A smoky trail

A recent study shows for the first time that emphysema, a chronic lung disease, is caused by a specific immune response induced by tobacco smoke. The US researchers found that cigarette recruited antigen-presenting cells as co-conspirators in the lung-destroying crime, using specific genes that regulate proteins, writes Kalyan Ray

From the cherry red tip of a lighted cigarette through the respiratory tract to vital lung cells, the havoc created by tobacco smoke seems almost criminal, activating genes and portions of the immune system leading to life-shortening emphysema, a chronic lung disease that leads to serious breathlessness.

One among the chronic obstructive pulmonary diseases, emphysema is known to have been caused by long-term exposure to pollution or cigarette smoking. But how exactly tobacco smoke was causing the disease was unknown.

Scientists have now described exactly the track the toxic smoke takes through the tissues and how they accomplish their destructive work.

“It’s like walking into a crime scene,” said Farrah Kheradmand, professor of medicine and immunology at Baylor College of Medicine in Texas, USA and a senior author of the report. The scientists took cells present in the “crime scene” apart, piece by piece to elucidate what occurred when, and how.

It is a complicated story that took more than four years for Kheradmand, her co-authors from Michael E DeBakey Veterans Affairs Medical Center and University of Texas MD Anderson Cancer Centre to reconstruct using sophisticated scientific tools. “Previously, emphysema was thought to be a non-specific injurious response to long-term smoke exposure,” she said and added, “This study shows for the first time that emphysema is caused by a specific immune response induced by smoke.” The specific change in the adaptive immune response is marked by increased in lymphocytes in the lungs. A non-specific response would not induce activation of the adaptive immunity, she told Deccan Herald. The findings were reported in the January 19 issue of Science Translational Medicine.

It is a combination of little genes affected by an epigenetic factor. Epigenetics are factors that affect the way genes are expressed after DNA forms. Cigarette smoke is an environmental epigenetic factor.

“DNA is written with a pen,” said Kheradmand, using a metaphor. “Epigenetics is written with a pencil. If you have enough genes affected by epigenetic factors strung together, it can tip you over into lung damage and emphysema. The inflammation that drives emphysema could also drive cancer development, a testable hypothesis that we have begun to pursue.”

The mice study shows cigarette smoke exposed-lung antigen presenting cells express new genes that promote activation of auto-reactive T-cells.

Humans have a wide spectrum of susceptibility factors that dictates how they respond to smoke over time. The study identified a major gene that is activated and initiates many of the pathway responsible for initiating the inflammation in the lungs. The US researchers found that cigarette recruited antigen-presenting cells (cells that orchestrate the immune system’s response to antigens) as co-conspirators in the lung-destroying crime, using specific genes that regulate proteins in their deadly role.

Role of antigen-presenting cells

To uncover the cause of tobacco-induced emphysema, they observed mice exposed to conditions that closely simulated how humans smoke. These animals developed lung disease in three to four months.

Certain inflammatory cells and genes were crucial in the process. For example, cytokine interleukin-17 was critical. “When we removed IL-17 from the mice, they did not develop emphysema in the same time span. The number of a type of immune cell – the gamma delta T-cell – would increase dramatically in the crime scene of the lung.” “But when we took them out, the inflammation worsened. The gamma delta T-cells went there to dampen the inflammation,” she said. “When they become overwhelmed, the disease ensues.”

They confirmed that a subset of antigen-presenting cells (cells that present antigen to activate the immune system) are the key to orchestrating the disease. They had first found these cells in studies of human lung tissue. Then, they duplicated that finding in mice.

The researchers took the cells out of the lungs of diseased-mice and transferred into healthy mice who had never been exposed to cigarette smoke. After three months, these mice showed inflammatory signs indicating that they were on the way to developing lung damage and emphysema.

When they analysed ‘gene chips’ to screen the disease-causing antigen-presenting cells recovered from lungs with emphysema, they uncovered the gene for osteopontin, which promotes initiation of the inflammatory cascade that damages lungs. Mice that lacked this gene were resistant to emphysema, said Kheradmand.

Public health implications

While the research is fascinating, does it have any public health significance? “The key public health implication is not so much development of new drugs (which might eventually follow the identification of one of the many the biological pathways identified in this paper), but enforcement of smoking laws and restrictions,” said Prabhat Jha, a public health specialist from the University of Toronto in Canada, who is not connected to the study.

“The paper adds more evidence on the mechanism by which smoking increases the risk of specific diseases, including emphysema. There are now over 40,000 scientific studies linking smoking with disease, and the proof that smoking is a major cause of emphysema and other diseases is beyond doubt,” Jha told Deccan Herald stressing on the need for government action to cut down tobacco usage.

France has tripled its tax on tobacco, and that cut consumption by more than half, and led to substantial declines in lung cancer deaths in young men (which is a sensitive indicator of recent changes in smoking in the population). India, China, Indonesia and other large emerging countries needed to adopt such measures, and quickly, he said.