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
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Summary |
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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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Introduction |
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The pathogenesis of idiopathic Parkinson's disease is currently unknown, but at the cellular level, significant microglial inflammation is observed in the region of dopaminergic degeneration (Orr et al., 2002
; Hunot and Hirsch, 2003) and some protection against its development occurs when long-term anti-inflammatory medications are taken (Chen et al., 2003). Microglia are the main immunocompetent cell within the CNS (Aloisi, 2001), capable of antigen presentation to lymphocytes (Kreutzberg, 1996) and exchange with blood macrophages (Flugel et al., 2001). The observation that small numbers of CD8+ T lymphocytes occur in proximity to degenerating nigral neurons (McGeer et al., 1988) and that components of the classical or antibody-triggered complement cascade occur in nigral Lewy bodies (Yamada et al., 1992) in patients with Parkinson's disease suggests that the pathological process may involve immune-mediated mechanisms.
Humoral immune mechanisms can trigger microglial-mediated neuronal injury in animal models of Parkinson's disease (He et al., 2002), although there is currently a lack of direct evidence that humoral immunity might be involved in the selective death of dopamine neurons in Parkinson's disease. We, therefore, compared the degenerating dopaminergic substantia nigra against the unaffected non-dopaminergic primary visual cortex in idiopathic Parkinson's disease and control patients for the presence of immunoglobulin M (IgM), immunoglobulin G (IgG), IgG subclasses 1–4 and IgG receptors FcRI–III. Although most Parkinsonian patients have sporadic disease, mutations in -synuclein and parkin cause inherited forms of Parkinsonism (Huang et al., 2004) and we also evaluated brain tissue from patients with mutations in these genes for IgG and FcRI expression.
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Patients
All idiopathic Parkinson's disease patients were participants in the Parkinson's New South Wales brain donor programme at the Prince of Wales Medical Research Institute [n = 13, duration 14 ± 6 years; mean age 75 ± 7 years: 4 of these died early (Hoehn and Yahr stages 1–3) from intercurrent illnesses and the other 9 died at end-stage (Hoehn and Yahr stages 4–5)]. Three familial Parkinson's disease cases were assessed: two had
-synuclein A53T gene mutations (durations 1 and 9 years, Hoehn and Yahr stages 1.5 and 4, aged 47 and 53 years respectively) (Spira et al., 2001) and one had a parkin gene mutation (duration 38 years; Hoehn and Yahr stage 5; aged 62 years) (Mizuno et al., 2001). Each clinical diagnosis of idiopathic Parkinson's disease was made by a movement disorder subspecialist neurologist and required the presence of at least two of the following cardinal signs: tremor, rigidity, bradykinesia and postural instability as well as a positive response to levodopa (Gelb et al., 1999). For each case, standardized neurological assessment occurred prospectively on a yearly basis. Responsiveness to and doses of levodopa were noted and disease severity formally staged using the Hoehn and Yahr scale. Prospective written consent for autopsy was obtained from all patients and their next of kin, and the project was approved by the Human Ethics Committee of the University of New South Wales under the Human Tissue Act of the State of New South Wales. After death a detailed neuropathological examination was conducted with application of current diagnostic criteria for idiopathic Parkinson's disease (depigmentation, cell loss and Lewy bodies in the substantia nigra and locus coeruleus) (Gelb et al., 1999) and at this time, prospective data were validated by retrospective questionnaires to relatives and treating physicians. All other neurological and neurodegenerative diseases were excluded, as were cases with head injury, brain tumour, infarction or systemic sepsis.
Controls
Twelve age-matched controls with no history of neurological or psychiatric symptoms and no neuropathological abnormalities were selected (aged 75 ± 9 years). These controls underwent the same clinical and neuropathological follow-up as the Parkinson's disease cases with the same standardized recording procedures. The demographic details of both patients and controls are shown in Table 1. There was no difference (unpaired t-tests, P > 0.05) between the groups in either mean age at death or post-mortem delay (14.5 h for cases and 19.9 h for controls). No patient or control had haematological, immune or inflammatory disorders, or was taking immunosuppressive medication at time of death.
