They come not single spies, but in battalions. The latest research helps explain why an individual may experience the 'atopic march' from one allergic disorder to another.
Animal dander was the culprit in my first asthmatic trauma. On a childhood sleepover, I was sharing my friend's spare bed with her cat. Its hair was all over my pillow. Far too shy to complain, I remember trying to breathe shallowly, in a vain effort to avoid inhaling the essence of cat from the bed. Not until three in the morning, face swollen and airways inflamed to the point that I could hardly breathe, did I finally gather the courage to wake my friend's parents. That night ended with hospital-administered inhalant bronchodilators and a good dose of antihistamines. But my lifelong struggle with allergic disorders and hyper-reactivity continues.
My mother, herself allergy-prone, remembers my inflamed and itchy skin lesions in infancy. These are classic symptoms of atopic eczema, better known in the United States as atopic dermatitis. Then, in my toddler years, as my father recounts, I started to show “this peculiar reaction” around animals, scratching at my throat as my eyes went red, watery and swollen. These typical symptoms of allergic rhinitis, or hay fever, owe their origins to human immune-system responses to specific protein allergens, for example those found in animal dander.
An allergy-prone child is likely to demonstrate sensitization to various allergens within the first few years of life. The sensitization phase takes place as the body gradually mounts an immune response to foreign substances introduced through the respiratory tract or through skin that lacks natural barrier functions, although the response can become systemic. In my case, for example, it may have been sensitization by way of my skin that led to my lungs becoming sensitized to inhaled allergens.
The mechanism of sensitization is dominated by Th2-type inflammation, in which T-helper type-2 (Th2) cells, a subgroup of white blood cells, produce cell-signalling proteins called cytokines that drive the allergic response (see 'Breathing new life into research', page S20). Exposure to an allergen causes another subgroup of white blood cells, activated by these Th2 cytokines, to produce specific immunoglobulin E (IgE) antibodies. These antibodies then bind to circulating white blood cells known as basophils, and to mast cells (similar to basophils but found mainly in connective tissue), priming them to release inflammatory mediators such as histamine upon re-exposure to the original allergen or structurally similar proteins.
Watermelons and eczema
For the past decade, from my teens to mid-twenties, my life has been plagued by allergic asthma. Perhaps more frustrating and stressful has been an explosion in my food allergies and chronic allergy-related atopic dermatitis, causing discomfort, sleeplessness caused by scratching, and skin abnormalities. “Make a note on her chart, displays symptoms characteristic of an atopic individual,” said my dermatologist, Mary Dobson, when I visited her clinic in Baton Rouge, Louisiana, for a particularly severe flare-up.
Atopy is the tendency to be hyperallergic, the genetic propensity to mount an IgE response to triggers including pollen, animal dander and food-based allergens. Thomas Platts-Mills, head of asthma and allergic disease at the University of Virginia in Charlottesville, describes the atopic individual of today as one who is 'better' at recognizing small quantities of foreign protein and reacting to it: “allergies are the price we pay for an immune system that protected us against big killers in the past”, he says.
Sometimes I feel like a walking illustration of the atopic march. This term describes a progression of allergic diseases through childhood into adulthood, and it involves a diverse interplay of factors. Some of these are genetic: variations or mutations in the genes controlling important constituents of the immune system or skin integrity. Others are environmental: allergen exposure, early-life infections, pollution and chemical irritants that break down the skin barrier and promote allergen sensitization1.
Atopic diseases now affect up to 20% of the population in developed countries2. Individuals with one atopic disease are more likely to develop a second or third atopic disorder, with many suffering from the 'triad' of atopic dermatitis, allergic rhinitis and asthma: a 2004 study by Donald Leung, head of paediatric allergy and immunology at National Jewish Health in Denver, Colorado, and colleagues, showed progression occurring from atopic dermatitis to allergic rhinitis in up to 75% of patients, and to asthma in 50%. And, although food allergies might seem to be completely different phenomena from this triad, many of the same mechanisms mediate these disorders as well.
When I started looking into my own food allergies, for instance, which involve strong inflammatory reactions to a range of fruits and vegetables including apples, cherries, kiwis, bananas, carrots, pineapples, tomatoes and even watermelon, I found out that they are probably due to a cross-reactivity phenomenon known as the pollen–food allergy syndrome.
