How cells die determines whether immune system mounts response

July 17, 2008

Every moment we live, cells in our bodies are dying. One type of cell death activates an immune response while another type doesn't. Now researchers at Washington University School of Medicine in St. Louis and St. Jude's Children's Research Hospital in Memphis have figured out how some dying cells signal the immune system. They say the finding eventually could have important implications in the treatment of autoimmune diseases and cancer.

In the July 18 issue of the journal Immunity, the researchers report a molecule, called high mobility group box-1 protein (HMGB1), which cells release when they die, seems to determine whether the immune system is alerted. But what happens to HMGB1 after it's made and whether the immune system ever gets the signal depends on how the cell dies.

"Cells die in two general ways: apoptosis, or programmed cell death, and necrosis, which results from injuries and infections," says Thomas A. Ferguson, Ph.D., a senior investigator on the study and professor of ophthalmology and visual sciences at Washington University. "In general, we don't want the immune system to respond to apoptosis, but we do want an immune response following necrosis because necrotic death can be a sign of infection. Necrotic cells release components to stimulate the immune system, and one is the HMGB1molecule."

Apoptosis normally is a healthy process that occurs all the time, so it shouldn't activate an immune response, according to co-senior investigator Douglas R. Green, Ph.D. the Peter C. Doherty Endowed Professor of Immunology at St. Jude's.

"Apoptosis is an orderly death that occurs during development and tissue turnover, and it's an important process that allows us to replace old, worn-out cells with fresh, new ones," says Green. "We don't need the immune system paying attention as our cells die through apoptosis. When it does react to apoptosis, we can develop autoimmunity, as in diabetes, arthritis and other autoimmune diseases in which the immune system will attack the 'self.'"

The researchers say scientists had believed that necrotic cells released HMGB1 whereas apoptotic cells did not. The problem is that experiments in Ferguson's laboratory and elsewhere have found that in some cases, apoptotic cells also release the HMGB1 protein.

"Whether they were apoptotic or necrotic, we found that dying cells were releasing the protein, but the cells that were undergoing apoptosis still weren't stimulating the immune system," Ferguson says. "So our question was, 'If the molecule being released is the same, why is it stimulating the immune system in one situation and not in another?'"

Further experiments showed that when they die, apoptotic cells also produce free radicals, and those reactive oxygen free radicals modify HMGB1 to prevent it from stimulating the immune system. In necrosis, no free radicals are produced, so HMGB1 both signals and stimulates an immune system response.

Free radicals have been thought to be bad for us, but in the case of cell death, they have the beneficial effect of preventing the immune system from attacking and destroying healthy cells. The finding may have important implications, both for some autoimmune processes and for cancer treatment. The researchers believe it may be possible to use HMGB1 to stoke up the immune system in response to cancer.

"Sometimes tumors can stimulate an immune response," says Green. "This study suggests that when we give chemotherapy, whether dying tumor cells make these reactive oxygen free radicals could be very important because if we can mount an immune response to the tumor, chemotherapy might be more successful, and we may be able to keep the cancer from coming back."

The inverse would be true in autoimmune diseases.

"If we could oxidize the danger signals coming from dying cells in a way similar to how apoptotic cells release free radicals to modify HMGB1, maybe autoimmunity could be down-regulated," Ferguson says.

Source: Washington University School of Medicine

Explore further: Immune receptor that's typically activated by bacteria major contributor to bladder dysfunctionion

Related Stories

Immune receptor that's typically activated by bacteria major contributor to bladder dysfunctionion

February 6, 2017
Bladder dysfunction is a reality for about half of patients with diabetes and now scientists have evidence that an immune system receptor that's more typically activated by bacteria is a major contributor.

Viral protein silences immune alarm signals

June 29, 2016
Viruses must avoid a host's immune system to establish successful infections—and scientists have discovered another tool that viruses use to frustrate host defenses. Researchers from The Children's Hospital of Philadelphia ...

'Danger' molecule may be new therapeutic target for male hypertension

February 13, 2015
Higher levels of a "danger" molecule may be one reason males tend to become hypertensive earlier and more severely than females, scientists say.

New study provides key insights into aspirin's disease-fighting abilities

September 24, 2015
A research team that includes a Rutgers professor has found that the main ingredient in aspirin targets the activities of an inflammatory protein associated with a wide variety of diseases. The discovery offers hope for the ...

HMGB1 may be linked to immunosuppression in patients who survive septic shock

June 1, 2017
A new study published online in the Journal of Leukocyte Biology suggests a new approach to treating patients with sepsis, one of the most frequent causes of morbidity and mortality in intensive care units (ICUs). Specifically, ...

New liver cancer target is a protein that accelerates inflammation

December 30, 2014
Hepatitis, alcohol consumption, even obesity can produce chronic inflammation in the liver and set the stage for cancer.

Recommended for you

Study reveals new mechanisms of cell death in neurodegenerative disorders

November 22, 2017
Researchers at King's College London have discovered new mechanisms of cell death, which may be involved in debilitating neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease.

Researchers find infectious prions in Creutzfeldt-Jakob disease patient skin

November 22, 2017
Creutzfeldt-Jakob disease (CJD)—the human equivalent of mad cow disease—is caused by rogue, misfolded protein aggregates termed prions, which are infectious and cause fatal damages in the patient's brain. CJD patients ...

Surprising roles for muscle in tissue regeneration, study finds

November 22, 2017
A team of researchers at Whitehead has illuminated an important role for different subtypes of muscle cells in orchestrating the process of tissue regeneration. In a paper published in the November 22 issue of Nature, they ...

How rogue immune cells cross the blood-brain barrier to cause multiple sclerosis

November 21, 2017
Drug designers working on therapeutics against multiple sclerosis should focus on blocking two distinct ways rogue immune cells attack healthy neurons, according to a new study in the journal Cell Reports.

New simple test could help cystic fibrosis patients find best treatment

November 21, 2017
Several cutting-edge treatments have become available in recent years to correct the debilitating chronic lung congestion associated with cystic fibrosis. While the new drugs are life-changing for some patients, they do not ...

Researchers discover key signaling protein for muscle growth

November 20, 2017
Researchers at the University of Louisville have discovered the importance of a well-known protein, myeloid differentiation primary response gene 88 (MyD88), in the development and regeneration of muscles. Ashok Kumar, Ph.D., ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.