The immune system, along with the central nervous system, may play a fundamental role in amyotrophic lateral sclerosis (ALS), also known as “Lou Gehrig’s disease,” Mount Sinai researchers report. Their study, published June 22 in Naturecould have important implications for the diagnosis and treatment of the devastating neurodegenerative disease.
Until now, studies of ALS have focused on the central nervous system. But the Mount Sinai team reported dysfunctions of both the immune and nervous systems in animal models and patients with ALS4, a juvenile and slowly progressive form of ALS caused by mutations in the gene. SETX†
“We have learned that mutations in SETX must be expressed in both the nervous system and the immune system to cause motor dysfunction in mice, and that dysfunction in the adaptive immune system characterizes ALS4 in both mice and humans,” said Laura Campisi, PhD, assistant professor of microbiology at the Icahn School of Medicine. at Mount Sinai, and co-lead author of the study with Ivan Marazzi, PhD, associate professor of microbiology at Icahn Mount Sinai.
Further evidence of immune system involvement, she adds, was detected in the high concentration of CD8 T cells† usually involved in the destruction of tumors and cells in the body that harbor pathogens; in the spinal cord and peripheral blood of ALS4 mice and patients. Those elevated CD8 T cell populations, known as TEMRA (terminally differentiated effector memory), correlate with ALS4 disease progression.
ALS is characterized by the gradual death of motor neurons, which seriously affects the functional ability of patients in many ways, including preventing the movement of arms and legs, speech, swallowing and, ultimately, breathing. There is no treatment or cure for ALS. Researchers have focused their efforts on neurons over the years, although more recent studies have shown evidence of interaction between the central nervous system and the immune system, long considered separate compartments.
The Mount Sinai study, in collaboration with neurobiologist Albert La Spada, MD, PhD, of the University of California, Irvine, is one of the first to examine whether the adaptive immune system, which builds the body’s protection when exposed to foreign pathogens, may be associated with some forms of ALS.
There is a great need to understand whether neurodegeneration is caused or exacerbated by immune dysfunction.”
dr. Laura Campisi, PhD, Assistant Professor of Microbiology, Icahn School of Medicine at Mount Sinai
For their study, researchers analyzed mice and human samples using state-of-the-art technologies such as mass and spectral cytometry and single-cell sequencing. “Our finding that peculiar immune signatures distinguish different forms of ALS could be important for designing ‘personalized’ treatments tailored to specific subgroups of patients,” she notes.
An additional advantage is that dysfunctional CD8 T cells linked to ALS4 can be detected in the peripheral blood, which is readily accessible compared to cerebrospinal fluid, which requires an invasive collection procedure. Another observation by the team from Mount Sinai; that TEMRA CD8 T cells associated with ALS4 protect mice against glioma, a type of cancer that occurs in the brain; opens the door to further therapeutic research in this area.
“Our discovery of a link between the immune system and the central nervous system in ALS4 disease has immediate implications for other types of ALS, other neurodegenerative disorders, and for cancer,” said Dr. Marazzi. “In addition to being a major breakthrough in the pathogenesis of ALS, our work underscores the pioneering work of Mount Sinai researchers in neuroscience and immunology.”
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