doi: 10.1111/j.1365-2222.2009.03298.

x Clinical & Experimental Allergy, 39, 1145–1151

c 2009

Blackwell Publishing Ltd
OPINIONS IN ALLERGY

Intrinsic asthma: not so different from allergic asthma but driven by

superantigens?
P. J. Barnes
National Heart & Lung Institute, Imperial College London, London, UK

Clinical &
Experimental
Allergy
Correspondence:
P. J. Barnes, Airway Disease Section,
National Heart and Lung Institute,
Dovehouse St, London SW3 6LY, UK.
E-mail: p.j.barnes@imperial.ac.uk
Cite this as: P. J. Barnes, Clinical &
Experimental Allergy, 2009 (39)
1145–1151.
Summary
The mechanisms of intrinsic or non-allergic asthma remain uncertain as allergens have no
obvious role in driving the inflammatory process in the airways. However, IgE synthesis occurs
in the airways, despite negative skin prick tests and serum-specific IgE. Furthermore, the
inflammatory process in the airways is very similar between allergic and non-allergic asthma,
with increased T-helper type 2 (Th2) cells, mast cell activation and infiltration of eosinophils.
This pattern of inflammation is associated with a similar expression of inflammatory mediators,
including Th2 cytokines and eosinophilotactic chemokines. There is increasing evidence that
microbial superantigens, particularly Staphylococcal enterotoxins are important in amplifying
inflammation in atopic dermatitis and chronic rhinosinusitis, in atopic and non-atopic patients.
Superantigens may also be important in intrinsic asthma as airway epithelial cells may be
colonized by Staphylococci and other superantigen-producing microbes. Superantigens
produced locally in the airways may lead to class switching of local B cells, resulting in
polyclonal IgE production in the airways and also specific IgE against the superantigen (which
functions as a ‘superallergen’). This leads to sensitization of mast cells, which can be activated
by the usual asthma triggers, such as exercise. Superantigens also cause clonal expansion of T
cells, resulting in increased Th2 cells and CD81 cells, while suppressing regulatory T cells.
Superantigens may also reduce responsiveness to corticosteroids, resulting in more severe
asthma. Finally, cytotoxic autoantibodies may also be implicated as IgG antibodies directed
against epithelial proteins, such as cytokeratin-18, have been detected in intrinsic asthma,
possibly as a result of epithelial damage and this may make epithelial cells more susceptible to
microbial colonization. The therapeutic implications are that antibodies against local IgE and
microbial superantigens or antibiotic therapy to eradicate the relevant superantigen-producing
microorganisms may improve the efficacy of conventional therapy with corticosteroids.

positivity was less frequent in severe (70%) than in mild

Introduction
There have been major advances in understanding the
molecular mechanisms of atopic (extrinsic) asthma and
other allergic diseases, but relatively little advancement in
our understanding of non-allergic or intrinsic asthma.
Intrinsic asthma is less common than extrinsic asthma,
making up about 10% of all asthmatics. Intrinsic asthma is
defined by a lack of a positive skin prick test (SPT) to
common allergens and a lack of circulating specific IgE.
However, its true prevalence is uncertain as these patients
are overrepresented in specialist clinics because asthma
tends to be more severe and difficult to control. For
example, in a survey of patients with difficult-to-treat
asthma, approximately 30% of patients had negative skin
tests [1] and in a larger group of patients, skin test
or moderate asthma (85%) [2]. It is not certain whether the
prevalence of intrinsic asthma is increasing globally in the
same way as the increase in extrinsic asthma and asso-
ciated atopic diseases, which has been associated with
‘Westernization’ of society. A study in children showed
that asthma prevalence appears to be increasing in non-
allergic more than in allergic asthmatics [3], but whether
this applies to the more typical late-onset non-allergic
asthma of adulthood is unknown.
Clinical phenotypes
The lack of positive skin tests might indicate that the
allergen is unidentified, which may be the case for
certain occupational allergens or fungal allergens [4].
1146 P. J. Barnes

