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.
