Research suggests that shutting down the immune response improves multiple sclerosis outcomes

A human immune system is a lot like the board game Mouse Trap: it’s a Rube Goldberg system of interacting parts. Only instead of a ball falling and causing a small plunger to jump into a bathtub – which in turn traps some plastic mice – do the proteins trigger other proteins to activate immune cells and direct them to the germs. But if these proteins mistakenly direct immune cells to healthy tissue, autoimmune diseases like multiple sclerosis – which attacks neurons – can occur.

A new study led by Kelly Monaghan, a researcher at the West Virginia University School of Medicine, suggests that part of the “Rube Goldberg” immune system holds promise as a potential target for MS therapies.

“Any time you have problems in the central nervous system, you have to go through a series of steps for the cells to get into the brain or the spinal cord,” said Monaghan, a doctoral student in the Department of Microbiology, of immunology and cell biology. “Gaining a better understanding of these MS-associated immune mechanisms may help inform new therapies.”

His findings appeared in the Proceedings of the National Academy of Sciences.

His study – funded by the National Institutes of Health – focused on STAT5, one of many proteins circulating in the body that can metaphorically turn genes on or off.

“STAT5 is a transcription factor,” Monaghan said. “It is a member of the STAT protein family, and it plays many different roles in cell proliferation and inflammation. Importantly, STAT5 proteins must form dimers to regulate gene expression. The interaction of two dimers results in the formation of tetramers, which regulate an independent set of target genes.”

Monaghan and his colleagues wanted to know if STAT5 tetramers played a role in signaling white blood cells to interact and move through the meninges. If they played such a role, the researchers wanted to know more about it.

“The meninges, if you don’t know, are a series of three membranes that surround the central nervous system,” she said. “They act as a sort of checkpoint, if you will, to regulate cell migration in the brain or spinal cord.”

Infiltration of immune cells into the meninges is a hallmark of multiple sclerosis.

In particular, Monaghan wanted to study the molecular chain of events that could cause the STAT5 tetramers to command another protein – called CCL17 – to tell T cells, a type of white blood cell, to attack the central nervous system by “firing friend”.

Monaghan and his team used two groups of mice to explore this topic. The first group had been genetically engineered so that their STAT5 tetramer proteins could not reorganize in such a way as to trigger the problematic CCL17 response. The second group was genetically normal.

The researchers injected both groups of mice with myelin-reactive T cells to induce an experimental form of MS called experimental autoimmune encephalomyelitis, or EAE.

In response, the genetically normal mice developed EAE in the conventional way, but the genetically modified mice did not. Interrupting their STAT5 tetramer “chain reaction” protected them from disease.

“It wasn’t completely ablated, but it was significantly reduced in severity,” Monaghan said. “It was quite convincing that they developed less severe disease, suggesting that CCL17 is the pathogenic protein acting downstream of the STAT5 tetramers.”

Not only did the genetically modified mice show milder, delayed paralysis, but later examination of their spinal cord revealed healthier nerves that were better at signal transduction.

“MS is very complicated,” Monaghan said. “We found that the complex immune interactions between cells are really what contributes to the difficulty of understanding this disease.”

According to the National Multiple Sclerosis Society, information like that from this study may point to future treatments for MS, a disease suffered by more than 2.3 million people worldwide.

“Patients diagnosed with MS suffer throughout their lives and, unfortunately, their clinical symptoms worsen as the disease progresses,” said Edwin Wan, Monaghan’s mentor and assistant professor in the Department of Microbiology, Immunology and Cell Biology. . “Current drugs for MS treatments are effective enough to reduce the relapse rate but cannot halt disease progression. The bottleneck in developing more effective drugs is that we don’t have a picture full picture of how the disease is initiated and progresses.”

The study results help complete this picture, bringing hypothetical MS treatments closer to reality.

“I think these findings may also have broader implications for other autoimmune diseases,” Monaghan said, “because there may be several other autoimmune diseases that are regulated by STAT5 tetramers and the STAT5 pathway. downstream signaling, which is quite exciting.”

The research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number P20GM109098. The content is the sole responsibility of the authors and does not necessarily represent the official views of the NIH.


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