Approximately one-third of asthmatic patients with nega- Table 1. Similarities and differences between extrinsic (allergic) and
tive skin tests have an elevation of total circulating IgE extrinsic (non-allergic) asthma
(4150 U/mL), supporting the view that at least some of the Extrinsic Intrinsic
patients with intrinsic asthma are sensitized to an uniden-
Clinical features
tified allergen [5, 6]. However, sensitization to a single
Skin prick test 1 
allergen is unusual, although patients who are classified as Age of onset Usually early Usually late
non-allergic asthma, who have selective sensitization to Genetics Familial Non-familial
the fungus Trichophyton, have been described [7]. Another Gender Equal Female preponderance
possibility is that skin tests that may have been positive in Exacerbations URTI URTI
childhood have become negative with ageing as intrinsic Allergens 
asthma is usually of late onset (440 years). Triggers Allergen 
Although intrinsic asthma is typically of late onset, it is Exercise Exercise
also sometimes found in children. It is more common in Irritants Irritants
females [as is the case for non-allergic rhinitis (AR) and Rhinitis Common Common
Nasal polyps Rare Common
dermatitis]. It tends to be more severe, requiring higher
Laboratory findings
doses of corticosteroids for adequate control. Anecdotally,
Specific IgE " 
it often starts following a severe upper or lower respira- Total serum IgE " " In 30%
tory tract infection, but patient recall is often unreliable in Airway IgE ( " Ce, Ie) " "
this respect. Clinically, intrinsic asthma behaves very Airway FceRI1ve cells " "
similar to allergic asthma, with variable airflow obstruc- Airway Th2 cells " "
tion and symptoms, symptom relief with bronchodilators Airway eosinophils " "
and a good therapeutic response to corticosteroid therapy, Th2 cytokines " "
even though higher doses may be needed. The triggers for Eosinophil chemokines " "
intrinsic asthma, such as exercise, cold air and inhaled Macrophage IL-10, IL-12 " 
irritants, are the same as in extrinsic asthma, apart from Autoantibodies  "
allergen triggers (Table 1). This strongly suggests that Th2, T-helper type 2 cell; URTI, Upper respiratory tract infection.
mast cell activation is similar between extrinsic and
intrinsic asthma. As in extrinsic asthma, many patients
with intrinsic asthma have concomitant perennial rhinitis mast cells and T cells in the airways (Table 1) [11, 12].
and a high proportion also have nasal polyps and chronic There is an increase in the expression of the T-helper type
rhinosinusitis. Intrinsic perennial rhinitis is well recog- 2 (Th2) cytokines IL-4, IL-5, IL-9 and IL-13, as well
nized, but there is also a non-allergic form of atopic as eosinophil-attracting chemokines CCL11 (eotaxin),
dermatitis with a similar appearance of the skin, but CCL7 (MCP-3) and CCL5 (RANTES) and their common
negative SPT and normal circulating IgE levels [8]. receptor CCR3 [13]. A reduction in the number of cells
Because the original classification of intrinsic asthma expressing the IL-4 receptor in intrinsic compared with
by Rackemann, it has been recognized that there is less extrinsic asthma has been reported and this has been
familial association with intrinsic asthma than with ex- associated with decreased numbers of cells expressing
trinsic asthma [9]. This may be expected in view of the the transcription factor STAT6, whereas GATA3-expres-
strong genetic predisposition to atopy and allergy, but it sing cells are increased in atopic and non-atopic
also indicates that environmental factors may be more asthma [14]. There is an increase in sputum macrophage
important in the causation of intrinsic asthma. numbers in intrinsic and extrinsic asthma patients, with
Aspirin-sensitive asthma constitutes a distinct subset of increased expression of IL-10 and IL-12 only in macro-
intrinsic asthma and these patients often develop asthma phages from allergic compared with non-allergic asth-
symptoms some years after developing rhinitis and nasal matics [15]. Of particular importance, e germline gene
polyps [10]. Aspirin-sensitive asthma appears to be due to promoter (Ie) transcripts and mature mRNA for the e
increased production of cysteinyl–leukotrienes, most heavy-chain gene (Ce) in the nasal and bronchial mucosa
probably from a polymorphism of the cysteinyl–leuko- suggest that local IgE synthesis may occur both in allergic
triene synthase gene, but the reason why a disease with a and in non-AR and asthma [16, 17]. Similarly, high-
distinct genetic predisposition has such a late onset is not affinity IgE receptors (FceRI) are expressed in allergic and
yet understood. non-allergic asthma [18]. Local IgE synthesis has also
been reported in patients with nasal polyps, which are
commonly associated with intrinsic asthma [19]. These
Immunopathology
findings in asthma are paralleled by a similar pathology
The pathology of intrinsic and extrinsic asthma is remark- and cytokine expression profile in allergic and non-AR
ably similar, with an increase in eosinophils, mucosal and dermatitis [8].

