CD4+ T cells contribute to neurodegeneration in Lewy body dementia

Science, 2021 · DOI: 10.1126/science.abf7266 · Published: November 12, 2021

Simple Explanation

The study found that T cells are present near Lewy bodies and damaged brain cells in people with Lewy body dementia (LBD). In LBD patients, specific T cells in the brain fluid showed increased levels of a protein called CXCR4, which helps cells move around. The fluid also had higher levels of a substance called CXCL12, linked to nerve damage. When exposed to a part of a protein found in Lewy bodies, certain T cells expanded and produced a substance called Interleukin 17A. This suggests that blocking CXCR4-CXCL12 could help stop harmful T cells from entering the brain in LBD.

Study Duration

Not specified

Participants

Healthy aged controls (n=162) and patients with clinical DLB and PD (collectively referred to as PD-DLB; n=148)

Evidence Level

Not specified

Key Findings

1
T cells are located in close proximity to Lewy bodies and dopaminergic neurons in the brains of individuals with LBD.
2
CD4+ T cells in the cerebrospinal fluid (CSF) of LBD patients exhibit upregulated expression of CXCR4.
3
Stimulation with a phosphorylated α-synuclein epitope leads to clonal expansion and increased Interleukin 17A expression by CD4+ T cells.

Research Summary

The immune system is implicated in the neurodegenerative process of Lewy body dementia. T cells home to the LBD brain and reside in close proximity to α-synuclein deposits. In conclusion, these results implicate Th17 cell involvement in the degeneration of neurons in LBD.

Practical Implications

Therapeutic Target

The CXCR4-CXCL12 signaling axis represents a potential therapeutic target for LBD.

Drug Repurposing

Existing CXCR4 antagonists could be repurposed to inhibit the trafficking of pathological Th17 cells into the LBD brain.

Autoimmunity in LBD

The study provides a mechanism for Th17 cell-mediated dopaminergic cell death via secretion of inflammatory IL-17A, implicating autoimmunity in LBD.

Study Limitations

1
The mechanism regulating T cell brain homing in LBD remains unknown.
2
Sample sizes for some analyses were relatively small.
3
Further research is needed to validate these findings in larger and more diverse cohorts.

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