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Tissue preparation
After autopsy the brains were immersion fixed in 15% buffered formalin for 2 weeks. The brainstem was dissected from the cerebrum at the level of the rostral midbrain, and then both cerebrum and brainstem were embedded separately in 4% agarose and cut on a rotary slicer into 3 mm coronal and transverse sections, respectively. Tissue samples were taken for neuropathological diagnosis, as previously described (Halliday et al., 1996
). For the present study, blocks were taken from both the midbrain at the level of the exiting third nerve and from the primary visual cortex and stored in 10% buffered formalin. Idiopathic Parkinson's disease and control midbrain and visual cortex were cryoprotected in 30% buffered sucrose solution, then frozen in mounting medium at –50°C, serially sectioned at 20 µm on a cryostat and mounted onto silanized slides. Idiopathic and familial Parkinson's disease midbrain tissue was paraffin embedded, sectioned at 10 µm on a microtome and then deparaffinized.
Immunohistochemistry
Sections were defatted, rehydrated in alcohols, and antigen retrieved in 4% aluminium chloride, as previously described (Shepherd et al., 2000). Routine immunoperoxidase staining was performed for 48 h at 4°C with a variety of primary antibodies (Table 2), detected with biotinylated secondary antibody (Vector, Burlingame, CA, USA) at a 1:200 dilution for 2 h at 37°C, followed by incubation in the tertiary complex (PK-6100, ABC Vectastain Elite Kit, Vector, Burlingame, CA, USA) at a 1:500 dilution for 2 h at room temperature. Slides were then incubated in Vector NovaRed (SK-4800, Vector, Burlingame, CA, USA) for 10–30 min to visualize the tertiary complex. Sections were then washed, dehydrated through graded ethanols to xylene, coverslipped with DePeX and allowed to dry. Human tonsillar tissue was used as positive control for the immunological markers analysed. Omitting primary antibodies produced appropriate negative controls.
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Double labelling fluorescent immunohistochemistry was performed to determine the identity of IgG, CD64 and CD16 immunopositive cells. Primary antibodies (Table 2) were mixed together and applied to the sections for 48 h at 4°C, then detected with host specific secondary fluorescent antibodies (Table 2) mixed together for 2 h at 37°C. Sections were coverslipped with glycerol and analysed using a Leica DM IRB confocal laser scanning microscope and an Olympus BX51 fluorescence microscope fitted with specific filter systems. The cross-reactivity and specificity of the fluorescent reactions were tested by incubating each primary antibody singly with the secondary antibody solution containing two fluorophores. In these experiments fluorescence microscopy revealed that only the appropriate fluorophore labelled the primary antibody with no cross-reactivity with the second fluorophore observed.
Analysis
The degree of pigmented cell loss in the substantia nigra pars compacta (SN) was evaluated using a previously published areal fraction method (Halliday et al., 1996). Briefly, the area occupied by pigmented neurons in the SN was measured and the areal fraction occupied by pigmented neurons determined for each case by point counting using an 11 x 11 eyepiece grid on x400 magnification. The area was multiplied by the fraction to determine the fraction of the SN occupied by pigmented cells, and the data expressed as a percentage of mean control values. Repeated measurements by the same or different investigators gave an average variance in the area of the SN of 3–7%. The degree of microglial activation was evaluated using a previously published areal fraction method (Shepherd et al., 2000). The areal fraction occupied by HLA-DP/DQ/DR-immunoreactive microglia in two SN sample regions of maximum staining intensity was determined for each case by point counting using an 11 x 11 eyepiece grid on x200 magnification. An average variance of 5–5.5% was demonstrated in repeated measures by the same or different investigators. Areal fraction measurements were used for quantitation as these describe the visual representation of cell densities.
The proportion of IgG-immunopositive to total pigmented SN neurons was quantified in each case and control at x200 magnification. An average variance of 3–5% was demonstrated in repeated measures by the same or different investigators. The degree of cellular immunoreactivity in the pigmented region of the SN and two randomly chosen areas of the visual cortex was evaluated using semiquantitative visual grading (none, mild, moderate, severe) at x100 magnification (with x200 magnification used for confirmation) consistent with standard neuropathological evaluations. There were no differences in the grade given by the same or different investigators on different days.
Statistical differences between groups were evaluated using Mann–Whitney U-tests (StatView software) and correlations between variables evaluated using Spearman rank tests. A P-value of <0.05 was accepted as the level of significance.
