Sunday, April 21, 2013


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.

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 (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).

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.

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.

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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