The immune system may play a fundamental role along with the central nervous system in amyotrophic lateral sclerosis (ALS), also known as “Lou Gehrig’s disease”, report the Mount Sinai researchers. Their study, published on 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 immune and nervous system dysfunctions in animal models and patients with ALS4, a juvenile and slowly progressive form of ALS, which is caused by mutations in the gene. SETX.
“We have learned that mutations in SETX must be expressed in both the nervous and immune systems to generate motor impairment in mice, and that dysfunction of the adaptive immune system characterizes ALS4 in mice as well as in humans,” says Laura Campisi, PhD, Professor adjunct 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-; which are usually involved in the destruction of tumors and body cells that harbor pathogens; in the spinal cord and peripheral blood of mice and ALS4 patients. These increased populations of CD8 T cells, known as TEMRA (terminal differentiation effector memory), correlate with ALS4 disease progression.
ALS is characterized by the progressive death of motor neurons, which severely affects the functional capacity of patients in various ways, including preventing movement of the arms and legs, speech, swallowing and, possibly, breathing. There is no treatment or cure for ALS. Researchers have focused their efforts over the years on neurons, although more recent studies have shown evidence of interaction between the central nervous and immune systems, long considered separate compartments.
The Mount Sinai study, in collaboration with neurobiologist Albert La Spada, MD, PhD, of the University of California at Irvine, is one of the first to determine whether the adaptive immune system, which enhances the body’s protection when exposed to pathogens, could be linked to some forms of ALS.
There is a great need to understand whether neurodegeneration is caused or worsened by immune dysfunction.”
Dr. Laura Campisi, PhD, Assistant Professor of Microbiology, Icahn School of Medicine at Mount Sinai
For their study, the researchers analyzed mice and human samples with cutting-edge technologies such as mass and spectral cytometry and single-cell sequencing. “Our finding that particular immune signatures distinguish different forms of ALS could be important for designing ‘personalized’ treatments tailored to specific subgroups of patients,” she notes.
An added advantage is that ALS4-related dysfunctional CD8 T cells can be detected in peripheral blood, which is easily accessible compared to cerebrospinal fluid, which requires an invasive procedure for collection. Another sighting by the Mount Sinai team-; that ALS4-associated TEMRA CD8 T cells protect mice against glioma, a type of cancer that occurs in the brain; opens the door to new therapeutic research in this area.
“Our finding of a link between the immune and central nervous systems in ALS4 disease has immediate implications for other types of ALS, other neurodegenerative disorders, and for cancer,” Dr. Marazzi said. “In addition to making important breakthroughs in the pathogenesis of ALS, our work highlights the pioneering work of Mount Sinai researchers in the fields of neuroscience and immunology.”
Campisi, L. et al. (2022) Clonally expanded CD8 T cells characterize amyotrophic-4 lateral sclerosis. Nature. doi.org/10.1038/s41586-022-04844-5.
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