Philip W. Askenase, MD, Chief, Section of Allergy and Clinical Immunology

Yale University School of Medicine

At Brown Medical School, Rhode Island Hospital

Thursday, November 15, 2001, 8:00 AM

ASTHMA: Your mother was wrong: Dirt is good.

IMMUNOPATHOGENESIS OF THE CURRENT ASTHMA EPIDEMIC

A. Introduction

Asthma is a very important subject. It is a chronic immunologic disease of the airways due to inflammation, that results in bronchial airway constriction which impairs breathing. Asthma runs a spectrum from benign, mild, and easily reversible, to severe and fatal. Unfortunately we are in the middle of an epidemic, running over more than 20 years of increasing frequency of asthma, of more severe asthma, and increasingly fatal asthma. In the last several years, two Yale college students, and a baseball pitcher on the New Haven Ravens Professional Baseball Team, that all were supposedly under adequate therapy, died suddenly from asthma.

Asthma is a multifactorial disease with a definite immunological pathogenesis. However, reasons for the recent epidemic are not clear, but hopefully will emerge over the early part of your time in clinical medicine. Asthma has been difficult to exactly define as a disease. Asthma certainly features partial, reversible airway narrowing, that is due to many factors to be discussed. In addition, a characteristic feature of asthma is a hyperreactivity of the airways and airway spasm when challenged directly with various broncho-constrictive agents, like methacholine or histamine, or by mediators released from local allergic and immune cells, or by non-specific irritants derived directly from the environment, such as cigarette smoke.

Very significant has been the emergence over the last several years of data demonstrating that asthmatic airways are the site of significant chronic immune inflammation. Thus, in a sense, asthma can be connected with a rheumatoid arthritis, inflammatory bowel disease, or even multiple sclerosis. Each is a chronic immune inflammatory disease, with each occurring in a different organ system. The definition of asthma often is subdivided into either allergic asthma, in which it has been determined that allergens from diverse sources first induce the allergic asthmatic responsiveness, and then on airway challenge elicit bronchial spasm and airway edema. The basis for the immune inflammation is both IgE antibodies on local mast cells and allergen-peptide specific CD4⁺ T cells. In contrast, for non-allergic asthma, thus far no allergen, no IgE, and no T cell cause has yet to be determined. However, there is similar inflammation, raising the possibility that unknown allergens are responsible.

The essence of asthma can be shown in dose response airway resistance curves of responses to inhaled bronchial constrictive agonists, like methacholine; comparing normals and asthmatics. In normal individuals, it takes high concentrations of methacholine (128 mg/ml) to cause a 20% change in the FEV1, and higher methacholine doses do no more. The FEV₁ is the Forced Expiratory Volume (FEV) in the first second. When abnormal this is a measure of airway narrowing. In contrast, to the normals, in a mild asthmatic, a challenging does of as little as four milligrams per ml (a 32 fold difference) of methacholine produces a 20% change in the FEV₁. Further, in a much more severe asthmatic, concentrations as small as one milligram per ml, in the aerosol of methacholine, causes a 20% change in FEV_1. This represents a 128 fold greater sensitivity to this bronchoconstrictive agonist in the asthmatic airways, compared to normals. Slightly higher does can cause even a 50% fall in FEV₁.

B. The Asthma Epidemic

Asthma is a disease of the industrialized 20^th century, that was first described in the mid 1800s, and may rarely have been present before that. The current asthma epidemic consists of rising prevalence, severity, and deaths from asthma. Currently in the United Kingdom, one in seven children have asthma. In the United States one in three pediatric emergency room visits is for asthma. Currently asthma is the most common chronic disease of childhood in the United States. Notably, this rising severity of asthma is not restricted to children, nor to the UK and the USA, but is widespread. At YNHH we have 1000 pediatric and 1000 adult ER visits for asthma per year. Further, asthma is increased in countries in Scandinavia, beyond the Arctic Circle where little can grow; also in both former East Germany, that recently has been polluted, and in former West Germany that has a far clearer environment, and even in the South Sea Islanders. All are affected in this epidemic. Uniquely in the United States, there is a socioeconomic aspect. Inner city children of lower income in families, predominately are experiencing the epidemic, compared to other countries of the world where in fact well off individuals have a greater prevalence in this asthmatic epidemic. Also in the USA the epidemic is not restricted to the inner cities. Witness the two Yale students above that came from high socioeconomic backgrounds, the New Haven Ravens Pitcher, and much published female teenage model; and the 34 year old Hispanic disk jockey, who all died suddenly.

