In a previous post, I discussed “The basics of neutrophilic asthma.” In this post, I would like to delve into the complex world of genes and biological pathways responsible for this rare asthma subgroup. Yes, this kind of stuff can get very complex. But it’s important we understand this stuff because it’s where any future treatment options and “potential cures” will come from. I promise to keep this simple.
Here we go!
What biological processes are involved?
It all begins with asthma genes or genes that tell cells to do something abnormal to cause asthma. In our case, it involves specific asthma genes responsible for increasing a person’s susceptibility to developing neutrophilic asthma. I will list some of the genes suspected of being responsible for neutrophilic asthma below. (You do not have to memorize them: there will be no test).
The purpose of the immune system is to trap, kill, and remove pathogens from our body during infections. When a pathogen infects the airways, for example, the immune cells release inflammatory markers such as histamine, leukotrienes, and cytokines. Some of these directly cause airway inflammation, although others circulate through the bloodstream to recruit other immune cells to the lungs.
Mast cells are the most common immune cells that release inflammatory markers during the asthma response. They are randomly scattered along the respiratory tract. Other immune cells recruited to the lungs during the asthma response and that secrete mediators include neutrophils, macrophages, and T-helper cells.
A theory explaining neutrophilic asthma is that certain asthma genes encode (produce, make) too many inflammatory markers responsible for the activation and recruitment of neutrophils to lung tissue. When in excess, they do more harm than good. In our case, they cause severe asthma.
That said, here are some of the genes, mediators, and immune cells thought to play a role in neutrophilic asthma.
Leukotriene B4 (LTB4)
It’s a leukotriene encoded by the LTB4 gene, so a mutation in this gene may cause an increase in LTB4.1 It’s released from mast cells, neutrophils, and macrophages. It is responsible for the activation and recruitment of neutrophils, eosinophils, mast cells, and other inflammatory cells to the site of inflammation, which in our case are cells lining airways.2 LTB4 may play a role in the activation and recruitment of neutrophils in such a way as to cause narrowed airways and diminished lung function.2,3
Tumor necrosis factor (TNF-α)
It’s encoded by the TNF gene. It’s another cytokine responsible for airway inflammation. It has also been implicated in a variety of diseases, including rheumatoid arthritis, diabetes mellitus, and cancerous tumors (hence the name). It is secreted by macrophages.4,5,6 A mutation in the TNF gene may result in obesity-associated asthma, another subgroup of severe asthma which may co-exist with neutrophilic asthma.
Interleukin 1 (IL1)
It’s a family of cytokines that usually works with TNF to cause acute and chronic inflammation. Treatment targeted at IL1 cytokines may reduce inflammation and improve asthma control.7,8
Interleukin 6 (IL6)
It’s encoded by the IL6 gene plays a role as the role in causing inflammation and has been implicated in neutrophilia and loss of lung function.9,10
Interleukin 8 (IL8)
It’s encoded by the IL8 gene and has been shown to attract neutrophils and T-helper cells to sites of infection.11,12 A future treatment may block their effects.
Interleukin 17 (IL17)
It’s a family of pro-inflammatory cytokines encoded by IL17 gene and secreted by T-helper 1 cells. It travels through the bloodstream and stimulates production and recruitment neutrophils to sites of infection. It may also do this indirectly by directing an increase in IL6 and IL8 production. A mutation in the IL17 gene may cause an elevated number of IL17. Two specific cytokines here that are suspected of playing a role in neutrophilic asthma are IL17A and IL17F. A future treatment may block their effects.2,13,14
T-helper 1 (Th1) cells
The role of Th1 in asthma is not clearly defined. This is contrary to the role of T-helper 2 (Th2) cells, which are known to play a significant role in allergic and eosinophilic asthma. A treatment that targets them is now in the testing phase.
These are some of the suspected culprits. Even though I gave a basic description of them, their exact role in asthma is not well understood. It’s possible they don’t play any role, and it’s also possible that other pathways are responsible. Still, this is a starting point that gives researchers something to work with.
The ultimate goal is to establish new treatment approaches to block these pathways to both prevent and control asthma. (This will be the topic of my next post).
What role do corticosteroids play? What is known is that neutrophilic asthma is usually observed in asthmatics who are already being treated with corticosteroids, and usually the highest doses.2
A theory postulated by researchers is that corticosteroids may contribute to neutrophil activation and prevent apoptosis (death) of neutrophils. So, it’s possible that the same medicines used to treat asthma may actually be the cause of severe asthma.
However, since most severe asthmatics are already on corticosteroids, this cause-effect relationship may be coincidental. Still, the realization that neutrophilic asthma only responds to the highest corticosteroid doses, or may not respond to them at all, is what is motivating the quest to better understand and find better treatment options for neutrophilic asthma.
What role does smoking cigarettes play?
It is possible, although not confirmed, that chemicals inhaled from cigarette smoke may also contribute to neutrophilic asthma. The immune response to these chemicals may be responsible for neutrophilia, along with airway changes responsible for severe asthma. This may also be the link between asthma and COPD, inspiring a new subgroup of severe asthma called Asthma/COPD Overlap Syndrome (of which I will also discuss in a future post).
If steroids are truly responsible for worsening asthma, it may be important to find some form of testing criteria for better helping physicians identify neutrophilic asthmatics. At the present time, there are no approved treatment options for this subgroup. However, there are some non-traditional and some experimental treatments worth trying. These will be the topic of my next post right here at asthma.net.