During a session at 38, the Congress of the French Society of Rheumatology (SFR 2025) in Paris, France, Nicolas Villain, MD, neurologist at Pitié-Salpêtrière Hospital in Paris, France, reviewed current evidence linking inflammation to neurodegenerative disease. His presentation focused on how systemic and central immune mechanisms may contribute to neuronal injury and progressive neurodegeneration.

Observational studies provide the earliest indications of such links, showing associations between certain systemic inflammatory diseases — including systemic lupus erythematosus, Sjögren syndrome, and Behçet disease — as well as some biologic or immunomodulatory treatments for systemic disorders, and the occurrence of degenerative dementias. Although these data do not establish causality, they suggest that chronic immune activation may influence long-term neurologic outcomes.

These associations are supported by the presence of both innate and adaptive immune systems within the brain. Key effectors of innate immunity include microglia and astrocytes, which also contribute to the maintenance of the blood-brain barrier (BBB). Components of adaptive immunity include the glymphatic system, identified approximately 15 years ago, and macrophages located in the cerebral perivascular spaces. These immune elements are mobilized in response to traumatic injury to brain tissue.

Autoimmune Models

Progressive multiple sclerosis (MS) represents a useful model to explore the relationship between autoimmune diseases and neurodegeneration.

• In contrast to individuals without neurologic disease, patients with MS show substantial infiltration of immune cells within the brain parenchyma, particularly B and T lymphocytes, accompanied by antibody production directed against myelin antigens.
• Even in the absence of active cellular infiltration, a latent inflammatory state persists, characterized by the chronic activation of microglia and astrocytes. This state promotes oxidative stress and the release of prodegenerative mediators, leading to neuronal and axonal loss, progressive synaptic degeneration, and eventual cerebral atrophy.
• Among the therapies for MS, only ocrelizumab, a monoclonal antibody targeting CD20 expressed on B lymphocytes, has demonstrated modest efficacy in slowing the progression of progressive forms of the disease. Other anti-CD20 agents have not shown comparable benefits in clinical trials.

Another instructive model is anti-IgLON5 autoimmune encephalitis, a rare disorder characterized by the production of immunoglobulin G4 antibodies directed against IgLON5, a neuronal surface protein involved in interneural communication. Loss of IgLON5 protein leads to neuronal disorganization and promotes the formation of tau proteins, which accumulate as aggregates. These deposits are associated with low-grade cerebral inflammation and infiltration by B and T lymphocytes.

Taken together, these observations support the hypothesis that persistent systemic inflammation can compromise the BBB and activate microglia and astrocytes. This activation is accompanied by cytokine production, which drives neuronal loss and synaptic dysfunction. Several clinical trials have evaluated agents targeting interleukin (IL)-1, IL-6, and IL-7, with mixed and inconclusive results.

Neurodegenerative Disorders

In primary neurodegenerative disorders, such as Alzheimer’s disease (AD), the inflammatory profile differs from that seen in autoimmune conditions. Brain tissue from patients with AD does not show B- or T-lymphocyte infiltration. Instead, microglial activation predominates and appears to occur in two phases.

• When pronounced, early microglial activation is associated with a more favorable prognosis.
• Secondary activation predicts more severe neurodegeneration.

Genome-wide association studies have identified clusters of gene variants that promote microglial activation, particularly through pathways involving triggering receptor expressed on myeloid cells 2. These findings suggest that microglial activation is not solely a secondary response to abnormal protein accumulation, such as tau or amyloid-beta.

In AD, the levels of regulatory T lymphocytes are reduced, leading to increased reactivity of microglia and astrocytes. Low-dose IL-2 is currently being evaluated in phase 3 trials with the goal of restoring regulatory T-cell populations. These studies followed numerous earlier trials of anti-inflammatory strategies in AD, none of which demonstrated a clear clinical benefit.

Aggregates of alpha-synuclein proteins are a defining pathologic feature in Parkinson’s disease (PD). The proposed mechanisms underlying their formation include mitochondrial and lysosomal dysfunction, although these pathways remain underexplored.

Current Perspective

Overall, immune-mediated mechanisms offer plausible pathways to explain certain aspects of the pathophysiology of AD and PD. However, current evidence remains at the hypothesis stage.

This story was translated from Univadis France, part of the Medscape Professional Network.