The potential role of the immune response in both the risk and pathogenesis of PD has long been a focus of research [3]. The HLA complex plays a pivotal role in immunosurveillance within the body and is associated with a number of autoimmune disorders. It is an attractive hypothesis that variation within those genes that regulate the immune response may be important in determining risk of PD [7]. In fact, HLA-DR positive microglial cells contribute to the neuroinflammation in the substantia nigra of brains from PD patients [8]. While there are observations that individuals taking high amounts of anti-inflammatory medications had a lower likelihood to develop PD [9], metaanalyses of several similar studies showed diverging results [10]. Furthermore, the components of the immune system are regulated by a highly complex network of cytokines and receptors. The present associations of HLA-DRA SNP probably represent only one contribution among many others, although the different HLA alleles are not entirely independent of each other. Variation in cytokine genes has been proposed to increase the risk of PD, particularly variants in the tumor necrosis factor alpha gene which is located in the Class III region of the HLA complex [11] . It is likely that rs3129882 is acting as a marker in linkage disequilibrium with other HLA alleles, and a more detailed look at HLA-A, -B, -DR and Class III genes is now warranted. Interestingly, after our initial submission of this manuscript, a meta-analysis of datasets from five PD genome wide association studies reported the association of additional HLA-DRA SNPs with PD [12].

(For those with 23andme results, the risk allele for rs3129882 is G)

(interesting--unsure of its significance)

Int J Neurosci. 2012 Dec 28.
Infections as a risk factor for Parkinson's disease: a case-control study.

1Institute of Epidemiology, Faculty of Medicine, Belgrade University , Belgrade , Serbia.

Abstract Objectives. The etiology of Parkinson' s disease (PD) is unknown. The aim of the study was to test the hypothesis that some infectious diseases are related to the occurrence of Parkinson' s disease (PD). Methods. Case-control study, conducted in Belgrade during the period 2001-2005, comprised 110 subjects diagnosed for the first time as PD cases, and 220 controls chosen among patients with degenerative joint disease and some diseases of digestive tract. Results. According to logistic regression analysis PD was significantly related to mumps (Odds ratio adjusted on occupation and family history of PD - aOR = 7.86, 95% confidence interval - CI = 3.77-16.36), scarlet fever (aOR = 12.18, 95%CI = 1.97 -75.19), influenza (aOR = 8.01, 95% CI = 4.61 -13.92), whooping cough (aOR = 19.90, 95% CI = 2.07 -190.66) and herpes simplex infections (aOR = 11.52, 95% CI = 2.25 -58.89). Tuberculosis, measles and chicken pox were not associated with PD. Other infectious diseases we asked for were not reported (12 diseases), or were too rare (4 diseases) to be analysed. Conclusion. The results obtained are in line with suggestion that some infectious diseases may play a role in development of PD.
PMID: 23270425 [PubMed - as supplied by publisher]

You should keep in mind that the "normal" values for all laboratory tests represent just 90% of the bell curve in a population: by definition, 10% of people without pathology will fall outside of the "normal" range. In other words, slightly higher or lower neutrophil counts in the absence of fever, sepsis, or other evidence of infection are probably just normal for you and mean absolutely nothing in terms of pathology. Chronic small deviations from "normal" blood counts are very far from evidence of CNS infection.

Inflammatory theories of neurodegenerative diseases are of interest but are very much in a speculative stage. Most of us would say any inflammation is a result of, more than a cause of, the underlying pathology-- "cells die and then are cleared by immune cells" is a story more consistent with the current state of evidence than the converse.

The idea of taking low-dose antibiotics to fight a neurodegenerative disease is nothing but a recipe for causing resistant bacteria to develop. Please don't do it.

