Disease mechanisms as subtypes: Immune dysfunction in Parkinson's disease

Contaldi, Elena; Magistrelli, Luca; Comi, Cristoforo

doi:10.1016/b978-0-323-85555-6.00008-4

Cited by 2 publications

(1 citation statement)

References 289 publications

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“…The elicited antibodies could conceivably be sequestered in pathological peripheral tissues after leaving the blood. Another possibility is that patients with PD may have a compromised immune system less able to respond to immunization 29 , which is supported by a recent report suggesting that B cell numbers in peripheral blood are reduced in patients with PD 30 . This potential alteration in immune response will be investigated in future clinical development studies in patients with PD.…”

Section: Discussionmentioning

confidence: 92%

Target engagement and immunogenicity of an active immunotherapeutic targeting pathological α-synuclein: a phase 1 placebo-controlled trial

Eijsvogel,

Misra,

Concha-Marambio

et al. 2024

Nat Med

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Investigational therapeutics that target toxic species of α-synuclein (αSyn) aim to slow down or halt disease progression in patients with Parkinson’s disease (PD). Here this 44-week, randomized, placebo-controlled, double-blind, single-center phase 1 study investigated safety, tolerability and immunogenicity of UB-312, an active immunotherapeutic targeting pathological αSyn, in patients with PD. The primary outcome measures were adverse event frequency and change in anti-αSyn antibody titers in blood and cerebrospinal fluid (CSF). Exploratory outcomes were changes in clinical scales and biomarker-based target engagement as measured by seed amplification assays. Twenty patients were randomized 7:3 (UB-312:placebo) into 300/100/100 μg or 300/300/300 μg (weeks 1, 5 and 13) intramuscular prime-boost dose groups. Safety was similar across groups; adverse events were mostly mild and transient. Two patients experienced three serious adverse events in total, one possibly treatment related; all resolved without sequalae. Anti-αSyn antibodies in serum from 12/13 and CSF from 5/13 patients who received three UB-312 doses confirmed immunogenicity. Mean serum titers (in log-dilution factor) increased from baseline by 1.398 and 1.354, and peaked at week 29 at 2.520 and 2.133, for 300/100/100 μg and 300/300/300 μg, respectively. CSF titers were 0 at baseline and were 0.182 and 0.032 at week 21, respectively. Exploratory analyses showed no statistical differences in clinical scales but a significant reduction of αSyn seeds in CSF of a subset of UB-312-treated patients. These data support further UB-312 development. ClinicalTrials.gov:NCT04075318.

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Section: Discussionmentioning

confidence: 92%

Target engagement and immunogenicity of an active immunotherapeutic targeting pathological α-synuclein: a phase 1 placebo-controlled trial

Eijsvogel,

Misra,

Concha-Marambio

et al. 2024

Nat Med

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Inflammation in the pathogenesis of neurodegenerative diseases

Goncharov,

Reverchuk,

Shupletsova

2023

Cytokines and inflammation

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Summary Introduction. Neurodegenerative diseases (ND) are common chronic disorders associated with progressive damage to the nervous tissue system. The participation of the immune system in the development of neurodegenerative diseases was confirmed by data on the activation of microglia, the presence of an imbalance in the composition and phenotype of peripheral immune cells and the presence of disorders of humoral immunity, dysbiosis of the intestinal microbiota in patients with this pathology. Discussion. It has been established that inflammation plays a key role in the pathogenesis of diseases associated with progressive damage to the nervous system. The article analyzes the mechanisms of development of “subclinical” chronic inflammation that leads to the development of old age and related diseases, including neurodegenerative pathology. At least three groups of factors associated with old age play a role in the formation of a “proinflammatory status”: mitochondrial dysfunction, the development of an age-related “proinflammatory” status of the immune system, and chronic stress. Mitochondrial dysfunction is associated primarily with disruption of mitophagy processes: failure of quality control mechanisms as a result of disruption of mitophagy processes leads to the accumulation of terminally damaged mitochondria, which become a threat to cell survival. Inadequate removal of damaged mitochondria leads to hyperactivation of inflammatory signaling pathways and subsequently to chronic systemic inflammation and the development of inflammatory diseases. A high level of deletions in the mitochondrial genetic apparatus that accumulates with age inevitably leads to increased formation of reactive oxygen species, which in turn are assumed to be one of the leading activators of the cytosolic NLRP3 protein, the main component of inflammasomes. Increased inflammosome formation ultimately leads to caspase-1-dependent production of proinflammatory interleukins. Age-related inflammatory imbalance is associated with the fact that during life the immune system, the main protective mechanism of which is the inflammatory response, copes with constant antigenic attacks. However, over time, upon reaching a certain threshold, the reaction of the immune system becomes excessive, characterized by increased production of coagulation factors, proinflammatory cytokines, acute phase proteins of inflammation, prostaglandins and leukotrienes. Conclusion. Immunological changes that develop during chronic (long-term) stress are the result of a disruption of the homeostatic connection between the neuroendocrine and immune systems, leading to the formation of an inflammatory background that complements the “pro-inflammatory status” that develops as a result of age-related changes in the immune system and disruption of mitophagy mechanisms.

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Disease mechanisms as subtypes: Immune dysfunction in Parkinson's disease

Cited by 2 publications

References 289 publications

Target engagement and immunogenicity of an active immunotherapeutic targeting pathological α-synuclein: a phase 1 placebo-controlled trial

Target engagement and immunogenicity of an active immunotherapeutic targeting pathological α-synuclein: a phase 1 placebo-controlled trial

Inflammation in the pathogenesis of neurodegenerative diseases

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