Immune systems of patients with bipolar disorder age prematurely

Damage to neurons occurs during mood swings, and the organism responds with an inflammatory reaction to rid itself of dead or dysfunctional cells

By Karina Toledo  |  Agência FAPESP – Research performed at the Federal University of São Paulo (UNIFESP) in Brazil has shown that the immune systems of individuals who suffer from bipolar disorder tend to age prematurely. According to Elisa Brietzke, who led the study, the discovery paves the way for new therapeutic approaches.

Brietzke was one of seven prizewinners in the tenth annual “For Women in Science” awards given annually by L’Oréal Brazil in partnership with the United Nations Organization for Education, Science & Culture (UNESCO) and the Brazilian Academy of Sciences (ABC).

“We believe damage to neurons occurs during the mood swings that are characteristic of the disease,” Brietzke told Agência FAPESP. “The organism then responds with an inflammatory reaction in an attempt to rid itself of dead or dysfunctional cells. If the inflammation is very intense or prolonged, it can be harmful.”

“Brietzke had previously shown in her PhD research (which was completed in 2010) that bipolar disorder can entail immunological alterations compatible with systemic inflammation.” 

“It was a paradigm shift. Bipolar disorder is traditionally considered a brain disease. The brain tissue was believed to be isolated from the rest of the body by the blood-brain barrier, a mass of endothelial cells that protect the central nervous system, but today we have evidence from studies with animals and post-mortem human tissue that inflammatory mediators are able to pass through the barrier and activate microglial cells in the brain’s own immune system,” Brietzke said.

The results of this initial study showed that some of the alterations found in the immune systems of elderly people can also be found in much younger people with bipolar disorder. A new project was therefore designed to confirm whether the immune system ages prematurely in these patients.

The investigation is part of the Thematic Project “Prevention in schizophrenia and bipolar disorder from neuroscience to the community: a multiphase, multimodal and translational platform for research and intervention”, with Rodrigo Affonseca Bressan as the principal investigator.

The project, which is also supported by the National Scientific & Technological Development Council (CNPq) through its National Support Program for Centers of Excellence (PRONEX), starts from the hypothesis that mental disorders are progressive diseases and hence accompany patients from the development risk phase onward.

“We set out to see whether immune aging is more pronounced in individuals who have had the disease for a long time than in more recent cases,” Brietzke said. “Preliminary results suggest it is. Both the duration of the disease and the number of mood swing episodes are determining factors.”

To reach this conclusion, the group compared data from 30 patients with early-stage bipolar disorder, 30 with late-stage bipolar disorder, and 30 healthy volunteers. The average age was 36 years. Blood samples were analyzed by flow cytometry to measure the percentages of different cells and cell components, as well as markers of inflammation (inflammatory cytokines) and cellular aging.

“Immune system cells can display markers of aging on their surfaces. In general, the older the patient, the higher the percentage of senescent cells. We found increased rates of senescent cells in patients with BD compared with control individuals of the same age,” Brietzke said.

The group also measured the size of telomeres, the caps at the end of DNA strands that protect our chromosomes, like plastic tips at the end of shoelaces. Telomeres are markers of biological age because they tend to decrease in length as we age. In this case, however, the researchers observed no difference between the two groups of BD sufferers and the healthy volunteers. 

For Brietzke, the results obtained so far suggest biological alterations due to BD should not be seen as confined to the brain, so treatment should not be confined to neurotransmitter modulation.

“Modulating the immune system and controlling inflammation can improve the patient’s mental condition,” she said. “This can be done with medication and also via other kinds of intervention, such as prescribing physical exercise. Controlling inflammation, moreover, can mitigate the metabolic alterations frequently found in patients with BD. Studies show that above-average proportions suffer from diabetes, obesity and cardiovascular disease, all of which are associated with aging.”

The deterioration in metabolic parameters in BD patients as the disease progresses was the focus of another recent study led by Brietzke with support from FAPESP.

For Women in Science Awards

The latest For Women in Science award ceremony took place on October 20 at Palácio Guanabara, the seat of Rio de Janeiro’s state government.

Two other researchers from São Paulo won awards. Alline Campos, affiliated with the University of São Paulo’s Ribeirão Preto School of Medicine (FMRP-USP), is focusing on the development of more effective drugs with fewer adverse effects for anxiety and depression.

Tábita Hunemeier, from the same university’s Bioscience Institute (IB-USP), is investigating the genetic basis for the morphological characteristics of Native Americans to search for variations that physically differentiate them from the populations of other continents.

The other four prizewinners were Daiana Ávila from the Federal University of the Pampa (UFP), Cecília Salgado and Karin Menéndez-Delmestre from the Federal University of Rio de Janeiro (UFRJ), and Elisa Orth from the Federal University of Paraná (UFPR).

The awards are given to researchers with outstanding work, résumés and potential in life sciences, mathematics, physics, and chemistry. Each awardee receives a grant of US$20,000 for investment in her research.

“The aim is to stimulate participation in science by women and give them a boost at the start of their careers,” Brietzke said. “When you look at the leading researchers in Brazil, you see they’re still mostly men, whereas the genders are evenly proportioned in the initial stages of any academic career.”