Brain’s Secret “Guardian Peptides” Unlock New Hope for MS and Alzheimer’s

Scientists have identified brain-produced peptides that help regulate the immune system, providing a potential new approach to treating diseases like MS and Alzheimer’s. Credit: SciTechDaily.com Scientists have discovered that the brain produces “guardian peptides” that maintain its immune balance, potentially offering new treatments for neuroinflammatory diseases like MS and Alzheimer’s.

The brain is in constant communication with the body’s immune system, working to maintain a delicate balance between defending against infection and protecting healthy tissue.

Researchers at Washington University School of Medicine in St. Louis have now uncovered how this balance is achieved. In a study with mice, they discovered that the brain and spinal cord produce fragments of immune-stimulating proteins, known as “guardian peptides,” which help the central nervous system regulate its immune activity. These peptides maintain a stable, healthy exchange of information with the immune system.

Published today (October 30) in Nature , this research could pave the way for new treatments for diseases like multiple sclerosis (MS) and Alzheimer’s, where immune regulation is crucial. Understanding Guardian Brain Peptides

“We have found guardian brain peptides that actively engage with the immune system to keep it in check, possibly preventing destructive immune responses,” said Jonathan Kipnis, PhD, the Alan A. and Edith L. Wolff Distinguished Professor of Pathology & Immunology and a BJC Investigator at WashU Medicine. “We think such peptides help the immune system to maintain a state of ‘immune privilege.’ We are intrigued by the possibility of developing such proteins from healthy brains into a therapy to suppress inappropriate immune responses and develop better disease-modifying therapies for neuroinflammatory diseases.”

Immune surveillance involves a subset of T cells that can initiate an immune response when alerted to a threat. That alert comes in the form of a tiny protein fragment – a sample of the potential threat – displayed on the surface of another group of presenting immune cells. If T cells deem the protein fragment threatening, they mount an attack. Immune Interactions at the Brain’s Borders

The researchers found that guardian peptides were presented by immune cells at the interface of the brain’s borders, where they attracted and activated a subset of immune T cells whose function is regulatory, such that these cells dampen abnormal immune reactions.

Min Woo Kim, a graduate student in WashU Medicine’s Medical Scientist Training Program and a researcher in the Kipnis lab, examined presenting immune cells from the brain and its associated immune tissues in healthy mice. He found an abundance of brain proteins presented by such cells, with the dominant protein being a component of myelin sheath, the protective cover on neurons that becomes damaged in MS.

The researchers found that in mice with MS, such proteins were drastically depleted. By adding the missing brain-derived peptides through injection of vesicles – membrane-bound compartments – into the cerebrospinal fluid of mice with MS, the scientists found that the therapy activated and expanded a subset of suppressor T cells. Motor function improved, and disease progression slowed in the treated mice compared with mice that received control vesicles. Novel Diagnostic Opportunities for Neurodegenerative Diseases

“We have identified a novel process in the brain where the organ actively engages with the immune system to present a healthy image of itself,” Kim said. “That image looks different in mice with multiple sclerosis. We think that other neuroinflammatory and even neurodegenerative diseases may have unique protein signatures presented to the immune system, opening the exciting possibility of using such signatures as a diagnostic tool for early diagnosis.”

Reference: “Endogenous self-peptides guard immune privilege of the central nervous system” by Min Woo Kim, Wenqing Gao, Cheryl F. Lichti, Xingxing Gu, Taitea Dykstra, Jay Cao, Igor Smirnov, Pavle Boskovic, Denis Kleverov, Andrea F. M. Salvador, Antoine Drieu, Kyungdeok Kim, Susan Blackburn, Clair Crewe, Maxim N. Artyomov, Emil R. Unanue and Jonathan Kipnis, 30 October 2024, Nature .
DOI: 10.1038/s41586-024-08279-y

WashU Medicine collaborators on the study include Cheryl Lichti, PhD, an associate professor of pathology & immunology; Clair Crewe, PhD, an assistant professor of cell biology & physiology; Maxim N. Artyomov, PhD, the Alumni Endowed Professor of Pathology & Immunology; and the late Emil R. Unanue, PhD, who died before seeing the study’s completion. Unanue, a 1995 Albert Lasker Basic Medical Research Award winner, was a pioneer in describing the interactions between T cells and presenting cells that make it possible for the former to recognize and respond to foreign invaders.

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