IS IDIOPATHIC PULMONARY FIBROSIS
(IPF) A DUST MITE ALLERGEN-INDUCED DISEASE?
INTRODUCTION
In spite of a substantial progress in
medical sciences during the 20th century the pathogenesis of numerous diseases
remains unknown and their therapy non-existent. Some of these diseases are
terminal and their diagnosis is equivalent to the death sentence. Idiopathic
pulmonary fibrosis (IPF) is one of the diseases with unknown etiology, poor
prognosis, and prevalence rates of 4.6-16.3 cases per 100,000 individuals. In
this manuscript we propose the hypothesis that continuing exposure toward house
dust mite allergen(s) could cause a lung fibrosis resembling the IPF. A timely
identification of factors capable of inducing IPF could lead to the cure of the
disease or control of its progression.
IDIOPATHIC PULMONARY FIBROSIS (IPF)
Pulmonary fibrosis is a pathological
process, usually affecting both lungs, and characterized by excessive
deposition of fibrous connective tissue and collagen in pulmonary interstitial
spaces (1). It is a common feature of various interstitial pneumonias. Correct identification of the cause of
fibrosis determines the prognosis. The
causes have been identified in asbestosis, silicosis, psittacosis or farmer’s
lung. The prognosis of these fibrotic diseases is usually favorable, providing
patients are no longer exposed to the environmental factors that may have
contributed to the disease. The prognosis is poor and the disease is considered
terminal if the cause remains unknown as in the case of IPF. The life expectancy of patients diagnosed
with IPF has been estimated as 2 to 5 years, although some of the patients are
surviving for more than 10 years after diagnosis (2). The existence of slow and
rapidly progressing, as well as familiar and sporadic forms of the disease,
suggests that IPF may not be a single disease. No drugs fo0r the treatment of
IPF have been approved by Food and Drug Administration (FDA) in the United
States of America, although corticosteroids and immunosuppressants are used off-label,
mostly with little or no beneficial effect. Pirfenidone has been approved in Japan and
European Community for the treatment of IPF and various potential antifibrotic
drugs are in preclinical development or clinical trials (3). It is conceivable
that the progressive nature of IPF is due to continuous exposure of patients to
toxins or allergens that may have caused the disease. Misdiagnosis of IPF is
not uncommon. Patients with hypersensitivity pneumonitis, scleroderma, drug
toxicity or other pulmonary diseases have been often referred to pulmonary
clinics for the treatment of IPF (K.C. Meyer, 2012, Personal Communication).
Currently IPF is viewed as a result of interplay of largely unknown genetic and
environmental factors. The genetic factors were identified only in a small
minority of patients (estimated as 2 to 20% of all IPF patients). For instance
genetic defects in surfactant protein A2 have been associated with IPF (4). In
some patients with familial IPF mutations in genes encoding RNA components of
telomerase have been found (5).
HOUSE DUST MITES AND THEIR ANTIGENS
House dust mites (HDM) are arachnids,
related to ticks and spiders. They are 0.5 mm in length and 0.25 mm in width;
they can be barely seen with naked eyes, but can be identified using 100 x or
higher magnification. There are at least
30 different species of HDM: the most
abundant species is Dermatophagoides (D.) pteronyssinus. HDM are present in most homes probably for
centuries, although their existence has not been recognized until 1964. It has
been estimated that up to 500 HDM can be found in one gram of house dust. Their
major source of food is decomposed human or animal skin cells, so that they
thrive near humans in mattresses, carpets, pillows and soft furniture. Since the
discovery of HDM many articles on all aspects of their taxonomy, physiology and
pathology have been published. The most complete source of information on HDM
is the book by M.J. Colloff (6). HDM
have been implicated in the pathogenesis of several, mostly allergic diseases,
including asthma, rhinitis, keratoconjuctivitis and atopic eczema. The role of
HDM in asthma was a subject of International Workshop in 1987 (7). Twenty-one
groups of allergens (2-10 in each group) are known to be produced by HDM and many
of them can be found in their fecal pellets. Most common allergens, Der p 1 and
Der f 1, belong to the Group 1 and are produced by D. pteronyssinus and D.
farina, respectively. Der p 1 was purified and characterized in 1980. It is a
cysteine proteinase that in addition to its allergenic properties, has been
found to disrupt epithelial tight junctions in human pulmonary epithelial cells
in vitro and, therefore, promote crossing of epithelial barrier by allergens (8).