Some points to consider-
1) Actually, we are talking about neuroinflammation rather than what we normally call inflammation. Some of the differences: different stars on the stage with microglia in the CNS and a collection of warriors in the periphery.
2) Neuroinflammation takes place behind the BBB which makes it much harder to gather data than day-to-day inflammation.
3) There is communication across/around the BBB between the two systems and the CNS response can be triggered by the other.
4) The response is an "auto-toxic" response and, unlike a true auto-immune response, does not seem to involve direct attack upon "self". It can never-the-less cause incredible damage due to its relentless nature.
5) This "collateral" damage results from a number of forces responding to one another and in constant danger of a feedback loop runaway situation, which can be deadly. An example of this in a non-PD instance is septic shock. This is not, as many assume, a classic battle with invading bacteria provoking an immune system counter attack. In reality, the "trespassers" may be long gone. Even years may have passed. But the system is in a hypervigilant state and becomes non-responsive to our signals to stand down. The resulting amplification via feedback loop mechanisms trigger collapse of vital functions and one quickly dies.

There is far more to this than I can explain here. I have been into it for ten years now and find that it explains virtually every weird "anomaly" about PD. If you want to get a glimmer as to just what PD is, a good starting point is HERE.

-Rick

Hi All,
After a long time, I am back on Neurotalk and find interesting discussions going on.... Of course, this one caught my attention and here is my two cents worth.
Mudfud, first let me say Welcome to the forum.
You wrote
"Inflammatory theories of neurodegenerative diseases are of interest but are very much in a speculative stage. Most of us would say any inflammation is a result of, more than a cause of, the underlying pathology-- "cells die and then are cleared by immune cells" is a story more consistent with the current state of evidence than the converse."

I am surprised at your definitive statements about inflammation and neurodegenerative disorders. There is a lot of literature (approximately 2500 articles in pubmed, search for key words inflammation and neurodegerative disorders) supporting this connection. It is not speculative, links have been well established. Inflammation may or may not be the cause (depending on which papers you select to quote), but certainly contributes to the general pathology of PD. In fact, modulation of inflammation and T cell responses are the basis of a PD vaccine being currently developed.

My reason for responding to your post is as follows: A lot of people read these posts for information. Though we are entitled to our opinions, scientific info presented here must be unbiased, current and factual. Of course my other reason is: Inflammation is my pet topic and I felt compelled to defend its role in PD

You sound like a biologist, welcome to the forum! Like to hear your take on PD and I hope you continue to post.

Girija

Hello, Girija-
I am surprised at your surprise. I wrote nothing controversial, and of course everything I wrote was unbiased, current, and factual.... *edit* Where were you when people were considering taking antibiotics because they have slightly elevated peripheral neutrophil counts?

As an NIH-funded biologist and physician working in the PD field, I am well aware of the literature describing connections between inflammation and neurodegenerative disease. I stand by my characterization of it as speculative in nature. The only truly certain thing is that it is present.... sometimes. No one understands whether inflammation is cause or effect/epiphenomenon in these diseases. The vast majority of the 2500 papers you refer to describe some inflammation or aspect thereof, but to my knowledge none proposes a well supported model (I would quite welcome one if you have a reference). The genetics do not support a significant causative role of inflammation. The cell biology does not, either. Severely immunocompromised patients are not protected from or have their PD cease progression. Neither pathological antibodies nor T-cells has ever been described for PD. The PD vaccine I am aware of is an immunization against synuclein,and would not support an inflammatory etiology for PD if it were to work. And so on.

Meanwhile we do have models of far greater explanatory power, supported by the genetics, which suggest PD is a disease of protein aggregation and insufficient clearance by the proteasome/lysosome resulting in neuronal death. This death leads to low level inflammation as dead neurons are cleared by immune cells.

The model I cite may end up being incorrect but there is no doubt it is the current consensus model in the field making a discussion of it unbiased, current, and factual.

Hope that helps.

....a brief introduction may be in order. Girija is a longtime community member and works in microbiology research. MudFud is a creature of mystery. And now, back to our story....

Girija, glad to see you back and I hope that all is well.

I must agree with most everything that Girija has said. Anyone making a definitive statement is to be taken with a grain of salt for the simple reason that everything about PD is conjecture and opinion. It isn't just that we on this forum don't know - it is that no one does. Periodically I post explaining that everything that I post should have a hidden prefix of IMHO attached.

That having been said, it is very clear that there is a major role for inflammation both within the CNS and without. Since there will be those who disagree I will post some reports that make this clear. In addition, I suggest that you visit HERE for an extensive explanation that accounts for most observations made thus far.