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Results |
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As expected, both idiopathic and genetic Parkinson's disease cases had significant pigmented cell loss (average 83% SN cell loss, P < 0.0001) and a significant increase in HLA-immunopositive microglia (average 37% of SN area occupied by activated microglia, P = 0.04) in the SN compared with controls (Fig. 1). The increase in HLA-immunoreactive microglia in Parkinson's disease SN was considered specific owing to the lack of upregulation observed in control SN (Table 3) and control and Parkinson's disease visual cortex (data not shown). Idiopathic and
-synuclein gene mutation cases had Lewy body formation in some of the remaining pigmented SN neurons (Fig. 1C), whereas no Lewy body formation was seen in the few remaining SN neurons in the parkin gene mutation case. Parkinson's disease cases at earlier disease stages had less cell loss than those with end stage disease (Table 3, P = 0.005) with greater SN cell loss correlating with increasing disease duration (R = 0.76, P = 0.002). In contrast, there was no significant difference between the number of HLA-immunopositive microglia over the disease course (Table 3, P = 0.39) or with longer disease durations (r = 0.08, P = 0.82) consistent with a steady inflammatory response throughout the disease.
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Immunopositive staining was observed on some pigmented dopamine neurons in the SN using antibody to IgG but not to IgM. Double label immunofluorescence experiments showed that IgG co-localized with
-synuclein in pigmented SN neurons (Fig. 2A–F). Confocal microscopy revealed IgG concentrating at the cell surface membrane of Parkinson's disease dopamine neurons (Fig. 2A and B) and also on their Lewy bodies (Fig. 2C–F). IgG-immunopositive pigmented neurons and neurites were found in the SN of all idiopathic patients and in the -synuclein and parkin gene mutation patients, but not in control SN or in idiopathic Parkinson's disease visual cortex (Fig. 2G–K). A mean 30 ± 12% of idiopathic Parkinson's disease SN neurons were immunoreactive for IgG with significantly more IgG immunopositive neurons in early-stage compared with end-stage disease (Table 3, P = 0.003). The proportion of IgG-immunopositive neurons negatively correlated with the degree of SN cell loss (R = –0.67, P < 0.0001) and positively correlated with the number of HLA-immunopositive microglia (r = 0.51, P = 0.01). On average, 
4% of remaining pigmented neurons contained Lewy bodies in idiopathic cases and double labelling revealed that all IgG-immunopositive pigmented neurons containing Lewy bodies had both proteins (-synuclein and IgG) in the inclusions (Fig. 2C–F). Analysis of the IgG subclass specificity of this response showed significant immunoreactivity for IgG1 on a large proportion of degenerating SN neurons in most cases (Table 3). There was less immunoreactivity for IgG3 and even less IgG2 on neurons (Table 3). Immunoreactivity for IgG4 was absent in all cases.
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The high affinity receptor Fc
RI (CD64) was present on large amoeboid-shaped cells near the pigmented neurons in -synuclein and parkin gene mutation Parkinson's disease and in 11/12 idiopathic patients, but not in control SN or in Parkinson's disease visual cortex (Fig. 3A–E). Double label immunofluorescence proved the identity of the FcRI-immunopositive amoeboid-shaped cells as activated phagocytic microglia bearing pigment remnants (Fig. 3F–I). No immunoreactivity for the inhibitory IgG receptor FcRII (CD32) was found in any midbrain or cortical section tested in any case. The low affinity IgG receptor FcRIII (CD16) was present on small SN cells in all cases (Fig. 4A) and in 7/12 controls (Fig. 4B). Double labelling experiments revealed that these small cells were not oligodendroglia but morphologically resembled lymphocytes (Fig. 4F and G). No oligodendroglia or FcRIII-immunopositive cells were IgG-immunopositive (Fig. 4D, E, H and I). No FcRIII immunoreactivity was found in the other controls or in the visual cortex (Fig. 4C).
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Discussion |
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The idiopathic cases analysed in the present study had typical levodopa responsive Parkinson's disease. The degree of cell loss and reactive microgliosis were similar to those previously described for similar case types (Fearnley and Lees, 1991
; Imamura et al., 2003). Although cell loss increased with disease duration, microglial upregulation remained relatively constant throughout the disease course. Similar in vivo findings show that the specific, early upregulation of SN microglia in Parkinson's disease correlates with disease severity and dopamine terminal loss, but not with disease duration (Ouchi et al., 2005). The activation of microglia in the SN in Parkinson's disease is not a generalized inflammatory response in the brain, but is highly localized (see also Ouchi et al., 2005), contrasting with the overall small increase in the immune response of microglia to ageing (Overmyer et al., 1999). These findings suggest that an inflammatory reaction may contribute to the pathogenesis of this disease.
