Rethinking Asthma

Not all asthma is the same. Sure, many of the symptoms are the same, such as chest pains, trouble breathing, and coughing. But underneath it turns out things are more complicated than we thought.

Nearly twenty-five million people have asthma in the United States alone, but for how common it is we know surprisingly little about the biology behind the disease. That’s starting to change. At Genentech, our scientists have been researching serious respiratory diseases for more than 25 years, and we’ve recently come across some new insights that are changing our perception of asthma.

We now know that asthma comes in different varieties, and we’ve identified some of the players behind it. By understanding how these players interact with each other, we may be able to tailor treatment options for particular types of asthma.

Not All Asthma is Created Equal

At its root, asthma is manifested by the intermittent narrowing of peoples’ airways. Environmental factors like dust, pet allergens, and mold can trigger asthma attacks. In many patients, increased and inappropriate activation of the immune system in response to these environmental factors may contribute to symptoms.

One type of immune cell, called T-helper cells (Th cells), helps organize our immune system to fight off pathogens. But when Th cells become inappropriately activated, they can contribute to inflammatory diseases like asthma. Th cells have many different roles in the immune system, and therefore come in different types.

Small proteins, called cytokines, are produced by different types of Th cells. One kind, called Th2 cells (T-helper 2 cells) is characterized by the production of a cytokine called interleukin 13, or IL-13, which is evolutionarily important for fighting off parasites. There is also increasing evidence that IL-13 can come from many different types of immune cells beyond Th2 cells. For decades, inappropriately high levels of Th2 activity (Th2-high) were thought to be the cause of inflammation in asthma. But a recent voyage of discovery in our labs has discovered a much more complex story.

We began by examining what genes were activated in airway tissues from people with asthma to see if the standard “Th2-high” model of asthma would hold up. Although many people with asthma do indeed have high levels of IL-13 and Th2-related inflammation, we identified a similarly-sized subset of people with asthma who actually had low levels of IL-13 and Th2-related inflammation (Th2-low). Clearly, the “Th2-high” theory didn’t apply to everyone.

"By challenging the commonly held belief that all asthma is the same, we have opened up new approaches to identify and treat this disease"

So we took a closer look at Th2-low patients, and found yet another surprise: some of the people with low Th2-levels had high levels of an entirely different type of T-helper cell. These cells, called Th17 cells (Th17-high), are defined by the activity of a different cytokine called IL-17, which is important for fighting off fungal and bacterial infections. This suggested that Th2 and Th17 could be used to develop biomarkers for different types of asthma, which could help us identify the right treatment option for the right patient.

One Goes Up, One Goes Down

As we continued our genetic hunt, we began to wonder whether IL-13 and IL-17 might actually be affecting each other. We noticed that tissues from asthma patients never had evidence for high activity of both Th2 and Th17 cells at the same time. In fact, cytokines like IL-13 in Th2-high asthma seemed to block the expression of genes normally associated with Th17 cells, while people with Th17-high asthma had low levels of genes associated with Th2 cells.

A clue to this puzzle comes from how asthma is managed today. Currently, some of the most commonly prescribed medicines for asthma are inhalers containing a type of steroid called glucocorticoids. While glucocorticoids help most asthma patients, some patients who use steroids for a long time redevelop asthma symptoms, but we didn’t really know why. Glucocorticoids may work in part by suppressing Th2 activity, but Th17 cells are notoriously resistant to glucocorticoids. When we examined airway tissues of Th2-high patients that had asthmatic symptoms despite treatment with glucocorticoids, our researchers found that some of them now had high levels of Th17-related genes. Essentially, by treating Th2-high patients with glucocorticoids we may actually have been promoting another distinct form of asthma.

Looking Ahead

We hope that by challenging the commonly held belief that all asthma is the same, we have opened up new approaches to identify and treat this disease that affects so many people around the world. Our research has shown that asthma comes in different forms and supports the use of biomarkers to develop medicines from multiple angles in order to help a diverse patient population. `QED Mark`

Read our accompanying story “Mapping Asthma” for further background.

Read more about these important findings in the following papers from Genentech scientists:

Science Translational Medicine. "TH2 and TH17 inflammatory pathways are reciprocally regulated in asthma"

American Journal of Respiratory and Critical Care Medicine. "T-helper Type 2–driven Inflammation Defines Major Subphenotypes of Asthma"