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Blackwell Publishing Ltd, Clinical & Experimental Allergy, 39 : 1145–1151

The increased local synthesis of IgE could account for
the similarities in mast cell activation, Th2 cells and the
similar eosinophilia between intrinsic and extrinsic atopic
diseases. While the inflammation in extrinsic disease is
driven by external allergens, such as house dust mite and
cat dander interacting with high- and low-affinity IgE
receptors, in intrinsic disease, there is no identified aller-
gen, although local IgE and high-affinity FceRI are
expressed. This suggests that an unidentified exogenous
antigen (without systemic sensitization), an infective
agent or an endogenous ‘allergen’ may be responsible for
activating the cellular machinery of atopy. Mast cell
activation is common to extrinsic and intrinsic asthma
and probably accounts for the clinical similarities of these
diseases with symptoms produced by several triggers,
such as exercise and cold air, which activate sensitized
mast cells with bound IgE.
Infections
While it is now well established that upper respiratory
tract virus infections are the most common cause of acute
exacerbations in allergic and non-allergic asthma [20],
the role of infections in driving or amplifying chronic
inflammation in asthma is less certain. A possible me-
chanism of intrinsic asthma is the development of IgE
antibodies to epitopes expressed by infectious agents.
There is some evidence that colonization of the airways
with atypical organisms, such as Chlamydia (Chlamydo-
phila) pneumoniae and Mycoplasma pneumoniae, is asso-
ciated with more severe asthma; this appears to apply to
both allergic and non-allergic asthma. This area is con-
troversial as these organisms are difficult to identify and
there are disagreements over the use of PCR and anti-
bodies to detect ongoing infection and on interpretation
of therapeutic trials with macrolide antibiotics, which
may have anti-inflammatory effects [21]. It is unlikely
that chronic colonization with these organisms per se
could account for intrinsic asthma, but it may be an
exacerbating factor as in extrinsic asthma. Specific IgE
antibody responses and increased IL-4 production in
response to M. pneumoniae infection have been described
[22, 23].
Staphylococcus aureus is thought to be an important
amplifying mechanism in allergic and non-allergic atopic
dermatitis and chronic rhinosinusitis with nasal polyps,
but might also be important in asthma [24, 25]. S. aureus
is able to invade epithelial cells and release its enterotox-
ins (exotoxins), which function as superantigens that have
the capacity to stimulate T and B cell proliferation directly.
They are also able to induce class-switching to IgE and the
production of allergen-specific IgE in mucosal B cells.
Specific IgE antibodies against Staphylococcal enterotox-
ins (termed ‘superallergens’) have been found in patients
with severe asthma, aspirin-sensitive asthma and nasal
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Blackwell Publishing Ltd, Clinical & Experimental Allergy, 39 : 1145–1151
Intrinsic asthma 1147
polyposis and are able to sensitize mast cells and dendritic
cells [26–28]. S. aureus is also capable of invading mast
cells and causing the release of cytokines [29]. It is there-
fore possible that patients with intrinsic asthma may in
some way be susceptible to colonization of the lower
airways with S. aureus, which, through the local released
of superantigens, drives an allergic inflammatory re-
sponse and local IgE formation, which is associated with
more severe asthma as the anti-inflammatory response to
corticosteroids is reduced. It is also possible that S. aureus
superantigens lead to chronic rhinosinusitis, which then
affects the lower respiratory tract without the need for
direct infection of the lower airways.
Superantigens
Superantigens are derived not only from Staphylococcal
species but also other bacteria (including Mycoplasma),
viruses, parasites and fungi, and all of them are immu-
nostimulatory, acting as Vb-restricted extremely potent
polyclonal T cell mitogens [30]. They bind major histo-
compatibility complex (MHC) class-II molecules without
any prior antigen processing by antigen-presenting cells
and stimulate large numbers of T cells on the basis of
epitopes specified by this receptor through their unique
ability to cross-link MHC class II and the b subunit of the T
cell receptor (TCR), forming a tight trimolecular complex.
They also appear to cause class-switching in B cells by
binding to Ig, resulting in clonal expansion and expres-
sion of polyclonal IgE and specific IgE directed against
the superantigen. Some superantigens may even become
incorporated into the genome and may thus provide
continuous endogenous stimulation [30].
In mice, nasal and inhaled Staphylococcal enterotoxin
B (SEB) induces lymphocytic inflammation and eosino-
philia in the lungs with increased production of IL-4,
together with airway hyperresponsiveness in both IgE-
and non-IgE-producing strains, demonstrating the capa-
city of superantigens to induce allergic inflammation
independent of any allergen [31]. Inhaled SEB also en-
hances the eosinophilic inflammatory response to inhaled
allergen in sensitized mice [32]. Similar experiments with
Staphylococcal enterotoxin A result in lung inflammation
characterized by increased CD81 cells and increased
secretion of IFN-g [33]. These animal studies demonstrate
the ability of small concentrations of locally applied
superantigens to induce complex inflammatory responses
in the lungs and suggest a mechanism for intrinsic or non-
allergic asthma. Inhaled bacteria may invade airway
epithelial cells and result in the release of various super-
antigens, which may directly activate Th2 cells to release
IL-4 and other Th2 cytokines, as well as causing class-
switching of B cells in the airways to release IgE locally,
which then sensitizes mast cells so that they are more
easily activated (Fig. 1). SEB stimulates the release of
1148 P. J. Barnes