Thus, the epidemic is world wide. Sadly, at the moment, the cause is unknown. It has been concluded that to have happened this fast it can not be genetic, and therefore that it must be environmental, but we don't know what the environmental causes are. It seems very much to be associated with Westernization or Industrialization. Thus, migrants from under developed areas to the West acquire allergy, and this asthmatic tendency. Similarly when Westernization is brought to non-industrialized areas, it brings allergy, and asthma. Thus, it is a disease of “Western civilization”. There are some reasons for this, that will be brought out. In Finland, there are curves of carefully obtained epidemiological data, gathered by physicians over decades, examining all of the young men entering the military service. These showed the epidemic dramatically in a country that is undoubtedly very different from our own. The data show that the incidence of asthma was negligibly low and steady state between 1920 and about 1960. Then, beginning in 1960, there has been a progressive rise, and not only a rise in the prevalence of asthma per se, shown in the slide with clear squares, but also of disabling asthma; rising from undetectable levels, and shown in the black circles, and also discharges from military service because of asthma, shown in the white circles, and never known before. This is among the best epidemiological data available to document the asthma epidemic. Currently in Finland the incidence of asthma in conscription age men is almost 7%. i.e. 7 out of every 100.

C. An overview of the Immunopathogenesis of Asthma and its Therapy

The next slide is an overview of the immunopathogenesis and the inflammatory factors which promote asthma. This serves as a background for what will be covered subsequently. Genetically disposed individuals who genetically respond to certain sensitizers, that include indoor allergens, such as the mold Altenaria, and house dust mites, make an immune response to these allergens, that features Th2 T Cells, and Th2-dependent IgE. There are certain enhancers of the response, such as rhinoviruses, ozone, diesel particles, and endotoxins (LPS) from bacterial infections that enhance the effects of the Th₂ cells and antibodies, that are interacting with challenging antigens in the airways. This produces inflammation medicated by Th2 T cells, mast cells, and eosinophils. Finally, this process leads to airway hyperreactivity. Importantly, this hyperreactivity is not only to allergens, but also to other seemingly nonspecific triggers; such as exercise and cold air in the world; and to aerosolized histamine, or methacholine in the laboratory; and importantly to passive tobacco smoke. All these can lead to wheezing and promote asthma. On the right hand side of the slide are factors that could reduce these disease-promoting tendencies; including at the top possible avoidance of the allergens, or giving a prophylactic immunization consisting of desensitizing shots of allergen immunotherapy, which we do in the Yale Dana Allergy Clinic. Moving down to the middle, are anti-asthmatics, and avoiding the enhancers, or giving anti-inflammatory drugs, and taking allergen immunotherapy shots. The latter probably also acts at this level as well. Finally, at the level of actual airway constriction, therapy is administered with topical corticosterroids, as a routine measure, and with beta₂ adrenergic receptor agonist inhalers when needed.

D. Important Allergens/Antigens in Asthma

Allergens that induce (sensitize) and then on re-exposure challenge can provoke airway asthma can be divided into those occurring outdoors, or those occurring indoors. The outdoor allergens include the pollens, such as the tree pollens, grass pollens, and ragweed pollen, as well as fungi, molds, weeds (including ragweed), and others. In addition, there are indoor allergens to which we have become much more attuned in recent years, perhaps because we now spend more time indoors (av. 23.5 hrs/day!!), and our houses are more tight to be energy efficient. The indoor allergens include: animal danders, with cat foremost, then dogs and rodents, (mice, rats, rabbits, guinea pigs, hamsters). Another important indoor allergen is house dust mites. These are tiny arthropod creatures that live in and are nourished by the dust. Their released particles, actually mite fecal particles, are aerosolized, then inhaled, and thereafter can readily cause and then later elicit asthma. Finally, and more recently, cockroaches found not only in inner city homes in America, but all over, including the suburbs, also release important allergens in asthma.

