSENSITIVITY reactions
which can affect nearly every organ or tissue of the
body. One organ or tissue, however, is often a pre-
dominant target.Anaphylactic shock,skin reactions,
and cytopenias are the most frequent reactions.
HYPERSENSITIVITY reactions can be either immune-
mediated or non-immune-mediated (pseudoaller-
gy).A number of different mechanisms are involved
and risk factors can serve as triggers.Autoimmunity
is still a mystery even though autoimmune diseases
are relatively common. Spontaneous autoimmune
diseases as well as drug- and chemical-induced
autoimmune reactions are divided into systemic
and organ-specific. Our current understanding of
the mechanisms involved in these adverse reac-
tions is very limited.
Selected readings
Descotes J (ed.) (2004) Immunotoxicity of Drugs and
Chemicals: An Experimental and Clinical Approach.Vol.
1: Principles and Methods of Immunotoxicology. Elsevi-
er,Amsterdam
Holgate ST, Church MK, Lichtenstein LM (2000) Allergy
(2nd Edition). Mosby, London
Gorski A, Krotkiewski H, Zimecki M (2001) Autoimmunity.
Kluwer Academic Publishers, Dordrecht, Boston
Recommended website
National Institutes of Health (NIH) (1998) Understanding
Autoimmune Diseases: http://www.niaid.nih.gov/
publications/autoimmune/autoimmune.htm (Acces-
sed March 2005)
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