several cytokines with a Th2 cell bias, as well as mast cell
mediators from nasal polyp tissue in vitro and to a greater
extent than from normal nasal tissue, indicating some sort
of sensitization to the effects of superantigens [34].
Some evidence for the superantigen mechanism is
provided by the overabundant use of certain IgE-heavy
chain variable regions (VH) such as the VH5, which are
known to be expanded by superantigens, in bronchial
biopsies of asthmatic patients and nasal biopsies of
patients with AR [35, 36]. However, such studies have not
yet been reported in non-allergic asthma and rhinitis.
There is evidence for local clonal expansion of airway T
cells in patients with intrinsic asthma compared with
circulating T cells, suggesting that this could be induced
by local superantigens [37].
Staphylococcal superantigens also inhibit the immuno-
suppressive activity of regulatory T cells (Treg) and may
therefore amplify the activity of Th2 cells and CD81 cells
[38]. SEB inhibits CD41CD251 Tregs by inducing the
protein glucocorticoid-induced TNF receptor-related pro-
tein-ligand in monocytes [39]. Superantigens have also
been shown to induce corticosteroid resistance by activat-
ing mitogen-activated protein (MAP) kinase cascades and
through the increased expression of a form of the gluco-
corticoid receptor GRb, which may block the action of
corticosteroids [40]. Finally, SEB has recently been shown
to stimulate Th17 cells, which may be important in
driving neutrophilic inflammation in more severe asthma
[41, 42].
Autoimmunity
Another possible mechanism of activating IgE signalling
without an exogenous allergen may be the production of
autoantibodies that activate this pathway. This would also
be consistent with the fact that intrinsic asthma has a late
onset and is more frequently seen in women. Anti-nuclear
antibodies are more common in patients with asthma than
non-asthmatics, but there is no difference between aller-
gic and non-allergic asthmatics, although patients with
aspirin-sensitive asthma have a higher frequency of these
antibodies [43]. However, there is no increase in auto-
antibodies against double-stranded DNA or anti-neutro-
phil cytoplasmic antibodies in asthma. Autoantibodies to
FceRI have been detected in the serum patients with
asthma (35% compared with 10% in non-asthmatics),

S. aureus

Epithelial damage exposes

Epithelial cells
cytokeratin-18 leading to
IgG autoantibodies
Sag
IgE switching
-
B cell T cell Clonal
expansion Treg Th17
IL-4
Y Y IL-13 -
IgE Y -
Sag
Y YYY IL-4 Th2
Fc RI CD8 +

