Brain Advance Access originally published online on October 11, 2005
Brain 2005 128(11):2665-2674; doi:10.1093/brain/awh625
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A possible role for humoral immunity in the pathogenesis of Parkinson's disease
1 Prince of Wales Medical Research Institute, University of New South Wales, Randwick, 2 Department of Neurology, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia and 3 Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan
Correspondence to: Professor G. M. Halliday, PhD, Prince of Wales Medical Research Institute, University of New South Wales, Randwick, Sydney, NSW 2031, Australia E-mail: g.halliday{at}unsw.edu.au
The pathogenesis of idiopathic Parkinson's disease is unknown, but nigral degeneration and depigmentation are associated with microglial inflammation and anti-inflammatory medications appear to protect against the disease. The possibility that humoral immunity may play a role in initiating or regulating the inflammation has been suggested by experimental studies triggering dopamine cell death using a variety of transfer strategies and the observation of CD8+ T lymphocytes and complement in the nigra in Parkinson's disease. We analysed the association between degeneration and humoral immune markers in brain tissue of patients with idiopathic (n = 13) or genetic (n = 2 with 
-synuclein and n = 1 with parkin mutations) Parkinson's disease and controls without neurological disease (n = 12) to determine the humoral immune involvement in Parkinson's disease. Formalin-fixed tissue samples from the substantia nigra and primary visual cortex for comparison were stained for -synuclein, major histocompatibility complex II (HLA), immunoglobulin M (IgM), immunoglobulin G (IgG), IgG subclasses 1–4 and IgG receptors Fc
R I–III. Antigen retrieval and both single immunoperoxidase and double immunofluorescence procedures were employed to determine the cell types involved and their pattern and semiquantitative densities. Significant dopamine neuron loss occurred in all patients with Parkinson's disease, negatively correlating with disease duration (r = –0.76, P = 0.002). Although all patients had increased inflammatory HLA immunopositive microglia, the degree of inflammation was similar throughout the disease (r = 0.08, P = 0.82). All patients with Parkinson's disease had IgG binding on dopamine neurons but not IgM binding. Lewy bodies were strongly immunolabelled with IgG. A mean 30 ± 12% of dopamine nigral neurons were immunoreactive for IgG in Parkinson's disease with the proportion of IgG immunopositive neurons negatively correlating with the degree of cell loss in the substantia nigra (r = –0.67, P < 0.0001) and positively correlating with the number of HLA immunopositive microglia (r = 0.51, P = 0.01). Most neuronal IgG was the IgG1 subclass with some IgG3 and less IgG2 also found in the damaged substantia nigra. The high affinity activating IgG receptor, FcRI, was expressed on nearby activated microglia. The low affinity activating IgG receptor, FcRIII was expressed on cells morphologically resembling lymphocytes, whereas immunoreactivity for the inhibitory IgG receptor FcRII was absent in all cases. This pattern of humoral immune reactivity is consistent with an immune activation of microglia leading to the targeting of dopamine nigral neurons for destruction in both idiopathic and genetic cases of Parkinson's disease.
Key Words: Parkinson's disease; microglia; humoral immunity; neuropathology
Abbreviations: IgG = immunoglobulin G; IgM = immunoglobulin M; SN = substantia nigra pars compacta
Received September 3, 2004. Revised July 30, 2005. Accepted August 1, 2005.
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