House dust mites are very small arthropods. They are invisible to the eye, and live in dust feeding mainly on epidermal sloughing from humans and animals, and produce fecal particles, shown in the upper left of the slide, that are akin to pollen granules in size, density, and shape. The particles become airborne, especially when the dust is disturbed, and eventually are inhaled by all humans. However, only those persons with immune response genes (MHC class II sequences to bind peptides) favoring production of Th2 T cells and then IgE, will respond with asthma, while normal individuals just show signs of immunization, such as specific in vitro T cell proliferation, but no allergy

Other important indoor allergens, are factors derived from cockroaches. This was highlighted in a recent study from Albert Einstein Medical School in the Bronx, documenting high levels of indoor cockroach allergen, and high levels of IgE sensitivity to cockroach, in children with asthma after examining allergen levels in dust samples in 476 children’s bedrooms. Using sensitive immunoassay techniques, cockroach allergen was detected in 85% of bedrooms, house dust mite in 50%, and cat allergen in 62%.

Cat is a most important indoor allergen. The slide emphasizes that the cat dander has nine lives. Thus, long after the cat is gone the dander can still be there as an allergen. Thus, those that are cat allergic need not have a cat to be in trouble. These symptoms can be aggravated rapidly merely by being in a room in which a cat has been for anytime over the last six months. In Scandinavia, it has been found that removal of a cat from the household of an asthmatic child does not eliminate this as a cause of asthma. This is because the child goes to school, and comes in contact with cat allergen on the clothes of other children. Thus, asthma will be provoked by this clothing contamination, necessitating immunotherapy for the child. Among the outdoor allergens, ragweed and grasses are the most common. The slide emphasizes that it is better to have someone else mow your lawn, since that is the most common way to acquire a high dose exposed to grass pollen allergens.

E. The Important Role of I_gE in Allergic Asthma

IgE antibodies are a central cause of allergic disease. The level of IgE in the serum is some what reflective of degree of allergic disease. Roughly 10 to 100 IgE u/ml is normal. Patients with Allergic Rhinitis might have I_gE in the range running from 50 to 1000 u/ ml; with a mean at 300 u/ml. On average, asthma patients have IgE levels running from 200 to 2,000 u/ml. Thus, asthma is a more severe IgE-mediated disease than is allergic rhinitis. The slide also shows Atopic Dermatitis, which is a severe, and more usually childhood allergic skin affliction, has very high serum IgE levels; around ±10,000 u/ml.

A great usefulness today of IgE antibodies lies beyond detecting who is allergic. IgE is a specific probe for the molecular cloning of allergens. Thus, human IgE antibodies can be used as probes in Western blotting, following protein electrophoresis of a given allergen. The example shown was grass allergens on an immuno blot probed with IgE from different patients. The blot shows that most of the patients were highly reactive to a certain protein band in the grass extract. From these data one could then make cDNA from mRNA extracts made from the grasses, and eventually express the product of these genes, so that they then could be screened with patient IgE for encoding specific allergens. Using these methods, allergens are being cloned in many allergies, due to the fact that only certain molecules coming from very diverse biological products like grasses, evoke allergic IgE responses in genetically susceptible individuals.

F. Immunopathogenesis of the asthmatic response.

Understanding the immunopathogenesis of asthma involves focusing not only on the immediate I_gE allergic reaction, but also on the late phase IgE/mast cell-dependent allergic reaction. In the immediate reaction, mast cells are coated with anti-allergen IgE and are challenged with allergen causing release of a variety of mediators that cause immediate bronchial spasm and airway resistance, following allergen challenge. These mediators include histamine, the mast cell proteolytic enzyme tryptase, leukotriene LTC4, and others. In addition, mast cells also release cytokines, among them IL-4, IL-5, and IL-13 that recruit various inflammatory cells, in particular eosinophils. The recruited eosinophils then release their mediators, causing a late phase inflammation, inducing bronchial wall edema, constriction and hyperactivity. These mediators include: eosinophil major basic protein (MBP), eosinophil peroxidase (EPO), eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDN), and very prominently LTC4, a strong broncho constrictor mediator.

In addition, T cells become sensitized upon exposure to the same allergen, and later on local challenge, are recruited to the airways to produce a very similar Th2 cytokine pattern, certainly IL-4, IL-5, and IL-13. The exact balance between the IgE mast cell and the Th2 T cell production of mediators, including Th2 cytokines, is not known exactly in all cases, but it is thought at the moment that both pathway are involved.