Certain pollen proteins, including ragweed allergens and the birch pollen allergen Bet v1, are common causes of allergic rhinitis and asthma. They are also common inducers of allergic sensitization to particular fruits and vegetables, in those of us with pollen–food acquired immunity dominated by the IgE antibody response (rather than the IgG4 response, which favours food tolerance)3. Sensitization occurs because of immunological cross-reactivity between the pollen allergen and structurally related food proteins, such as the apple protein Mad d1. The recognition of food proteins by pollen-specific IgE antibodies can then lead to IgE-mediated reactions including inflammation and itching of the mouth, as well as late-phase Th2 inflammatory responses such as atopic dermatitis.
The pollen–food allergy syndrome provides one link between the various manifestations of allergy. Another lies in the condition of the skin, the first line of defence against infections and allergens. It has long been hypothesized that skin barrier abnormalities and hydration impairments, such as various dry skin conditions, might have systemic consequences for allergen sensitization and inflammation (see 'Into the breach', page S12). The inflamed and broken skin characteristic of atopic dermatitis aids contact between environmental allergens and the immune cells that initiate and sustain Th2 pathway responses.
It sometimes seems that my skin is providing less of a barrier to the outside world than it should. I tend to have dry skin, and even tiny nicks on my legs, hands and feet can turn into chronic lesions. My more severe atopic dermatitis flare-ups seem to be closely linked to my food allergy symptoms, and to subsequent bouts of worsened asthma. But what molecular mechanisms underlie my symptoms?
“The common disease features of the allergic diseases that comprise the 'atopic march' strongly suggest a common underlying mechanism,” says Steven Ziegler, head of immunology at Benaroya Research Institute in Seattle, Washington. Ziegler's group, as well as other groups, has identified high levels of one important protein of the cytokine family, called thymic stromal lymphopoietin (TSLP), as a likely common factor. “TSLP expression is elevated in humans with these diseases, as well as in mouse models, and blocking TSLP can prevent disease in these mouse models,” explains Ziegler.
TSLP is highly expressed by the outermost skin cells in atopic dermatitis lesions, especially chronic lesions. When expressed in high quantities, it has been shown to promote local environments dominated by Th2-type inflammation. A 2007 study also showed that TSLP is released from human epithelial cells in response to infections and physical trauma4. So the explanation for accidental breaks in my skin turning to atopic dermatitis may be that the TSLP protein is mediating a Th2 inflammatory response initiated by the mechanical injury.
Studies using mouse models have also shown an association between TSLP expression by cells at barrier surfaces, including the skin, gut and lung, and more basophils in the spleen, blood, lung and bone marrow where blood-circulating basophils mediate systemic Th2-type allergic responses. Earlier this year, Mark Siracusa, an immunologist at the University of Pennsylvania in Philadelphia and colleagues showed that such TSLP-mediated increases in basophil activity led to a body-wide elevation of IgE levels and allergic inflammation in mice5. Moreover, they showed that TSLP-elicited human basophils differ from healthy basophil populations in the ability to create a state of systemic susceptibility to Th2 inflammation.
What these results indicate is that abnormal TSLP production at one barrier surface can trigger the proliferation, mobilization and activation of immune system cells that promote allergies throughout the body. This might help to explain why the exposure of cells lining my gut (a barrier surface) to a food allergen such as watermelon might be linked to worsening of my eczema symptoms, and why a flare-up of my eczema (at another barrier surface) might aggravate my asthma symptoms.
TSLP is now a therapeutic target. Michishige Harada, of the laboratory for respiratory diseases at Institute of Physical and Chemical Research in Japan, and colleagues had already revealed in 2009 that a particular genetic variant of TSLP leads to increased protein expression, for example in response to viral respiratory infection. This discovery, pointing to TSLP as a genetic orchestrator of the atopic march, was reinforced by further studies from the same group, published in 2011, which established long-form TSLP gene variants as factors of susceptibility to atopic asthma6. Based on these studies and others, establishing TSLP as a major causative factor of atopic march disease progression, Ziegler says there is now an anti-TSLP drug in phase II clinical trials.
“With no pharmacologic cure for asthma in sight, there is a need for drugs which can halt the atopic march,” says Leung. He believes that the current scientific data strongly support the use of systemic anti-TSLP drugs as an intervention strategy. Although it is too late to save me from my sleepover trauma, the parents of children with early signs of atopy should be watching with the keenest of interest.