People with Cushing’s show ‘paradoxical’ immune profile: Study

Researchers note both systemic inflammation, cellular immunosuppression

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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People with Cushing’s syndrome, including those with Cushing’s disease, exhibit immune system alterations that could contribute to some symptoms of the disease, a small study suggests.

Analyses of immune cells from Cushing’s patients indicated signs of both systemic (whole body) inflammation as well as immunosuppression, which scientists believe might contribute to certain cardiovascular and infectious complications seen in Cushing’s.

The findings were published in Clinical and Translational Medicine as a letter to the editor, titled “Concomitant systemic inflammation and cellular immunosuppression in patients with Cushing’s syndrome.”

Cushing’s syndrome encompasses a family of diseases marked by excessive levels of cortisol, a steroid hormone. This includes Cushing’s disease, wherein elevations happen because of a tumor in the pituitary gland.

Among a range of other symptoms, people with Cushing’s are prone to cardiovascular complications and are more susceptible to some infections.

A growing body of evidence suggests certain immune responses might underlie these complications. Indeed, cortisol can modulate inflammation and exert immunosuppressive effects, leading scientists at Radboud University Medical Center, the Netherlands to hypothesize that the excess cortisol in Cushing’s might cause abnormal reprogramming of the innate immune system.

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Immune systems and Cushing’s

The system comprises immune cells that serve as first responders to infection or injury and that promote general responses against any threat.

The scientists examined immune profiles in the blood of 19 adults (15 women, four men) with Cushing’s syndrome and 19 sex-matched healthy people, who served as controls. Eight patients had Cushing’s disease.

The patients didn’t have coexisting health conditions that could influence the immune system and weren’t on medications with such effects. Their blood samples were collected at diagnosis (mean age, 48.8) before cortisol-lowering medications were started. Blood samples were collected from healthy controls on the same day.

As expected, blood cortisol levels were significantly higher in patients, but concentrations of other steroid hormones didn’t differ between the two groups.

Monocytes and neutrophils, two cell types of the innate immune system, comprised a significantly higher percentage of the total immune cells in the blood of Cushing’s patients over healthy people.

But the Cushing’s group showed lower percentages of lymphocytes, a family of immune cells belonging to the adaptive immune system, which takes over when the innate system can’t control the threat. The adaptive immune system drives slower, but has threat-specific immune responses that can memorize the threats and provide long-lasting defense and protection.

Among Cushing’s patients, more monocytes and fewer lymphocytes in the blood were each associated with higher cortisol levels.

Inflammation, immunosuppression coexist in Cushing’s

Cushing’s patients also had significantly higher blood levels of 12 inflammation-related proteins relative to healthy people, which “suggests systemic inflammation in [Cushing’s syndrome] patients,” the researchers wrote.

Additional experiments indicated patients also showed certain signs of immunosuppression, with immune cells being less active in response to threats than expected.

For example, when exposed to stimuli that would be considered a threat, lab-grown immune cells from healthy people released certain pro-inflammatory molecules in response — a standard immune reaction. The release of a number of these molecules was diminished in immune cells from Cushing’s patients.

Moreover, monocytes from Cushing’s patients exhibited some defects in trained immunity, the process by which innate immune cells can remember certain stimuli and adjust their response the next time they’re exposed to it — a process that helps the body resist reinfections. Patients’ monocytes were able to mount trained immunity toward certain threats, but not others.

“The different pathways through which trained immunity is induced in monocytes by different stimuli … might explain these differences,” wrote the researchers, who also found the production of certain pro-inflammatory molecules by patients’ trained monocytes after re-exposure to a general danger signal was strongly associated with urine cortisol levels.

Taken together, “our results indicate that [Cushing’s syndrome] patients show paradoxical characteristics of concomitant systemic inflammation and cellular immunosuppression,” the researchers wrote, noting the findings might be behind both cardiovascular and infectious complications in Cushing’s. Specifically, the increased inflammatory profile might contribute to cardiovascular problems, whereas diminished immune responses toward threats could contribute to increased susceptibility to infection.

“Future studies with larger populations are needed to further elucidate the specific molecular mechanisms behind these immunological alterations and to assess their reversibility after achieving remission of the disease,” the scientists wrote, adding the findings may aid in managing Cushing’s syndrome and help patients who are treated chronically with [steroids].