A remarkable part of this story is the production of cytokines by mast cells, and also by basophils. This was unknown until several years ago. However, it is now documented that these traditional cells of allergy with IgE Fc receptors (FceR₁), that are able to release immediate-acting histamine and leukotrienes, also produce cytokines with a delayed time course when activated via IgE. The list of cytokines produced by mast cells and basophils is growing. At the moment, at the mRNA level, human mast cells produce TNFa and IL-4. Rodent (mainly mouse), mast cells produce TNFa, GM-CSF, TGFb, interferon-g, MCP-1 MCAF, and IL-1 1, 2, 3, 4, 5, 6, 7, 10 and 13." Further, at the protein level human mast cells have been shown to produce TNFa and IL-4, human basophils TNFa and IL-4, and rodent mast cells produce Interleukins 1, 3, 4 and 6. This is a prodigious production of cytokines by these cells of allergy that usually are thought to participate solely in immediate allergic reactions, but now are recognized to produce various cytokines in the tissues that lead to a late inflammatory reaction. These cytokines characterize the late phase reaction, which is thought to be the very important clinically in allergic asthma, and the target of anti-inflammatory therapy.

The eosinophil is a most important effector cell in these responses. Some histological preparations can show brightly staining unactivated eosinophils in and near the vasculature, while other eosinophils then migrate into the tissues, and histologically stain less well. Electomicroscopy shows these eosinophils have degranulated. These are various properties of post activated eosinophils. The unactivated eosinophils are normally dense eosinophils and thus exhibit normal density. Activated eosinophils sometimes are found in the circulation in severe cases, and are known as hypodense eosinophils, since they develop a lower density after activation via cytokines and other mediators. The participation of of eosinophils in asthma may be related to primordial former anti-parasite responses that no longer are very important in our germ-free and parasite-free America and the Westernized industrialized world. Accordingly, the allergy system probably developed for reacting to ectodermal parasites like ticks, and endodermal parasites like worms. These anti-parasite responses frequently recruit and activate eosinophils to damage the parasites. In the instance of allergy and asthma, eosinophils damage the airways, stimulated somewhat inappropriately by a few pollen granules, or by mite fecal particles; perhaps perceived by the immune system as parasites.

Another important aspect is the histology of fatal asthma. The airway lumen is filled with inflammatory T cells and eosinophils, along with much inspiated mucus. On occasions patients have died of asphyxiation from filling the airways with dense inspisated mucus. In fatal asthma, at the epithelial layer, there are multiple layers of epithelial cells and epithelial goblet cells, probably driven to proliferate by cytokines like IL-4 and IL-13. Also there is a very prominent basement membrane, and underlying collagen layer, with overlying inflammatory infiltrate in which eosinophils again are very prominent. The eosinophils damage the airways at multiple levels. There is epithelial damage due to the release of various eosinophil toxins. Bronchial hyperactivity occurs in part through direct actions of MBP on the airway, and also leukotrienes, and platelet activating factor (PAF) and synergistic activation of nearby mast cells through MBP and EPO, causing mast cells to release their mediators, and via Th2 cytokines, such as IL-13.

G. Role of Th₂ T cells in the pathogenesis of asthma

It is widely known that CD4 T Cells are divided into two prominent subsets called Th1 and Th2, by the profile of cytokines they produce. The Th1 cells produce IL-2 and IFN-g, while Th2 T cells produce IL-4, IL-5, IL-9, and IL-13. Functionally the Th1 cells are concerned with delayed-type hypersensitivity (DTH), mainly via production of IFN-g to activate macrophages to deal with intracellular microorganisms like mycobacteria. In contrast, the Th2 cells are mainly helper T cells, activating B cells for production of immunoglobulins, particularly IgE which is important in allergy and asthma. It is now clear that T cells also are important in mucosal inflammation in asthma. Not only do T cells induce the inflammation of asthma, but they are responsible for induction of airway hyperreactivity, from release of cytokines and inflammatory mediators. Thus, CD4 Th2 cytokines are prevalent in asthma. IL-3 and IL-4 likely induce mast cell proliferation and activation. IL-4 induces IgE B cells, and IL-5 working in concert with IL-3 and GMCS-F induce eosinophil differentiation, endothelial adhesion, survival, and importantly eosinophil activation. IL-13 has important affects on airway mucosa and airway smooth muscle cells; inducing airway hyperreactivity. Thus, Th2 cells are recruited to the mucosal airways. There they are activated by allergen peptide/MHC class II complexes on APC/dendritic cells, and become surface positive for IL-2 receptors (CD25). In humans these activated Th2 T cells also express HLA-DR molecules i.e. MHC class II. In mild asthma the numbers of T cells in the airway are normal, but those that are present are IL-2 receptor positive, suggesting that the Th₂ T cells already are activated. Finally, studies show these T cells are producing cytokines. They are positive for mRNA encoding IL-4 and IL-5 via in situ staining with oligonuleotide probes, and positive for IL-4 and IL-5 protein with mAb histochemistry.

