New research implicates immune system in Rett syndrome

May 11, 2015

WORCESTER, MA - New research by investigators at the University of Massachusetts Medical School suggests the immune system plays an unsuspected and surprising role in the progression of Rett syndrome, a severe neurological disorder affecting children. Immune cells known as macrophages are unable to perform their normal function and are instead amplifying the disease. The finding, recently published in Immunity, points to the immune system as a promising target for slowing the progression of Rett syndrome.

"Rett syndrome patients have a mutation that makes macrophages hyper-sensitive to specific stress signals," said Vladimir Litvak, PhD, assistant professor of microbiology and physiological systems and co-senior author of the study. "It's like being in a car with only a gas pedal; that part of the immune system is constantly on. This causes damage to the surrounding tissue and eventually wears out the macrophages so they die off en masse.

"This study points to the immune system as an important contributor to the disease," Dr. Litvak said. "If we can find a way to modulate the immune system, take our foot off the gas a bit if you will, it's possible we could delay the progression of symptoms in patients."

Rett syndrome is a neurodevelopmental disorder that is caused primarily by mutations in the gene encoding for MeCP2, an important epigenetic regulator. In the brain, MeCP2 is found in high concentrations in neurons and is associated with maturation of the central nervous system and the formation of synaptic connections. Children with the disorder appear to develop normally but begin to lose acquired cognitive and motor skills at 6 to 18 months of age as symptoms start to show. As they age, patients are unable to acquire verbal skills and suffer from lack of motor control.

Though the hallmark of Rett syndrome is neurological, related symptoms include gastrointestinal and digestive issues that can lead to poor weight gain and nutritional problems, as well as heart, bone and muscle complications. Previous studies indicated that microglia, a type of macrophage found in the brain, may have a role in the disease.

"Knowing that microglia play an important role in the pathogenesis of Rett syndrome, we thought that other types of macrophages might be contributing to the disease as well," Litvak said.

What Litvak found is that the MeCP2 gene is responsible for establishing a threshold for the activation of macrophages in the presence of stimuli and stressors such as hypoxia, corticosteroids and inflammation. During the course of a normal day, macrophages encounter varying levels of these stimuli. In cells with the MeCP2 mutations, the macrophages are far more sensitive and respond to much lower levels of stimuli and stress. This activation causes additional stress which keeps the macrophages "turned on" in a cycle that amplifies and further damages the cells and surrounding tissues. It's likely this damage is contributing to the progression of the disease and onset of symptoms, according to Litvak.

"We know how to modulate the immune system. And with a bone marrow transplant we can even replace a person's entire immune system. It's unlikely that we could cure Rett syndrome without addressing the MeCP2 in neurons, but this study provides evidence that by addressing the disease in the immune system we could potentially delay the onset of symptoms," Litvak said.
Yang (Amy) Xu, a PhD candidate in the Graduate School of Biomedical Sciences, and Aaron E. Lampano, PhD, a postdoctoral fellow in the Litvak Lab, contributed to the study. This work was done in collaboration with the Kipnis lab at the University of Virginia. Jonathan Kipnis, PhD, Director of the Center for Brain Immunology and Glia at the University of Virginia was a co-senior author of the study.

About the University of Massachusetts Medical School

The University of Massachusetts Medical School, one of the fastest growing academic health centers in the country, has built a reputation as a world-class research institution, consistently producing noteworthy advances in clinical and basic research. The Medical School attracts more than $240 million in research funding annually, 80 percent of which comes from federal funding sources. The mission of the Medical School is to advance the health and well-being of the people of the commonwealth and the world through pioneering education, research, public service and health care delivery with its clinical partner, UMass Memorial Health Care. For more information, visit

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