The levels of specific IgG for Der p
1 have been found to be higher in serum of individuals known to be exposed to
HDM than in non-exposed subjects (9).
HYPOTHESIS
HDM allergens cause in sensitive
individuals immediate-type hypersensitivity reaction with production of IgE and
activation of mast cells. We are proposing that in some individuals long-term
exposure to HDM allergens can lead to chronic hypersensitivity pneumonitis that
is often misdiagnosed as IPF. We visualize that long term exposure to HDM
allergens may cause chronic inflammation and fibrosis while immediate-type
hypersensitivity reaction could be suppressed. Our hypothesis is supported by
the fact that dust mites particles smaller that 5µm could reach alveoli (10). Local
inflammation favors the formation of pro-fibrogenic growth factors and
cytokines (TGFβ, IL-1β, IL-4, IL-5, IL-13, IL-25). Our hypothesis is supported
by findings that basophiles, exposed to Der p 1, are known to produce large
amounts of cytokines, such as IL-4, IL-5 and IL-13 (11). Furthermore, Der p 1
disrupts tight junctions in lung epithelial cells in vitro (8), as well as
barrier function of such human surfactant molecules as SP-A and SP-D (12),
effects that can facilitate fibrogenesis and proteolysis of lung epithelial
cells. Der p 1 is also likely to activate fibroblasts and promote formation of
contractile myofibroblasts directly through its specific protease activating
receptors (13), or indirectly through pro-fibrogenic cytokines.
CONCLUSIONS
The progressive nature of IPF, as
compared to pulmonary fibrosis of known etiology, is likely due to chronic
exposure of patients to HDM allergens that caused the disease originally. The
patients develop chronic allergic response leading eventually to massive
irreversible fibrosis and death.
The acceptance of our hypothesis
should lead to a drastic change in the approach to the treatment of patients
with pulmonary diseases of unknown etiology. The patients with idiopathic
non-productive cough and/or suspicion of interstitial pneumonia should be
advised by their primary healthcare providers to consult an allergist to
determine (using skin prick test or blood levels of IgG specific for Der p 1) whether
they are allergic to HDM extract. In case of a positive finding the patients
should be advised to minimize their exposure to the HDM allergens by modifying
their environment. This should include encasing mattresses, box springs and
pillows into allergen-impermeable covers, removal of carpeting, upholstered
furniture, drapes and stuffed toys from their houses, use of only washable bed
sheets and covers, lowering humidity and use of air filters. If these changes
will not lead to a cure or a substantial improvement in patients’ condition,
allergen immunotherapy can be considered (14).
Our hypothesis also points out
additional therapeutic targets for the development of novel drugs for patients
with pulmonary diseases associated with an allergy to HDM extracts. Antibodies
to Der p 1 and/or other HDM allergens as well as Der p 1 – antagonists may be
useful in the treatment of IPF.
SUMMARY
The prognosis of pulmonary fibrosis
is highly dependent on the identification of its cause by health care providers
as well as on patients’ environment and lifestyle. If the cause of the disease
is not identified, patients are diagnosed as having IPF, a terminal disease
with short life expectancy. The pathology of IPF cannot always be clearly
differentiated from that of some of the other lung diseases, including chronic
hypersensitivity pneumonitis. Clinical course of IPF can also differ substantially
in various patients. We are proposing that some patients, currently diagnosed
with IPF, actually suffer from chronic hypersensitivity to dust mite allergens
and that in hypersensitive individuals dust mite allergens can induce the
release of pro-fibrinogenic cytokines, epithelial damage and eventually
fibrosis. This hypothesis leads to new targets and approaches to the therapy of
fibrosis, including avoidance of excessive exposure to dust mite allergens,
therapeutic use of dust mite allergens antibodies and chemical blockade of dust
mite allergens-induced cytokine release.
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