In both idiopathic and genetic cases of Parkinson's disease, we found pigmented dopamine neurons immunolabelled with IgG and associated with an increase in activated microglia expressing the high affinity IgG receptor FcRI. In the same tissue we found FcRI-immunopositive SN microglia containing pigment granules consistent with a phagocytic attack on the IgG-immunopositive pigmented neurons. These immunological changes peaked at early disease stages when the disease mechanism is thought to be most active (Clarke et al., 2000). These significant immune changes in Parkinson's disease might be merely associated with the disease as epiphenomena, or alternatively could be involved in disease pathogenesis.
There is some evidence for the concept that IgG binding might be a generic response to the death of CNS neurons. This process may increase with age owing to the known humoral changes occurring over time (Ginaldi et al., 1999a–c; Boren and Gershwin, 2004). These changes include the expansion of natural killer cells and of T cells which progressively acquire phenotypes intermediate between T lymphocytes and natural killer cells, decreases in circulating memory B cells, and T-cell dysfunction associated with reduced thymic generation of naive T cells, virus-induced expansion of terminal effectors and increased levels of memory cells producing type I and II cytokines. In addition, circulating autoantibodies are increased with age (Boren and Gershwin, 2004) and do bind non-specifically to degenerating neurons under conditions of traumatic (Stein et al., 2002) or degenerative (D'Andrea, 2005) blood–brain barrier compromise. However, the IgG binding following trauma or in Alzheimer's disease is only found on neurons in the advanced stages of degeneration and only in the vicinity of the blood–brain barrier compromise. In our Parkinson's disease cases, IgG coated both damaged (containing Lewy bodies) and apparently undamaged neurons, with some neurons having extensive immunolabelling of their dendritic tree (Fig. 2). None of the cases examined had evidence of blood–brain barrier compromise, consistent with specific studies on this issue (Haussermann et al., 2001), although dysfunction of midbrain efflux pumps for small molecules has recently been identified in the blood–brain barrier of Parkinson's disease patients (Kortekaas et al., 2005). Additionally, the degree of IgG labelling did not increase over time, as may be expected if there is a continual blood–brain barrier problem, or decrease suddenly, as may be expected with a transient breakdown then recovery of the barrier. On the contrary, the neuronal IgG labelling related to the degree of neuronal loss and microglial activation. In the absence of a compromised blood–brain barrier to large molecules, these findings suggest that IgG coating is a part of the disease phenotype occurring prior to the gross degeneration of the pigmented SN neurons.
The second possibility is that humoral immune mechanisms play a role in initiating the selective removal of dopamine SN neurons in Parkinson's disease. Antibody coating (opsonization) of a cell can enable its ingestion and degradation through interaction with the Fc receptors of phagocytic macrophages, and can also activate the complement system via the classical complement cascade (Roitt et al., 2001). Rather than simply a disease epiphenomenon, neuronal IgG may be involved in the pathogenesis of dopamine neuronal death by triggering either complement activation or attack by surrounding microglia. There is experimental evidence that humoral mechanisms can mediate damage to the SN through both mechanisms. Previous studies have demonstrated components of the classical (antibody-triggered) but not the alternative complement cascade on Lewy bodies in Parkinson's disease (Yamada et al., 1992). The potential relevance of complement activation was shown by Defazio et al. (1994), who demonstrated that adding serum from Parkinson's disease patients to mesencephalic dopamine neurons in culture produced a reduction in dopamine neuronal function and viability only in the presence of complement. Though the identity of the substance in serum causing complement activation was not identified, our data suggest it could be IgG. Similar in situ targeting of selective neurons by IgG and patient serum occurs in the immune-mediated disease human T-lymphotropic virus Type 1 associated myelopathy/tropical spastic paraparesis and correlates with decreased neuronal firing, neuronal damage and disease progression (Jernigan et al., 2003; Kalume et al., 2004; Levin et al., 1998, 2002). In the present study, there was a strong association between neuronal IgG labelling in Parkinson's disease and the progression of neurodegeneration.