But, if we limit it to inflammation and neuroinflammation (not the same thing BTW), here is enough to convince most-

1- JS Hong, formerly with the NIH Triangle Park in North Carolina, along with Bin Liu and Zhang are the heavy weights here. The full text is available from the abstract-

1. J Neural Transm. 2010 Aug;117(8):971-9. doi: 10.1007/s00702-010-0428-1. Epub 2010
Jun 23.

Neuroinflammation is a key player in Parkinson's disease and a prime target for
therapy.

Qian L, Flood PM, Hong JS.

Comprehensive Center for Inflammatory Disorders, University of North Carolina,
Chapel Hill, NC 27599, USA. qianl@email.unc.edu

Parkinson's disease (PD) is a neurodegenerative movement disorder characterized
by the progressive loss of dopaminergic neurons in the substantia nigra and
depletion of dopamine in the striatum, which lead to pathological and clinical
abnormalities. Increasing evidence has demonstrated that inflammation is the
fundamental process contributing to neuron death in PD. Neuroinflammation, which
is characterized by activated microglia and infiltrating T cells at sites of
neuronal injury, is a prominent contributor to the pathogenesis of progressive
PD. Microglia play a critical role in forming a self-propelling cycle leading to
sustained chronic neuroinflammation and driving the progressive neurodegeneration
in PD. This activation depends heavily on the respiratory burst within the
microglia, which in turn regulates a number of downstream pro-inflammatory
activities. On the other hand, the adaptive immune responses, most notably T
cells, are now emerging as important components of the inflammatory response that
contribute to the pathogenesis of PD. This review paper focus on the
understanding of the inflammatory etiology of PD, as well as the molecular
signaling involved in this inflammatory response, with the aim to provide more
effective treatments to slow down or halt the progression of chronic
inflammation-induced CNS disorders, such as PD.

PMCID: PMC3392895
PMID: 20571837 [PubMed - indexed for MEDLINE]

2- This one bridges the gap with the misfolding proteins-

1. Environ Health Perspect. 2011 Jun;119(6):807-14. doi: 10.1289/ehp.1003013. Epub
2011 Jan 18.

Neuroinflammation and α-synuclein dysfunction potentiate each other, driving
chronic progression of neurodegeneration in a mouse model of Parkinson's disease.

Gao HM, Zhang F, Zhou H, Kam W, Wilson B, Hong JS.

Laboratory of Toxicology and Pharmacology, National Institute of Environmental
Health Sciences, National Institutes of Health, Department of Health and Human
Services, Research Triangle Park, North Carolina 27709, USA. gao2@niehs.nih.gov

BACKGROUND: Mechanisms whereby gene-environment interactions mediate chronic,
progressive neurodegenerative processes in Parkinson's disease (PD)-the second
most common neurodegenerative disease-remain elusive.
OBJECTIVE: We created a two-hit [neuroinflammation and mutant α-synuclein (α-syn)
overexpression] animal model to investigate mechanisms through which mutant α-syn
and inflammation work in concert to mediate chronic PD neurodegeneration.
METHODS: We used an intraperitoneal injection of the inflammogen
lipopolysaccharide (LPS; 3 × 106 EU/kg) to initiate systemic and brain
inflammation in wild-type (WT) mice and transgenic (Tg) mice overexpressing human
A53T mutant α-syn. We then evaluated nigral dopaminergic neurodegeneration, α-syn
pathology, and neuroinflammation.
RESULTS: After LPS injection, both WT and Tg mice initially displayed
indistinguishable acute neuroinflammation; however, only Tg mice developed
persistent neuroinflammation, chronic progressive degeneration of the
nigrostriatal dopamine pathway, accumulation of aggregated, nitrated α-syn, and
formation of Lewy body-like inclusions in nigral neurons. Further mechanistic
studies indicated that 4-week infusion of two inhibitors of inducible nitric
oxide synthase and NADPH oxidase, major free radical-generating enzymes in
activated microglia, blocked nigral α-syn pathology and neurodegeneration in
LPS-injected Tg mice.
CONCLUSIONS: Microglia-derived oxidative stress bridged neuroinflammation and
α-syn pathogenic alteration in mediating chronic PD progression. Our two-hit
animal model involving both a genetic lesion and an environmental trigger
reproduced key features of PD and demonstrated synergistic effects of genetic
predisposition and environmental exposures in the development of PD. The chronic
progressive nature of dopaminergic neurodegeneration, which is absent in most
existing PD models, makes this new model invaluable for the study of mechanisms
of PD progression.