H. Therapeutic use of Corticosteroids in Asthma

The most widely used agent used for asthma is corticosteroids, either systemically in severe cases, or locally i. e. topically by airway aerosol, in milder cases. Steroids have an affect on the diverse cells that are active in asthma. Thus, CD4 T cells have decreased lymphokine production, macrophages have decreased prostaglandin and leukotriene production, and also decreased enzymatic and cytokine release. Mast cells show less proliferation and less cytokine release, and bronchial smooth muscle cells evidence much less beta adrenegic receptor coupling. At the blood vessel level there is decreased permeability. Finally and most importantly, eosinophils are strongly inhibited by corticosteroids, and are decreased in adhesion, chemotaxis, activation, and release of mediators.

Thus, steroids are powerful, and broad spectrum therapeutic reagents that affect cells and mediators at many levels in the asthma syndrome, producing a strong anti-asthmatic effect. Similarly, steroids are the most important drugs in other diseases like rheumatoid arthritis and inflammatory bowel disease, that also feature chronic immunological inflammation. Of course steroids have some serious side effects, making their use the subject of great clinical skill, and significant danger to the patients. However, the development of aerosolized steroids for airway therapy, that do not readily enter into the systemic circulation, has made their use much more common in asthma. Despite the growth of more useful steroids, and wider use of these agents, and also of other agents useful in asthma, we are none-the-less undergoing an epidemic of a great increase in asthma. This makes one think that perhaps there is some defect in our thinking about these therapies. It is possible that somehow this contributes to the illness rather than being so helpful, perhaps by masking symptoms, that yet allows important steroid-resistant aspects to progress. The effect of steroids can be seen in airway function and airway inflammatory cell numbers in subjects newly using aerosolized steroids. Thus, over the first 6 weeks there is a significant fall in asthmatic symptoms, a significant rise in the PC20, which is another function test for airway narrowing, and there are significant falls in local tissue mast cells, eosinophils, and T cells. Thus, these are very powerful and effective agents for the treatment of asthma.

I. Use of Cromolyn in Asthma

Another important agent is disodiumcromoglycate or cromolyn that is a very benign compound with practically no side effects. Unfortunately not all patients are susceptible to its actions. As an aerosol in the airways, cromolyn has been shown to decrease mast cell mediator release, to decrease eosinophil accumulation, and decrease neutrophil activation and accumulation, and decrease macrophage activation, decrease platelet activation, and to decrease the activity of neuromuscular reflexes, and stabilize eosinophils.

J. Pothential Th₁ and Th₂ Imbalances on the Asthma Epidemic (“germ-free influences”)

Returning now to the epidemic, what are some of the factors that could be pushing things towards this great and difficult increase in asthma? Of what I will discuss, nothing is proven. You yourself have the opportunity of entering into this field and coming up with the crucial factors, and thus turning things around. The ideas to be presented here are mere background.

One interesting idea is that in recent years, Western life styles and improved health, and a general lack of Th1 infections, has promoted the occurrence of asthma. The idea is that there is a Th1/Th2 balance. Asthma is a Th2 disease due to promotion of Th2 cells, Th2 inflammation, and help for B cells to produce IgE. In contrast, Th1 cytokines include IL-2, IL-12, TNFa, and IFN-g. They mediate cell mediated immunity and Th1 delayed-type hypersensitivity responses, and simultaneously inhibit Th2 responses. In contrast, Th2 cytokines include IL-4, IL-5, IL-10, and IL-13. They lead to antibody Th2 responses IgE and Th2 inflammation of asthma. Conversely, this Th2 cytokine response reciprocally inhibits Th1 responses. It has been noted that more polluted former Eastern block Europe has a greater rate of childhood infections, that undoubtedly involve Th1 mechanisms, and importantly, there also is less asthma than in the West. The Th1 infections may actually protect from allergy and asthma, which are Th2 responses. Thus, there has been less allergies and asthma in the former Eastern block.

