Asthma is a potentially life-threatening condition in which patients experience bronchial spasms that obstruct the airway. More often than not, the telltale wheezing and shortness of breath are caused by the immune system’s reacting to allergens, but occasionally asthma is induced by physical activity. Asthma is a global health problem, affecting over 200 million people worldwide.
There is no cure for asthma: patients cope with it by avoiding allergens or activities that trigger it and often rely heavily on inhaled or oral corticosteroids to open airways in case of asthmatic attack.
Patients with asthma routinely show high levels of inflammatory “Th2 cytokine” proteins in their bloodstream, so-named because they are secreted by immune cells called Th2 helper cells. These messenger molecules exacerbate asthma and other allergies, making them a target for drug treatment: some patients who don’t respond to common treatments are helped by treatment with monoclonal antibodies targeting Th2 cytokines.
Ample evidence supports the idea that heightened Th2 cell signaling is the cellular signature of allergy and asthma. Thus, several LJI investigators are searching for genes or proteins that either foment or subdue Th2 cell activity in affected patients.
In that effort, LJI scientist Pandurangan Vijayanand, M.D., Ph.D, recently applied next-generation computational approaches to take a global snapshot of gene expression in both Th1 and Th2 cells. To do so, he surveyed the entire genome of both asthmatic and control non-asthmatic individuals for short stretches of DNA called enhancers, which switch target genes on and off. This analysis, conducted with LJI’s Bjoern Peters, Ph.D., and Anjana Rao, Ph.D., identified a manageable number of genes inappropriately switched on in Th2 cells of asthmatic patients, factors that could potentially serve as novel therapeutic targets.
T helper signaling whips up the inflammation that drives asthmatic attacks. But the cellular perpetrators are mast cells, which release the histamine actually provokes physiological symptoms. A few years ago, LJI researcher Toshiaki Kawakami, M.D., Ph.D., discovered that a proinflammatory protein called histamine-releasing factor (HRF) activated a receptor expressed on mast cells, causing them to release histamine. Since then, his lab has identified two peptides that can block HRF activity and decrease airway inflammation in mouse models of asthma, discoveries could lead to similar approaches in patients.
Turning off LIGHT
Finally, LJI immunologist Michael Croft, Ph.D., is applying his expertise in autoimmune disease to counteract airway wall thickening and tissue scarring, known as fibrosis, seen in asthmatic patients. Croft found that activity of a pro-inflammatory factor called LIGHT increases airway wall thickness and perturbs lung function in asthma. LIGHT is a member of the TNF protein family, factors strongly implicated in autoimmunity. His lab has since discovered that when asthma model mice were treated with drugs that block LIGHT, mice showed less airway fibrosis after allergen exposure.
Croft is developing the idea that LIGHT inhibitors may be effective in reversing tissue destructive effects of fibrosis not only in asthmatic lung but in chronic obstructive pulmonary disease (COPD) or skin diseases like scleroderma or eczema. Drugs targeting LIGHT are now in safety trials and could be used in the future in patients with fibrosis.
From The Lab
A step toward helping patients breathe deeplyLJI scientists track down a protein that may add to lung damage in asthma and related diseases
LJI scientists uncover immune cells that may lower airway allergy and asthma riskStudy opens up new path to research to fighting allergic diseases
ImmunoprofilingBillions of highly diverse and specialized immune cells work together to keep us healthy. LJI scientists are deciphering the molecular code that defines who these cells are and how they interact with each other, ushering in a new era of high-resolution immunoprofiling.
Billions of highly diverse and specialized immune cells work together to keep us healthy. LJI scientists are deciphering the molecular code that defines who these cells are and how they interact with each other, ushering in a new era of high-resolution immunoprofiling.