PMCID: PMC3114815
PMID: 21245015 [PubMed - indexed for MEDLINE]

Those will get you started and do check out the blog.

-Rick

Acute inflammation is caused by damage to the body from toxins, pathogens or injury. Chronic inflammation is usually caused by such dietary mistakes as sugar, arachidonic acid and Omega-6 excess, as well as stress or the persistence of the acute inflammation triggers.

So the question is, what is causing the inflammation in PD and what is keeping it chronic? I have seen putative causes all over the map from various injuries in the foot, neck or head, blood vessel problems in the brain, infectious pathogens of various kinds from Lyme to Candida and others, toxins like different metals, pesticides and herbicides, all of which are capable of causing inflammation. Mutant alpha-synuclein forming lewy bodies aided by malfunctioning ubiquitin proteasome is another possibility but I don't think it is necessarily the only cause unless all those other causes are all mutating the protein. If they aren't, what is?

There is some question whether Lewy bodies are a cause of cell death anyway. See http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2892607/ . "In conclusion, although Lewy bodies are the neuropathological hallmark of the diagnosis, the pathophysiology of the neurodegenerative process can hardly be explained by them since the number of Lewy bodies is far too low for the severe symptoms. They appear to be neither associated with the cell loss nor do they correlate with the severity of clinical symptoms. Robert D. Terry [131], who did a lot of work explaining neurodegenerative diseases by synaptic failure, resumed: “It seems that not the α-synuclein of the Lewy body (…) is fatal to the neuron. We had better look elsewhere in that regard.”

Chronic inflammation is damaging but what is causing the inflammation and what is making it chronic?

Dear All,

I am posting my responses to mudfud's comments. I am providing a few abstracts (human and animal model studies) supporting my views and if anyone is interested, I will be happy to go into details.

Point 1 “literature describing connections between inflammation and neurodegenerative disease. I stand by my characterization of it as speculative in nature. The only truly certain thing is that it is present.... sometimes.”

I am posting a couple of references connecting alpha-syn, inflammation and PD. You probably know that Drs. Masliah and Chesselet are well known PD researchers and hence quoting their paper.

Exp Neurol. 2012 Oct;237(2):318-34. doi: 10.1016/j.expneurol.2012.06.025. Epub 2012 Jun 27.#1. Regionally-specific microglial activation in young mice over-expressing human wildtype alpha-synuclein. Watson MB, Richter F, Lee SK, Gabby L, Wu J, Masliah E, Effros RB, Chesselet MF. Department of Neurology, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA.

Abstract Parkinson's disease (PD) is characterized by widespread alpha-synuclein pathology and neuronal loss, primarily of the nigrostriatal dopaminergic neurons. Inflammation has been implicated in PD, and alpha-synuclein can initiate microglial activation; however, the kinetics and distribution of inflammatory responses to alpha-synuclein overexpression in vivo are not well understood. We have examined the regional and temporal pattern of microglial activation and pro-inflammatory cytokine production in mice over-expressing wild-type human alpha-synuclein driven by the Thy1-promoter (Thy1-aSyn mice). An increased number of activated microglia, and increased levels of TNF-α mRNA and protein were first detected in the striatum (1 month of age) and later in the substantia nigra (5-6 months), but not the cerebral cortex or cerebellum; in contrast, IL-1β and TGF-β remained unchanged in the striatum and substantia nigra at all ages examined. Microglial activation persisted up to 14 months of age in these regions and only minimal increases were observed in other regions at this later age. Increased concentrations of serum TNF-α were observed at 5-6 months, but not at 1 month of age. The expression of toll-like receptors (TLRs) 1, TLR 4 and TLR 8, which are possible mediators of microglial activation, was increased at 5-6 months in the substantia nigra but not in the cerebral cortex, and TLR 2 was increased in the substantia nigra at 14 months of age. With the exception of a slight increase in the striatum of 14 month old Thy1-aSyn mice, MHCII staining was not detected in the regions and ages examined. Similarly, peripheral CD4 and CD8-postive T cells were increased in the blood but only at 22 months of age, suggesting later involvement of the adaptive immune response. These data indicate that, despite the presence of high levels of alpha-synuclein in other brain regions, alpha-synuclein overexpression caused a selective early inflammatory response in regions containing the axon terminals and cell bodies of the nigrostriatal pathway. Our results suggest that specific factors, possibly involving a regionally and temporally selective increase in TLRs, mediate alpha-synuclein-induced inflammatory responses in the SN,\