Conversely, it seems that the “germ free”, “cleaner” and more “modern” Western world has more asthma. Thus, the idea has arisen that frequent Th1 infections from more primitive times, can protect against asthma, which is due to Th2 mechanisms, by providing a Th1 cytokine milieu to inhibit Th2 responses. In addition, “improved” “Western” living standards, and recent discarding of some immunizations and vaccinations, plus the overt antibiotic overuse of Westernization, that eliminates routine infections before they can induce a protective Th1 response, and obsession with hygiene, all lower the incidence of potentially asthma-protecting Th1 infections, that could hold back the Th2 allergic asthmatic process. Thus, these factors favor Th2 asthma responses to the allergens that already are in the environment all the time or have been increased by Western ways of living such as: more indoor time, tighter houses, and more pets. Importantly, this unblocked Th2 responsiveness occurs preferentially in those individuals of the atopic genotype that preferentially favor Th2 responses to allergens. Also, there has been a fall in Th1 tuberculosis and tuberculin DTH responses, and a fall of vaccinations, now that we believe we have conquered small pox; all possibly leading to further loss of Th1 protection from Th2 allergic asthmatic responses. Thus, leading to the comment: “give us this day our daily germs”.

An example of these considerations is a recent study of Japanese children treated with mycobacterial BCG (Bacille Calmet Gurein) to prevent tuberculosis. Such a program goes on in many Westernized countries, like Canada, but not the US. In the Japanese study of hundreds of children, the 2/3rds that developed a positive PPD skin DTH response to the immunization, with BCG, which is cutaneous DTH Th1 responsiveness, were compared for allergies to those that did not develop a positive PPD response to BCG. Interestingly, there were significantly more allergies asthma, rhinitis, and allergic eczema in the group of children who received BCG, but did not develop a positive Th1 PPD, compared to those that developed this Th1 response. Thus, a Th1 response occurred in the children who did develop the positive PPD, and they had less allergy and asthma i.e. were protected. Correlating were increased levels of IL-4, IL-13 and decreased IFN-g in the PPD negative, i.e. Th2-reacting, in the allergic and asthmatic group. The bottom line is that individuals that develop a brisk Th1 response to a typical intercellular bacterium like Mycobacteria, may then, and likely previously, produced Th1 cytokines that help repel a Th2 response to ordinary environmental allergens, resulting in a lower incidence of atopic allergic diseases and asthma.

Thus, the hypothesis has been put forth that Th1 infections oppose allergy and asthma. The situation can be viewed as in the slide, a see-saw with Th1 responses at one end (left) and Th2 responses at the other end (right), and in between a fulcrum. The factors opposing atopy and allergies would be: pollution, crowding, vaccinations, and unsanitary conditions and also consequent tuberculosis and viral infections; all stirring up the Th1 side of things, and resulting in Th1 cytokines that inhibit Th2 responses. On the other hand, factors favoring atopy, allergy and asthma are those that are anti-infections, such as a cleaner and more “germ free” environment, and antibiotic overuse, and loss of vaccinations. All of these will favor Th2 responses to existing environmental allergens, by lifting Th1 cytokine inhibition of Th2 cytokine responses.

K. Loss of Parasites and Westernization Favors Allergies and Asthma (parasite-free influences)

A dramatic example of these environmental and immunological considerations in the pathogenesis of allergy and asthma comes from studies of South Sea Islanders. These isolated island pre-industrial people of the Eastern Highlands of Pupua, New Guinea, when "discovered" by Western explorers, lacked virtually everything that “modern civilization” had to offer, including electricity, blankets, television, computers, and video games. Also, they lacked any asthma, and had intestinal helminthic parasites associated with high IgE responses. Because blanket bedding and upholstered furniture were unheard of in Pupuan society, which is the major breeding ground for dust mites these mites did not exist. Taken together, asthma was virtually unknown. However, today with Westernization, the Pupuans have no parasites, and also possess pillows and mattresses and box springs, and of course profuse dust mites, and now have asthma, with an incidence of over 7% (7 per 100 people!!), which is among the highest levels anywhere in the world. In Summary, here is a good example of the price of “progress”, and the problems that can be brought by Westernization, on the incidence and severity of allergic diseases, particularly asthma.

