Evidence for a role of adaptive immune response in the disease pathogenesis of the MPTP mouse model of Parkinson's disease.
Parkinson's disease (PD) is the second most common neurodegenerative disease and results from the loss of dopaminergic neurons of the nigrostriatal pathway. The pathogenesis of PD is poorly understood, but inflammatory processes have been implicated. Indeed increases in the number of major histocompatibility complex II (MHC II) reactive cells have long been recognised in the brains of PD patients at post-mortem. However whether cells expressing MHC II play an active role in PD pathogenesis has not been delineated. This was addressed utilising a transgenic mouse null for MHC II and the parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In wild-type mice MHC II levels in the ventral midbrain were upregulated 1-2 days after MPTP treatment and MHC II was localized in both astrocytes and microglia. MHC II null mice showed significant reductions in MPTP-induced dopaminergic neuron loss and a significantly reduced invasion of astrocytes and microglia in MHC II null mice receiving MPTP compared with controls. In addition, MHC II null mice failed to show increases in interferon-γ or tumour necrosis factor-α in the brain after MPTP treatment, as was found in wild-type mice. However, interleukin-1β was significantly increased in both wild-type and MHC II null mice. These data indicate that in addition to microglial cell/myeloid cell activation MHC Class II-mediated T cell activation is required for the full expression of pathology in this model of PD.
Institute of Medical Sciences, Foresterhill, University of Aberdeen, Aberdeen, AB25 2ZD, United Kingdom.
Heather L
HL
Martin
Institute of Medical Sciences, Foresterhill, University of Aberdeen, Aberdeen, AB25 2ZD, United Kingdom.
Matteo
M
Santoro
Institute of Medical Sciences, Foresterhill, University of Aberdeen, Aberdeen, AB25 2ZD, United Kingdom.
Sarah
S
Mustafa
Institute of Medical Sciences, Foresterhill, University of Aberdeen, Aberdeen, AB25 2ZD, United Kingdom.
Gernot
G
Riedel
Institute of Medical Sciences, Foresterhill, University of Aberdeen, Aberdeen, AB25 2ZD, United Kingdom.|Ocular Immunology Program, Centre for Ophthalmology and Visual Science, the University of Western Australia, Western Australia, 6009, Australia.|Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Western Australia, 6009, Australia.
John V
JV
Forrester
Institute of Medical Sciences, Foresterhill, University of Aberdeen, Aberdeen, AB25 2ZD, United Kingdom.
Peter
P
Teismann
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D056704:Adaptive Immunity / Q000235:genetics / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020267:MPTP Poisoning / Q000139:chemically induced / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D000949:Histocompatibility Antigens Class II; D008840:Microfilament Proteins; D012333:RNA, Messenger; D015102:3,4-Dihydroxyphenylacetic Acid; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase
MHCII; MPTP; Parkinson's disease; microglia; neuroinflammation