paper 2
Exp Neurol. 2012 Dec 21. pii: S0014-4886(12)00456-6. doi: 10.1016/j.expneurol.2012.12.008. [Epub ahead of print] Commentary:

Progressive inflammation as a contributing factor to early development of Parkinson's disease. Pradhan S, Andreasson K

Parkinson's disease (PD) is a progressive neurodegenerative disorder with three cardinal features of pathology: 1. Aggregation of α-synuclein into intraneuronal structures called Lewy bodies and Lewy neurites. 2. Dysregulated immune activation in the substantia nigra (SN). 3. Degeneration of dopaminergic neurons in the nigrostriatal circuit. The largely correlative nature of evidence in humans has precluded a decisive verdict on the relationship between α-synuclein pathology, inflammation, and neuronal damage. Furthermore, it is unclear whether inflammation plays a role in the early prodromal stages of PD before neuronal damage has occurred and Parkinsonian motor symptoms become apparent. To gain insight into the interaction between the inflammatory response and the development of neuronal pathology in PD, Watson et al. characterized neuroinflammation in a wild-type α-synuclein overexpressing mouse model of prodromal PD. They demonstrate, for the first time, the existence of early and sustained microglial mediated innate inflammation that precedes damage to the nigrostriatal circuit. Additionally they observe the spread of inflammation from the striatum to the SN. This study suggests that early dysregulated inflammation may contribute to progressive nigrostriatal pathology in PD, although the initiating factor that triggers the inflammatory response remains elusive. The novel concept of an early inflammatory response in the development of PD has important implications for preventive and therapeutic strategies for PD.


Point 2: “but to my knowledge none proposes a well supported model (I would quite welcome one if you have a reference). “
Dr. Gendelman proposed a model based on their data; check his presentations and publications if you are interested.

Point 3: “Neither pathological antibodies nor T-cells has ever been described for PD.”

Here are three papers talking about T cell involvement in PD/
J Clin Invest. 2009 Jan;119(1):182-92. doi: 10.1172/JCI36470. Epub 2008 Dec 22.

Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease.

Brochard V, Combadière B, Prigent A, Laouar Y, Perrin A, Beray-Berthat V, Bonduelle O, Alvarez-Fischer D, Callebert J, Launay JM, Duyckaerts C, Flavell RA, Hirsch EC, Hunot S INSERM, UMR S679, Experimental Neurology and Therapeutics, Hopital de la Salpetriere, Paris, France.
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-gamma-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 IFNgamma. Further, our data may provide a rationale for targeting the adaptive arm of the immune system as a therapeutic strategy in PD


J Immunol. 2010 Mar 1;184(5):2261-71. doi: 10.4049/jimmunol.0901852. Epub 2010 Jan 29.
Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson's disease. Reynolds AD, Stone DK, Hutter JA, Benner EJ, Mosley RL, Gendelman HE. Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Abstract Nitrated alpha-synuclein (N-alpha-syn) immunization elicits adaptive immune responses to novel antigenic epitopes that exacerbate neuroinflammation and nigrostriatal degeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. We show that such neuroimmune degenerative activities, in significant measure, are Th17 cell-mediated, with CD4(+)CD25(+) regulatory T cell (Treg) dysfunction seen among populations of N-alpha-syn-induced T cells. In contrast, purified vasoactive intestinal peptide induced and natural Tregs reversed N-alpha-syn T cell nigrostriatal degeneration. Combinations of adoptively transferred N-alpha-syn and vasoactive intestinal peptide immunocytes or natural Tregs administered to MPTP mice attenuated microglial inflammatory responses and led to robust nigrostriatal protection. Taken together, these results demonstrate Treg control of N-alpha-syn-induced neurodestructive immunity and, as such, provide a sound rationale for future Parkinson's disease immunization strategies.

