Levels of Inflammatory Molecule IL-36 Gamma Reflect MG Severity, Study Finds

Inês Martins, PhD avatar

by Inês Martins, PhD |

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Kate Stringaris, a researcher with the NIH's National Heart, Lung and Blood Institute in Bethesda, Maryland, separates lymphocytes from a blood sample as part of an investigation into natural killer immune cells.

The inflammatory molecule interleukin-36 (IL-36) gamma is associated with the severity of myasthenia gravis (MG), and may participate in disease processes by activating certain immune cells, a recent study suggests.

The study, “Increased serum IL-36γ levels are associated with disease severity in myasthenia gravis patients,” was published in the journal BMC Neurology.

MG is caused by antibodies wrongly attacking the neuromuscular junctions, where nerve cells communicate with muscles. But several immune cells and molecules contribute to the disease.

IL-36 is a cytokine — a type of signaling molecule — that activates certain immune cells, such as dendritic cells and helper T-cells, and contributes to a pro-inflammatory immune response.

This molecule has been implicated in other autoimmune diseases, such as lupus and multiple sclerosis, but whether it also plays a role in MG is unknown.

Researchers at the Tianjin Medical University General Hospital, in China, set out to measure the levels of IL-36 in MG patients and to establish potential correlations with clinical characteristics.

The researchers included 97 patients treated at their hospital from January 2016 to September 2019, and 49 healthy people (controls) from the hospital’s Health Care Center. Patients and controls both had an average age of 57 years, but controls had a greater proportion of women (61% vs. 45%).

Among patients, 81% had antibodies against acetylcholine receptors (AChR), the most common autoantibodies in MG, and 26% had a thymoma (tumor in the thymus gland), which usually means a worse prognosis. Also, most patients (71%) were classified as having mild disease; the remaining had severe MG.

The levels of three IL-36 proteins — IL-36 alpha, IL-36 beta, and IL-36 gamma — were examined before treatment in patients and controls. While no significant differences were seen in the IL-36 alpha and beta proteins, participants with MG had significantly higher levels of the gamma protein that controls.

Also, IL-36 gamma seemed to correlate with the severity of MG, as people with mild disease had lower levels than those with severe disease — though still significantly higher than controls. People with generalized MG, a more serious form of disease, also had more IL-36 gamma in the blood than those with ocular disease.

Levels of IL-36 alpha and beta, however, did not change with disease severity or nature. Likewise, neither of the three proteins showed significantly different levels in people with and without anti-AChR antibodies or in patients with or without thymoma.

Finally, the scientists randomly selected a group of 30 patients to examine how IL-36 levels changed with achieving disease remission. Results showed that levels of IL-36 alpha and gamma were significantly lower compared to the active phase of disease. IL-36 beta showed no significant differences between both phases.

“In this study, we clarified that serum IL-36γ [gamma] levels were elevated in MG patients compared with [healthy controls] … [but] were decreased during remission,” the researchers wrote.

While some studies have explored the participation of IL-36 in autoimmune diseases, little is still known about the mechanisms through which the protein exerts its effects. In MG, the investigators believe this may happen by two mechanisms: one is the activation of dendritic cells and T-cells, which can promote disease processes and aggravate MG progression; the other is by promoting the secretion of multiple inflammatory factors, such as IL-6 and TNF alpha, which have been implicated in MG.

Among the study’s limitations, the team cited the small group of participants, and the use of oral corticosteroids by some patients, which can mask immune alterations.

Still, the findings “indicate that IL-36γ is positively correlated with the severity of MG,” they wrote. “Additionally, IL-36γ may be involved in the immunopathological process of MG, suggesting that it may be a potential immune marker for MG.”