Autoimmunity in the Dopaminergic System: an underexplored Mechanism in Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide, traditionally defined by dopaminergic neuron loss in the substantia nigra and the accumulation of misfolded α-synuclein aggregates. While proteinopathy has long been considered the primary driver of pathology, growing evidence suggests implicated immune and autoimmune-like mechanisms in PD onset and progression.

Innate immune activation in PD is characterized by microglial reactivity, upregulation of human leukocyte antigen (HLA), and elevated pro-inflammatory cytokines, correlating with disease severity. Adaptive immune dysregulation is reflected by α-synucleinreactive T cells, impaired regulatory T cell function, altered B cell populations, and circulating α-synuclein autoantibodies, which may initially exert protective effects but acquire pathogenic properties as disease advances. These immune alterations parallel features of classical autoimmune disorders, suggesting immune-mediated targeting of dopaminergic neurons.

Understanding immune involvement has informed novel therapeutic strategies. Antibody-based therapies targeting pathogenic α-synuclein and immunomodulatory approaches directed at inflammatory pathways, including NLR family pyrin domain containing 3 (NLRP3) inflammasome and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling, aim to modify disease progression rather than merely alleviate symptoms. However, precise regulation of immune-targeted therapies is necessary, as excessive suppression or unintended activation has the potential to aggravate neuroinflammation or impair host immune defense.

While it remains unclear whether immune dysregulation initiates pathology or amplifies existing neuronal damage from alternative underlying causes, its consistent presence across studies highlights its importance in PD pathogenesis. Recognizing this perspective improves our understanding of PD and supports the development of novel, disease-modifying therapies aimed at preserving dopaminergic neuron integrity and improving long-term outcomes.