In vivo immunization of guinea pigs with bovine mesencephalic homogenates (Appel et al., 1992) or hybrid dopamine cell line homogenates (Le et al., 1995) causes selective damage to the SN involving microglial activation and loss of dopamine cells. Stereotaxic injection of IgG isolated from Parkinson's disease patients into rodent SN induces microglial activation followed by injury to dopamine neurons (He et al., 2002). In these immune-mediated animal models of the disease, IgG is observed on 30% of the dopamine neurons prior to microglial activation and neuronal death (He et al., 2002), a similar proportion to that observed in our study. Knockout of FcR protects mice from both microglial activation and dopamine cell death (He et al., 2002), proving that the interaction of neuronal IgG with its microglial receptor is critical for the dopamine cell death. In Parkinson's disease, microglia are activated in the vicinity of degenerating SN neurons (McGeer et al., 1988; Banati et al., 1998; Mirza et al., 2000) and this microglial activation is a constant feature of multiple different toxin-induced animal models of Parkinson's disease (Kurkowska-Jastrzebska et al., 1999; Kim et al., 2000; Gao et al., 2002a, b). Direct inhibition of microglial activation (He et al., 2001; Liu et al., 2000; Wu et al., 2002) or therapeutic immunization using adoptive transfer of immune cells (Benner et al., 2004; Boska et al., 2005) is neuroprotective in these models. The cross-linking of the FcR on microglia with antibody ligand on foreign cells can initiate phagocytosis, antibody-dependent cell-mediated cytotoxicity, and the release of proinflammatory cytokines and oxygen free radicals (Ulvestad et al., 1994). Our finding that activated microglia express high affinity activating IgG receptors (FcRI) in both idiopathic and genetic forms of Parkinson's disease suggests that the activation of microglia may be induced by the neuronal IgG. The FcRI-immunopositive SN microglia contained pigment granules, supporting their potential involvement in a phagocytic attack on IgG immunopositive pigmented neurons. IgG binding to dopamine neurons may result in their selective targeting and subsequent destruction by activated microglia in idiopathic and familial Parkinson's disease.
Different immunoglobulin classes and subclasses mediate specialized effector functions (Roitt et al., 2001), including complement fixation (IgM > IgG3 > IgG1), opsonization (IgG1 > IgG3) and antibody-dependent cellular cytotoxicity (IgG1 > IgG3). IgM (present study) and IgE (Hunot and Hirsch, 2003) do not label dopamine or other cell types in Parkinson's disease brain. The lack of IgM suggests that complement fixation is not an early or dominant event. Of the IgG subclasses, we found predominantly IgG1 followed by IgG3 deposition on pigmented SN neurons and Lewy bodies. IgG1 has the highest affinity for FcRI with the dominant function of this receptor being antibody-dependent cellular cytotoxicity (Roitt et al., 2001). The dominance of IgG1 and FcRI in Parkinson's disease SN is more consistent with a role for neuronal IgG in the direct targeting of neurons by the surrounding microglia rather than through complement activation. However, in myasthenia the complement pathway is activated by IgG1 (Hughes et al., 2004) and complement can trigger microglia through the CR3 receptor. The presence of both antibody and complement on Parkinson's disease neurons may synergistically enhance the microglial toxicity.
Death of dopamine neurons is believed to involve defective proteolytic processing (parkin) and abnormal protein accumulation (-synuclein) in these forms of familial Parkinson's disease. Although the identity of the antigen or antigens responsible for IgG binding to dopamine neurons remains unclear, the fact that antibody-mediated cytotoxicity is passively transferable (Benner et al., 2004; Boska et al., 2005) and acts on microglia via their Fc receptor argues that our finding of the presence of IgG on dopamine neurons in both typical idiopathic and genetic forms of Parkinson's disease is relevant to disease pathogenesis. It is possible that the final common pathway of these aetiologically diverse cellular injuries involves altered expression of proteins or other macromolecules on the dopamine neuron surface triggering immune recognition and IgG binding. Subsequent antigen-induced cross-linking of FcR on microglia triggering their activation may underlie the mechanism behind propagation of inflammation. Diverse insults to SN dopamine neurons could thus set in motion a self-sustaining cascade of events whereby dopamine neurons become the target of a selective humoral immune-mediated injury effected through activated microglia. We believe that antibody-directed microglial activation may represent a common and potentially treatable mechanism for the ultimate degeneration of dopamine neurons in Parkinson's disease.
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Acknowledgements |
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We thank the tissue donors who made this work possible, David Veivers for the human tonsillar tissue, Heather McCann for her guidance in the laboratory, Anita Ophof for assistance with the quantitation and Heidi Cartwright for the preparation of the figures. This study was supported by research funds from the Parkinson's Disease Foundation and the National Parkinson Foundation of the United States to G.M.H., the National Health and Medical Research Council of Australia to G.M.H. and D.B.R., and an Australian Government International Postgraduate Research Scholarship to C.F.O.
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