Inflammation in the pathogenesis of Parkinson’s disease

Introduction
Classical dogma taught that the brain is immunologically privileged and does not mount an endogenous immune response. Immunohistochemical and molecular biological evidence accumulated over the past decade, however, has shown that the brain is capable of sustaining an immune response and that the result may be damaging to host cells. The brain, rather than being immunologically privileged, may be particularly vulnerable since neurons are postmitotic.

They cannot divide so that, once lost, they are not replaced. The evidence for a chronic inflammatory reaction in the brain is particularly strong in Alzheimer’s disease (AD), where it has been extensively studied,[1,2] but there is also evidence suggesting that a local immune reaction occurs in affected regions of the brain in Parkinson’s disease (PD).[3]

The inflammation is silent because the brain has no pain fibres. Moreover, the local immune reaction does not involve the peripheral immune system. It occurs without antibodies and without significant involvement of T cells. Instead, the reaction depends upon the synthesis of inflammatory components by local neurons and glia, and especially resident phagocytes—which, in the brain, are the microglia. The complement system, microglia, and inflammatory cytokines appear to play key roles.

The complement system
The complement is a phylogenetically primitive system, considerably predating the adaptive immune system, which developed in later vertebrates. It is thus not surprising that the system can be activated by molecules other than antibodies. One such molecule, which is found elevated in the substantia nigra in PD, is C-reactive protein. Once activated, the complement cascade Figure 1 produces anaphylatoxins that promote further inflammation, opsonizing components that mark material for phagocytosis and the membrane attack complex, which is directly lytic to cells. The membrane attack complex inserts itself into viable cell membranes, causing them to leak and produce cell death. It is intended to destroy foreign cells and viruses, but host cells are at significant risk of bystander lysis.

The presence of complement proteins, including all components of the membrane attack complex, has been shown intracellularly on Lewy bodies and on oligodendroglia in the substantia nigra in PD [4,5] and familial PD.[6] Such oligodendroglia have been described as complement activated oligodendroglia. Staining for all the complement components is either absent or very weak in control substantia nigra.[4,5]

Microglia
Microglia constitute about 10% of all glia. They are generally in the resting state in the normal adult brain. When activated, they upregulate or newly express a variety of receptors and other molecules involved in inflammation and phagocytosis. In the activated state, they also produce large amounts of superoxide anions and other potential neurotoxins. In culture, microglia have been shown to contribute to neurotoxicity, including that of dopaminergic cells.[7]

A profusion of reactive microglia is seen in the substantia nigra and striatum, not only in idiopathic PD, [5,8] but also in familial PD,[6] as well as in the parkinsonism-dementia complex of Guam (EGM et al, unpublished data, 2001). The presence of many activated microglia in the substantia nigra of humans dying years after exposure to the toxin MPTP testifies to the fact that once the fire of inflammation is lit, it continues to burn long after the initiating event.[9]

Reactive microglia are also seen in the basal ganglia in 6-hydroxydopamine and MPTP animal models of PD, and there are several reports that anti-inflammatories inhibit dopaminergic neurotoxicity in such animal models.[3]

Microglia can be activated by products of the classical complement cascade, by various inflammatory cytokines, and by chromogranin A,[10,11] which has been reported to occur in PD substantia nigra.[12]

Cytokines
Inflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1, and interleukin-6, amplify and sustain inflammation and immune responses. In the periphery, they are thought to be primarily responsible for many of the clinical and pathological manifestations of such diseases as rheumatoid arthritis and inflammatory bowel syndrome. It is of some interest, therefore, that increased levels of interleukin-1ß, interleukin-6, and tumor necrosis factor-alpha have been found in the basal ganglia and CSF of PD patients.[3]

The increase in tumor necrosis factor-alpha was particularly dramatic, being 366% in tissue and 432% in CSF.[13] Moreover, the presence of glial cells immunoreactive for tumor necrosis factor-alpha and/or interleukin-1ß has been reported in the substantia nigra of PD patients.[14,15]

Intensity of the inflammatory reaction
The large increase in levels of the inflammatory cytokines and the profusion of reactive microlgia seen in the substantia nigra in PD suggests an intense inflammatory reaction. In order to gain a better understanding of the intensity of the reaction, the levels of the messenger ribonucleic acids for key inflammatory proteins in the brains of PD cases can be compared with controls. Preliminary results are shown in Figure 2.[16]

The messenger ribonucleic acids for all components of the classical complement pathway are markedly elevated in the parkinsonian substantia nigra and caudate, but not in areas outside the basal ganglia. This is illustrated for C1q and C9, the initial and final components, in Figure 2A. Figure 2B illustrates that the same holds true for HLA-DR, a marker of activated microglia, and for C-reactive protein, an acute phase molecule capable of activating the complement cascade. Figure 2C compares the elevations of these messenger ribonucleic acids in PD substantia nigra to those in AD hippocampus and in an arthritic joint removed surgically because of intractable pain. The inflammatory reaction in affected brain regions in these neurodegenerative diseases seems to be, at least by this measure, more intense than that in arthritic joints.

Conclusions
The evidence that a chronic inflammatory reaction may be contributing to neuronal death is certainly not as strong in PD as it is in AD, where there are epidemiological data [17] and one small pilot trial [18] to support the hypothesis that anti-inflammatory agents might delay the onset and slow the progression of the disease. Nevertheless, it seems possible that treatment with anti-inflammatory agents might slow the progress of dopaminergic cell death in PD.

Anti-inflammatory treatment of PD cases might also serve to inhibit the onset of dementia, a condition to which those with parkinsonism seem to be more prone than the general population. Postmortem examination of the cortex and hippocampus of PD patients with dementia reveals the same type of inflammatory changes seen in those regions in persons dying with primary AD (EGM et al, unpublished data, 2001). The human and economic benefits would be significant.

Acknowledgments
The authors’ work on Parkinson’s disease was supported by grants from the Pacific Parkinson’s Research Institute, the Parkinson Foundation of Canada, and the MRC of Canada, as well as donations from individual British Columbians.

Drs Edith and Patrick McGeer are both professor emeriti in the Kinsmen Laboratory of Neurological Research, Department of Psychiatry, University of British Columbia. Dr Yasojima is a research fellow in the same laboratory.