image: The upper half of the scheme (above the dashed line) illustrates immune mechanisms in Parkinson's disease (PD), while the lower half is specific to multiple sclerosis (MS). In PD, α-synuclein accumulation activates microglia, leading to the release of IL-1β, which promotes astrocyte activation and neuroinflammation. Activated microglia present antigen to T cells, promoting Th17 differentiation and IL-17A production. In MS, autoreactive T cells are primed by antigen-presenting cells (APCs) in the periphery, cross the blood–brain barrier (BBB), and infiltrate into the CNS. Within the CNS, Th1 and Th17 cells release IFN-γ and IL-17A, contributing to demyelination and neuronal injury
Credit: Professor Qiang Liu, Tianjin Medical University General Hospital, China Image source link: https://link.springer.com/article/10.1007/s44466-025-00011-3
Published in Volume 1 of the journal Immunity & Inflammation on December 18, 2025, the article "Reinventing brain immunity in neurodegeneration" contrasts the immune landscapes of Parkinson's disease (PD)—a classic neurodegenerative disorder—and multiple sclerosis (MS), a prototypical neuroimmune disease. “While MS research has successfully yielded various disease-modifying therapies (DMTs), treatments for PD largely remain symptomatic,” the authors argue that “a deeper understanding of PD's immunology, informed by lessons from MS, is key to bridging this therapeutic gap.”
The review details how in PD, misfolded alpha-synuclein protein acts as a "danger signal," triggering persistent activation of microglia (the brain's resident immune cells) and subsequent inflammation that damages dopamine-producing neurons. Notably, about 40% of PD patients harbor T cells that recognize alpha-synuclein, potentially by dendritic cells presenting misfolded α-synuclein released from degenerating neurons. These activated immune cells directly or indirectly contribute to further neuronal damage.
While in MS, distinct microglial activation phenotypes have been observed. Certain microglial subsets and astrocytes exacerbate neuronal injury through releasing pro-inflammatory and cytotoxic mediators, such as TNF-α, reactive oxygen intermediates and nitric oxide (NO). In addition, self-reactive CD4+ T cells attack myelin sheaths, aided by microglia, infiltrating macrophages and astrocytes, leading to demyelination and neurodegeneration as well.
“Broader systemic immune factors also play roles in both conditions,” the authors point out. PD shares genetic risk loci with several immune disorders, and disturbances in gut microbiota are thought to link peripheral inflammation to brain pathology. Similarly, MS relapse is closely tied to peripheral immune activation, underscoring the bidirectional communication between the CNS and the body's immune system.
“Current PD research relies on diverse preclinical models due to limitations in human and primate studies.” the authors further point out. They summarize current immune‑associated genes that are found to be implicated in PD and MS, and compare the advantages and limitations of each immune-associated preclinical model of PD or MS, including the toxin-induced models, genetic models in laboratory animals, and inflammation-based models. These genes and models provide valuable evidence for studying mechanism and developing potential strategies.
Therapeutically, the mature immunotherapeutic landscape of MS provides a valuable roadmap for PD drug development. Immune modulation is a promising frontier, strategies like targeting key immune and inflammatory regulators implicated in disease progression, restoring lysosomal function to enhance α-synuclein clearance, as well as inhibiting the release of pro-inflammatory cytokines using immuno-suppressants, have shown potential.
Vaccination strategies targeting α-synuclein have also gained attraction. And considering the role of gut-brain axis in PD, the microbiome-based therapies have also been evaluated for their potential in alleviating motor and non-motor symptoms of PD patients. However, challenges remain, including the complexity of immune networks, patient heterogeneity, and a lack of long-term clinical data for PD immunotherapies.
The authors conclude that comparing PD and MS not only deepens the understanding of neurodegeneration but also lays a foundation for precision medicine strategies based on immune regulation. “Future research focusing on the dynamic crosstalk between immune cells and stage-specific immune signatures will be vital for advancing new treatments,” Prof. Qiang Liu remarks.
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Reference
DOI: 10.1007/s44466-025-00011-3
About Immunity & Inflammation
Immunity & Inflammation is a newly launched open-access journal co-published by the Chinese Society for Immunology and Springer Nature under the leadership of Editors-in-Chief Prof. Xuetao Cao and Prof. Jules A. Hoffmann. Immunity & Inflammation aims to publish major scientific questions and cutting-edge advances that explore groundbreaking discoveries and insights across the spectrum of immunity and inflammation, from basic science to translational and clinical research.
Website: https://link.springer.com/journal/44466
About Authors
Professor Qiang Liu from Tianjin Medical University General Hospital, China
Prof. Qiang Liu is the Vice President of Tianjin Medical University General Hospital and the Director of the Tianjin Neurological Institute. He has received numerous awards, including the Xplorer Prize in Medical Science, the Chinese Medical Science and Technology Award (Youth Award), the Shulan Medical Youth Award, the American Heart Association (AHA) Scientist Development Grant, and the International Society of Neuroimmunology (ISNI) Clinical Mid-Career Award. His research focuses on the immune mechanisms of brain diseases and clinical intervention.
Dr. Huachen Huang from Tianjin Medical University General Hospital, China
Dr. Huachen Huang is an Assistant Research Fellow at the Tianjin Neurological Institute, Tianjin Medical University General Hospital. Her research focuses on the immune mechanisms underlying neural injury and repair.
Funding information
This work was supported in part by the National Natural Science Foundation of China (Grant Numbers 82225015, 82488301, 82171284, 82301495 and 82301545), the New Cornerstone Science Foundation through the XPLORER PRIZE, and the National Key R&D Program of China (Grant Numbers 2021ZD0202400 and 2022YFC2502401).
Method of Research
Systematic review
Subject of Research
Not applicable
Article Title
Reinventing brain immunity in neurodegeneration
Article Publication Date
18-Dec-2025
COI Statement
The corresponding author Qiang Liu is a member of the Editorial Board of the journal Immunity & Inflammation. However, he was not involved in the peer-review or decision-making process for this manuscript. The authors declare no other competing interests.