Mast cell IL-5

Bronchoconstriction

Eosinophils Neutrophils
Fig. 1. Possible microbial mechanism of intrinsic asthma. Invasion of airway epithelial cells by Staphylococcus aureus (and other microorganisms)
causes the release of Staphylococcal superantigens (Sag) (and other superantigens), which act on airway B lymphocytes to cause class-switching with
the local production of polyclonal IgE, together with IgE directed against SSa (which acts as a ‘superallergen’). This causes mast cell activation and
release of bronchoconstrictor mediators and sensitizes mast cells to activation by triggers, such as exercise and cold air (via changes in surface
osmolality). SSa also cause polyclonal expansion of T cells, resulting in increased T-helper type 2 (Th2) cells and CD81 cells. Th2 cells release IL-9, which
induces the expression of high-affinity IgE receptors (FceRI) in mast cells and IgE synthesis by B cells (together with IL-13). IL-5 promotes eosinophilic
inflammation. SSa may also reduce corticosteroid responsiveness in T cells, resulting in the need for higher doses to control asthma. SSa also inhibit the
function of regulatory T cells (Treg), resulting in further enhancement of Th2 and CD81 cells. SSa may also activate Th17 cells, leading to neutrophilic
inflammation. Staphylococcal infection of epithelial cells may also lead to damage and exposure of epitopes on epithelial structural proteins, such as
cytokeratin-18, resulting in the formation of cytotoxic IgG antibodies, which further damage epithelial cells, making them more susceptible to further
microbial colonization.

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Blackwell Publishing Ltd, Clinical & Experimental Allergy, 39 : 1145–1151

but do not appear to be more common in intrinsic
compared with extrinsic asthma [44]. Circulating antibo-
dies to cytokeratin-18 and a-enolase, which occur in
epithelial cells, have been described in patients with
intrinsic asthma and more severe asthma [45, 46]. IgG
autoantibodies from patients with intrinsic asthma have
recently been shown to have cytotoxic effects on epithe-
lial cells, whereas these antibodies are not found in
extrinsic asthma [47]. It is possible that these autoanti-
bodies damage airway epithelial cells so that superanti-
gen-producing organisms are able to infect the airway
surface more easily.
Therapeutic implications
The clinical management of intrinsic asthma is similar to
that of allergic asthma, with inhaled corticosteroid as the
mainstay of therapy with the addition of long-acting
inhaled b2-agonists if this is insufficient to control symp-
toms [48]. Patients with intrinsic asthma are usually more
severe and require higher doses of inhaled corticosteroids
to control symptoms, which may reflect the fact that there
may be a degree of corticosteroid resistance as a result of
superantigen exposure and activation of MAP kinase
pathways [40]. Anti-IgE therapy with omalizumab may
be indicated for patients with severe allergic asthma who
are not controlled with maximal inhaled therapy or who
require oral steroids, but is not indicated for intrinsic
asthma [49]. However, the demonstration that intrinsic
asthma is associated with local IgE production suggests
that anti-IgE strategies may be appropriate in intrinsic
asthma. So far, there are no trials of omalizumab in
patients with intrinsic asthma. It is possible that inhaled
omalizumab, which is ineffective in extrinsic asthma [50],
might be effective in patients with intrinsic asthma.
If superantigens are involved in the pathogenesis of
intrinsic asthma, measures to eradicate microorganisms
such as S. aureus might be effective. The role of antibiotic
therapy in asthma is uncertain, with variable results with
macrolides and no consistent studies with antibiotics
against Gram-positive bacteria. Another approach may
be to neutralize the effect of superantigens such as
Staphylococcal enterotoxins with specific antibody ther-
apy. Intravenous immunoglobulin (IVIG) has been used in
the treatment of toxic shock syndrome associated with
Staphylococcal enterotoxins [51]. IVIG has been reported
to be effective in some patients with severe asthma,
although this has been disputed in controlled trials [52].
However, IVIG has not specifically been studied in pa-
tients with intrinsic asthma. As discussed above, auto-
antibodies to epithelial proteins have been reported and so
the use of immunosuppressants, such as cyclosporine,
may be indicated. Cyclosporine has been disappointing in
the treatment of asthma in non-selected patients with
severe disease [53], but perhaps might be more effective in
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Intrinsic asthma 1149
patients with intrinsic asthma. Inhaled immunosuppres-
sants, such as cyclosporine or tacrolimus, might also be
effective, with a lower risk of adverse effects. Several new
treatments for severe asthma are currently in develop-
ment, including cytokine inhibitors, chemokine receptor
antagonists and kinase inhibitors, which presumably
would be as effective in intrinsic as in allergic asthma [54].
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