HMGB1 Protein may be the key to better asthma treatment: study

A new study, published in the Journal of Allergy and Clinical Immunology, has investigated a potential new approach to designing drugs for the treatment of asthma. Better interventions could be on the horizon. Current medications can effectively treat the symptoms for many people but, as the lead author of the current study, Dr Ruth Sander, said: “For a number of people with asthma, particularly severe asthma, treatment is not 100 percent effective. Although a number of new therapies are under investigation for allergy-related asthma, there is still a need for new therapies for asthma that is not related to allergies.” The steady rise in asthma cases; its potential to be fatal, and the shortfalls of medication for some individuals, all make asthma research an important field of study. A recent study, conducted at the University of Leicester in the United Kingdom, investigated the role of a specific protein in asthma called high-mobility group box 1 (HMGB1). The researchers hope that their findings might pave the way to designing more effective treatments. HMGB1 is a chromatin protein, meaning that it helps to organise DNA and regulate its transcription in the nucleus of cells. It is secreted by immune cells – including monocytes, macrophages, and dendritic cells – and promotes the inflammatory response. The current study used mucous and muscle tissue from the airways of people with mild to moderate cases of asthma. Smooth muscle in the airways is known to contribute significantly to the symptoms of asthma; it over contracts, increases in mass, and releases chemicals involved in the inflammation response. Once analyzed, data from the samples showed that HMGB1 is, as expected, a pivotal factor in the etiology of asthma. “We have shown that the amount of HMGB1, a protein that can be released in the airways by cells involved in inflammation or by damaged cells, is increased in the mucous from the airways of people with severe asthma.” Dr Sanders continued: “To our knowledge, this is the first study to show a direct effect of HMGB1 on enhancing airway muscle contraction in response to stimuli. The findings of this research bring us a step closer to improved treatments for people with severe asthma.” This is the early phase of studies into this new target pathway, and new pharmaceuticals are a long way down the line. However, it marks an important leap forward; by understanding HMGB1 and its role in asthma, novel interventions can eventually be trialled. Separately, a team of researchers at the Leiden University Medical Center (LUMC) in the Netherlands has recently shown that the body’s immune cells triggered by the consumption of gluten in patients with celiac disease may also lead to a rare form of lymphoma. For a small number of people living with celiac disease, a gluten-free diet is not enough to stop the otherwise severe symptoms. These patients are classified as having refractory celiac disease (RCD), which usually affects between two and five percent of celiac disease patients. In one type of RCD called RCDII, the white blood cells found in the wall of the small intestine divide and multiply in excessive numbers. In approximately half of the RCDII patients, these cells, called lymphocytes, go on to develop into a particularly rare form of lymphoma. This rare and very aggressive form of white blood cell cancer is called enteropathy-associated T-cell lymphoma. The body’s T cells – a type of immune cell that controls the body’s reaction to gluten, among other things – have a very strong inflammatory reaction to gluten. When they detect the protein they produce cytokines, which in turn stimulate other immune cells. This leads to the extremely inflammatory and painful response typical of celiac disease, but in some rare cases, it also leads to cancer. Researchers have known that the onset of this rare form of lymphoma depends on the cytokine IL-15, which makes malignant cells multiply. In this latest research, however, scientists in the Netherlands have now shown that three other cytokines – TNF, IL-2, and IL-21 – can also cause malignant cell proliferation. These findings serve to further clarify how the body’s immune system responds to gluten and how this can stimulate the growth of cancerous cells in RCDII. Dr Lara Bennett, science communications manager at Worldwide Cancer Research, comments on the significance of the findings: “This is another great example of the importance of early-stage, discovery research. This is a rare type of cancer but the findings could be of real benefit to this small but important group of patients with refractory coeliac disease.” LUMC researcher and Worldwide Cancer Research scientist, Dr Jeroen van Bergen, explains why the next important step in this research is identifying where exactly in the development of lymphoma these three cytokines get involved. “It is likely that at the time of lymphoma diagnosis, the patient has already experienced decades of intestinal inflammation,” Dr van Bergen says. “We need to determine the extent to which it would actually help to block these newly discovered growth factors with targeted drugs at the time of diagnosis. In the meantime, we have tested a large number of potential drugs in the laboratory, and two of them seem promising. But this is only interesting in terms of a new treatment if these growth factors still have a role to play in the growth and development of the lymphoma after diagnosis.”