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

Summary
Clinical & The mechanisms of intrinsic or non-allergic asthma remain uncertain as allergens have no
Experimental 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
Allergy 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.
Correspondence: Superantigens may also reduce responsiveness to corticosteroids, resulting in more severe
P. J. Barnes, Airway Disease Section, asthma. Finally, cytotoxic autoantibodies may also be implicated as IgG antibodies directed
National Heart and Lung Institute,
against epithelial proteins, such as cytokeratin-18, have been detected in intrinsic asthma,
Dovehouse St, London SW3 6LY, UK.
E-mail: p.j.barnes@imperial.ac.uk
possibly as a result of epithelial damage and this may make epithelial cells more susceptible to
Cite this as: P. J. Barnes, Clinical & microbial colonization. The therapeutic implications are that antibodies against local IgE and
Experimental Allergy, 2009 (39) microbial superantigens or antibiotic therapy to eradicate the relevant superantigen-producing
1145–1151. microorganisms may improve the efficacy of conventional therapy with corticosteroids.

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

Introduction
or moderate asthma (85%) [2]. It is not certain whether the
There have been major advances in understanding the prevalence of intrinsic asthma is increasing globally in the
molecular mechanisms of atopic (extrinsic) asthma and same way as the increase in extrinsic asthma and asso-
other allergic diseases, but relatively little advancement in ciated atopic diseases, which has been associated with
our understanding of non-allergic or intrinsic asthma. ‘Westernization’ of society. A study in children showed
Intrinsic asthma is less common than extrinsic asthma, that asthma prevalence appears to be increasing in non-
making up about 10% of all asthmatics. Intrinsic asthma is allergic more than in allergic asthmatics [3], but whether
defined by a lack of a positive skin prick test (SPT) to this applies to the more typical late-onset non-allergic
common allergens and a lack of circulating specific IgE. asthma of adulthood is unknown.
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 Clinical phenotypes
example, in a survey of patients with difficult-to-treat The lack of positive skin tests might indicate that the
asthma, approximately 30% of patients had negative skin allergen is unidentified, which may be the case for
tests [1] and in a larger group of patients, skin test 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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 Intrinsic asthma 1147

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

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1148 P. J. Barnes

several cytokines with a Th2 cell bias, as well as mast cell through the increased expression of a form of the gluco-
mediators from nasal polyp tissue in vitro and to a greater corticoid receptor GRb, which may block the action of
extent than from normal nasal tissue, indicating some sort corticosteroids [40]. Finally, SEB has recently been shown
of sensitization to the effects of superantigens [34]. to stimulate Th17 cells, which may be important in
Some evidence for the superantigen mechanism is driving neutrophilic inflammation in more severe asthma
provided by the overabundant use of certain IgE-heavy [41, 42].
chain variable regions (VH) such as the VH5, which are
known to be expanded by superantigens, in bronchial
Autoimmunity
biopsies of asthmatic patients and nasal biopsies of
patients with AR [35, 36]. However, such studies have not Another possible mechanism of activating IgE signalling
yet been reported in non-allergic asthma and rhinitis. without an exogenous allergen may be the production of
There is evidence for local clonal expansion of airway T autoantibodies that activate this pathway. This would also
cells in patients with intrinsic asthma compared with be consistent with the fact that intrinsic asthma has a late
circulating T cells, suggesting that this could be induced onset and is more frequently seen in women. Anti-nuclear
by local superantigens [37]. antibodies are more common in patients with asthma than
Staphylococcal superantigens also inhibit the immuno- non-asthmatics, but there is no difference between aller-
suppressive activity of regulatory T cells (Treg) and may gic and non-allergic asthmatics, although patients with
therefore amplify the activity of Th2 cells and CD81 cells aspirin-sensitive asthma have a higher frequency of these
[38]. SEB inhibits CD41CD251 Tregs by inducing the antibodies [43]. However, there is no increase in auto-
protein glucocorticoid-induced TNF receptor-related pro- antibodies against double-stranded DNA or anti-neutro-
tein-ligand in monocytes [39]. Superantigens have also phil cytoplasmic antibodies in asthma. Autoantibodies to
been shown to induce corticosteroid resistance by activat- FceRI have been detected in the serum patients with
ing mitogen-activated protein (MAP) kinase cascades and 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
 Intrinsic asthma 1149

but do not appear to be more common in intrinsic patients with intrinsic asthma. Inhaled immunosuppres-
compared with extrinsic asthma [44]. Circulating antibo- sants, such as cyclosporine or tacrolimus, might also be
dies to cytokeratin-18 and a-enolase, which occur in effective, with a lower risk of adverse effects. Several new
epithelial cells, have been described in patients with treatments for severe asthma are currently in develop-
intrinsic asthma and more severe asthma [45, 46]. IgG ment, including cytokine inhibitors, chemokine receptor
autoantibodies from patients with intrinsic asthma have antagonists and kinase inhibitors, which presumably
recently been shown to have cytotoxic effects on epithe- would be as effective in intrinsic as in allergic asthma [54].
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-
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