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Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease
Vanessa Brochard, … , Etienne C. Hirsch, Stéphane Hunot
Vanessa Brochard, … , Etienne C. Hirsch, Stéphane Hunot
Published December 22, 2008
Citation Information: J Clin Invest. 2009;119(1):182-192. https://doi.org/10.1172/JCI36470.
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Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease

Abstract

Parkinson disease (PD) is a neurodegenerative disorder characterized by a loss of dopamine-containing neurons. Mounting evidence suggests that dopaminergic cell death is influenced by the innate immune system. However, the pathogenic role of the adaptive immune system in PD remains enigmatic. Here we showed that CD8+ and CD4+ T cells but not B cells had invaded the brain in both postmortem human PD specimens and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD during the course of neuronal degeneration. We further demonstrated that MPTP-induced dopaminergic cell death was markedly attenuated in the absence of mature T lymphocytes in 2 different immunodeficient mouse strains (Rag1–/– and Tcrb–/– mice). Importantly, similar attenuation of MPTP-induced dopaminergic cell death was seen in mice lacking CD4 as well as in Rag1–/– mice reconstituted with FasL-deficient splenocytes. However, mice lacking CD8 and Rag1–/– mice reconstituted with IFN-γ–deficient splenocytes were not protected. These data indicate that T cell–mediated dopaminergic toxicity is almost exclusively arbitrated by CD4+ T cells and requires the expression of FasL but not IFNγ. Further, our data may provide a rationale for targeting the adaptive arm of the immune system as a therapeutic strategy in PD.

Authors

Vanessa Brochard, Béhazine Combadière, Annick Prigent, Yasmina Laouar, Aline Perrin, Virginie Beray-Berthat, Olivia Bonduelle, Daniel Alvarez-Fischer, Jacques Callebert, Jean-Marie Launay, Charles Duyckaerts, Richard A. Flavell, Etienne C. Hirsch, Stéphane Hunot

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Could this explain the link between vitamin D and PD

Submitter: Zakariyya Vali | zv5@le.ac.uk

Leicester Medical School, University of Leicester, UK

Published January 7, 2009

Dear Editor
With great interest I have read the article by Brochard et al (1). This study is interesting because it could shed some light on a possible mechanism explaining the involvement of vitamin D in PD. Studies have shown vitamin D levels to be significantly lower in patients with PD (2,3). It has also been reported that vitamin D has immuno-modulatory actions, with suggestion of T lymphocytes being the main target of action (4). Most interesting is research by Cippitelli et al (5) which describes the effect of 1,25(OH)2D3 on the activation of the FasL gene in T lymphocytes. They show that 1,25(OH)2D3 inhibits activation-induced cell death, FasL mRNA expression, and that 1,25(OH)2D3-activated VDR represses FasL promoter activity. Combining these findings with the importance of the FasL in DN cell degeneration highlighted here by Brochard et al, could provide an explanation for a possible role of vitamin D in the pathogenesis of PD, consequently leading to novel treatments. A randomised trial is currently taking place at Emory University looking at the clinical effects of vitamin D repletion in patients with PD(6); it will be interesting to see what the results show once the trial is completed.

References

  1. Brochard V, Combadiere B, Prigent A, Laouar Y, Perrin A, Beray-Berthat V, et al. Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J.Clin.Invest. 2008 Dec 22. pii: 36470. doi: 10.1172/JCI36470.
  2. Evatt ML, Delong MR, Khazai N, Rosen A, Triche S, Tangpricha V. Prevalence of vitamin d insufficiency in patients with Parkinson disease and Alzheimer disease. Arch.Neurol. 2008 Oct;65(10):1348-1352.
  3. Sato Y, Kikuyama M, Oizumi K. High prevalence of vitamin D deficiency and reduced bone mass in Parkinson's disease. Neurology 1997 Nov;49(5):1273-1278.
  4. Mullin GE, Dobs A. Vitamin d and its role in cancer and immunity: a prescription for sunlight. Nutr.Clin.Pract. 2007 Jun;22(3):305-322.
  5. Cippitelli M, Fionda C, Di Bona D, Di Rosa F, Lupo A, Piccoli M, et al. Negative regulation of CD95 ligand gene expression by vitamin D3 in T lymphocytes. J.Immunol. 2002 Feb 1;168(3):1154-1166.
  6. http://clinicaltrials.gov/ct2/show/NCT00571285

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