Alpha-synuclein insoluble inclusions manifest in brain oligodendrocyte cells as multiple system atrophy, an uncommon and deadly neurodegenerative illness. The pathophysiological results are characterized by neurodegeneration, demyelination, and neuroinflammation. Myelin, the protective coating that surrounds nerve axons, is made by oligodendrocytes.
The pathology caused by overexpression of alpha-synuclein in oligodendrocytes induced changes that included infiltration of CD4+ and CD8+ T cells into the brain, as observed in human post-mortem brains, according to a 2020 Acta Neuropathological study by Ashley Harms, Ph.D., and colleagues from the University of Alabama at Birmingham. The study used a mouse model to demonstrate these changes.
In the mouse model, the UAB researchers also demonstrated that mice with a genetic deficiency in CD4+ T cells had less peripheral immune cell infiltration and less demyelination. The proinflammatory cytokine interferon-gamma, or IFNγ, was significantly produced in addition to an increase in CD4+ T-cells that were also positive for the transcription factor T-bet in mice with a healthy immune system that were overexpressed in alpha-synuclein in the mouse model.
Now, using the mouse model and genetic and pharmacological methods, Harms and colleagues have demonstrated in a study published in Acta Neuropathological Communications that IFNγ is produced by invading CD4+ T-cells and that IFNγ drives the mechanisms that induce multiple system atrophy.
The UAB Department of Neurology associate professor Harms stated, “These results suggest that IFNγ represents a potential future disease-modifying therapeutic target in multiple system atrophy.” “Future studies are needed to determine the timing and duration of treatment, but these results are promising.There is no known disease-modifying treatment for multiple system atrophy yet.
An artificial virus that causes oligodendrocytes to overexpress human alpha-synuclein is used in the animal model.
The UAB researchers demonstrated that the lack of Tbet in the mouse model of multiple system atrophy led to decreased neuroinflammation, demyelination, and neurodegeneration using animals in which the necessary transcription factor for IFNγ in Th1 helper T cells, Tbet, has been eliminated.
Nonetheless, since Tbet modulates other routes besides IFNγ, it remained unclear that IFNγ was the cause of that illness.
The researchers treated the mice with IFNγ-neutralizing antibodies before and during alpha-synuclein overexpression to precisely ascertain the function of IFNγ in the mouse model. The antibody treatment, they discovered, decreased demyelination, and inhibited both neuroinflammation and the entry of CD4+ and CD8+ T cells into the brain.
In the mouse model of multiple system atrophy, CD4+ T cells, not other resident or invading immune cells, produce the majority of the IFNγ, as demonstrated using a genetically ingenious trick—a Thy1.1 reporter mouse. Thy1.1 is co-expressed in any cell that generates IFNγ thanks to the reporter mouse’s Thy1.1 gene being placed into the IFNγ gene’s promoter. Since Thy1.1 is a protein found on the cell surface, it can be used to identify cells that produce IFN.
The researchers retrieved brain tissue from the reporter mice after alpha-synuclein was overexpressed. They then utilized immunohistochemistry to identify immunological groups known to produce IFNγ, such as CD4+ T cells, CD8+ T cells, natural killer cells, astrocytes, and microglial cells. It was discovered that the vast majority of Thy1.1 was expressed on the cell surface of CD4+ T lymphocytes in reaction to alpha-synuclein overexpression.
“These data indicate the fact that the CD4+ T cell effector a subtype, Th1 cells, facilitate the illness process via the generation of IFNγ,” Harms explained. As our findings show that other immune cell types like CD8+ T cells, B cells and natural killer cells do not substantially produce IFNγ following alpha-synuclein overexpression in oligodendrocytes; but CD4+ T cells are able to drive multiple system atrophy pathology via IFNγ expression.
Journal Reference
Nicole J. Corbin-Stein et al, IFNγ drives neuroinflammation, demyelination, and neurodegeneration in a mouse model of multiple system atrophy, Acta Neuropathologica Communications (2024). DOI: 10.1186/s40478-023-01710-x.