L. Role of Home Dust Mites in the Asthma Epidemic

The above, and numerous observations, lead to the possibility that house dust mites are implicated in the asthmatic epidemic. Certainly warm, moist, humid bedding provides ideal mite culture conditions. Also, because of energy and fuel considerations, modern heated and "tighter" homes, favor the growth of house dust mites. Thus, Japan has gone from traditional Japanese-style homes, that are very bare and well ventilated, to Western style enclosed buildings; favoring mites that cause asthma. On the other hand in Arizona there is marked dry heat and thus poor culture conditions for mites. However, there also is a rise in asthma in Arizona suggesting that other antigens are involved; particularly Juniper tree pollen. Thus, the Th1:Th2 imbalance, and a rise in the environmental allergens, like house dust mites, but not only house dust mites, increase the likelihood of allergic Th2 asthma. Finally, in Sweden at the Arctic Circle, the asthma epidemic progresses at temperatures that do not allow growth of mites. Here the allergens are cat and dog, present in tight homes with pets. Thus, the epidemic is world-wide, in allergic individuals, but importantly to different allergens.

M. Parasite Th2 Responses Block Allergy (more parasite-free influences)

In addition, on a broader, historical biologic prospective, there has been a prior loss of helminth parasite infections in human beings, due to sanitation, with resulting loss of protection from allergies. Thus, in former times, parasitic worm infestation led to anti-parasite IgE and to other IgE antibody responses, that blocked FceR1 on mast cells. This filling up of FceR1 blocks these receptors, leaving little FceR available for the quantitatively far lesser anti-IgE Ab responses to environmental allergens to sensitize the mast cells. Thus, there are no allergies.

Therefore, another important consideration, which may not have been so very important over the last 20 years, is this relationship of helminth parasites to human allergic diseases. It is known that allergy cells, such as mast cells and eosinophils, are elevated in those infested with parasitic worms, that leads to a general Th2 response with production of IgE. It is now established in several instances that these Th2 responses actually mediate immune resistance and rejection to the parasites. One good example is immune resistance to ectoparasitic arthropod ticks, in which IgG1, IgE, and T cells lead to accumulations of basophils and eosinophils, that then degranulate, result in rejection of the ticks. In the case of some helminthic parasite infestations of the GI tract, IgE antibodies saturate mast cells and other cells with Ig FceR1 receptors, also giving some measure of allergy protection. Thus, if FceR1 receptors are full of anti-parasite and associated IgE, then there is no room left for IgE antibodies to environmental allergens. Thus, there will be no allergy.

This indeed has been the observation made in primitive central Amazonian Brazil where natives are infested with GI parasites and have negative skin tests to environmental allergens. In fact their skin mast cells cannot be passively sensitized with anti-ragweed IgE antibody brought from here. As a consequence of this mast cell: FceR1 blockade they have a very low incidence of allergy and asthma. Thus, generally, there are no allergies in the jungle, where there are negative skin tests to environmental allergens. In contrast, the "parasite-free" West, individuals has numerous available mast cell FceR1 for environmental allergen specific IgE bind to, and then subsequently, on allergen challenge, cause symptoms. In summary, a lack of parasites in the sanitary West enhances allergies and perhaps asthma.

N. Summary

In conclusion, the immunopathogenesis of asthma is quite complex, involving IgE, mast cells, and Th2 T cell cytokine mechanisms; acting together. The reactivity is to environmental allergens, principally the house dust mite, and animal to danders and plant pollens. Despite the progress of seemingly effective drug therapy, there has been a growing World wide epidemic of asthma, and of serious asthma, that seems to be associated with Westernization or industrialization, and is due to environmental factors, or “civilized” practices. Some of this increased incidence of asthma and allergies, may be due to a loss of the specific natural infections that promote Th1 immunity, such as tuberculosis, and vaccinia, tipping things further in a Th2 direction, particularly in the allergen-exposed and genetically susceptible individual. Thus, these “natural” Th1 responses probably in former times, inhibited atopic-allergic asthma by inhibiting Th2 responses and IgE. Thus, a loss of Th1 infections has promoted Th2 allergy and asthma, by favoring Th2 immune responses to environmental allergens, like house dust mites, in genetically susceptible individuals. This results in the development of allergies and then asthma. Thus, allergy and asthma can be seen as a disease of civilization, a consequence firstly of sanitation, and loss of parasites, and consequent blocking FceR1 responses; and secondly allergies and asthma arise from the progress toward a germ-free society with loss of protective and counteracting, Th1 responses.