Another one for t cells
Trends Immunol. 2010 Jan;31(1):7-17. doi: 10.1016/j.it.2009.09.003. Epub 2009 Oct 31.T cell-microglial dialogue in Parkinson's disease and amyotrophic lateral sclerosis: are we listening? Appel SH, Beers DR, Henkel JSDepartment of Neurology, Methodist Neurological Institute, The Methodist Hospital Research Institute, The Methodist Hospital, Houston, TX, USA. sappel@tmhs.org <sappel@tmhs.org>
Abstract Neuroinflammation is a pathological hallmark in Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), and is characterized by activated microglia and infiltrating T cells at sites of neuronal injury. In PD and ALS, neurons do not die alone; neuronal injury is non-cell-autonomous and depends on a well-orchestrated dialogue in which neuronally secreted misfolded proteins activate microglia and initiate a self-propagating cycle of neurotoxicity. Diverse populations and phenotypes of CD4(+) T cells crosstalk with microglia, and depending on their activation status, influence this dialogue and promote neuroprotection or neurotoxicity. A greater understanding of the T cell population that mediates these effects, as well as the molecular signals involved should provide targets for neuroprotective immunomodulation to treat these devastating neurodegenerative diseases.


Point 4 "The PD vaccine I am aware of is an immunization against synuclein,and would not support an inflammatory etiology for PD if it were to work. And so on."

Dr. Gendelman’s group is developing a vaccine too. His approach is quite novel, , and is backed by good data.
Parkinsonism Relat Disord. 2012 Jan;18 Suppl 1:S218-21. doi: 10.1016/S1353-8020(11)70067-Immunization strategies for Parkinson's disease. Ha D, Stone DK, Mosley RL, Gendelman HE Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA.

Abstract Parkinson's disease (PD) is the most common neurodegenerative movement disorder. Currently, no curative treatments or treatments that interdict disease progression are available. Over the past decade, immunization strategies were developed in our laboratories to combat disease progression. These strategies were developed in laboratory and animal models of human disease. Induction of humoral immune responses can be elicited against misfolded protein aggregates. Robust cell-mediated immunity against nitrated misfolded protein(s) accelerates disease progression through effector T cell responses that facilitate neuronal death. We propose that shifting the balance between effector and regulatory T cell activity can attenuate neurotoxic inflammatory events. We now summarize our works that support immune regulation in PD with the singular goal of restoring homeostatic glial responses. New methods to optimize immunization schemes and measure their clinical efficacy are discussed.


Expert Rev Neurother. 2011 Dec;11(12):1703-15. doi: 10.1586/ern.11.163.b Pathways towards an effective immunotherapy for Parkinson's disease. Hutter-Saunders JA, Mosley RL, Gendelman HE. Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA.

Abstract immunizations that target specific types of immune responses are used commonly to prevent microbial infections. However, a range of immune responses may prove necessary to combat the ravages of neurodegenerative diseases. The goal is to eliminate the 'root' cause of neurodegenerative disorders, misfolded aggregated proteins, while harnessing adaptive immune responses to promote neural repair. However, immunization strategies used to elicit humoral immune responses against aberrant brain proteins have yielded mixed success. While specific proteins can be cleared, the failures in halting disease progression revolve, in measure, around adaptive immune responses that promote autoreactive T cells and, as such, induce a meningoencephalitis, accelerating neurodegeneration. Thus, alternative approaches for protein clearance and neural repair are desired. To this end, our laboratories have sought to transform autoreactive adaptive immune responses into regulatory neuroprotective cells in Parkinson's disease. In this context, induction of immune responses against modified brain proteins serves to break immunological tolerance, while eliciting adaptive immunity to facilitate neuronal repair. How to harness the immune response in the setting of Parkinson's disease requires a thorough understanding of the role of immunity in human disease and the ways to modify such immune responses to elicit therapeutic gain. These are discussed in this review.

Point 5: " Meanwhile we do have models of far greater explanatory power, supported by the genetics, which suggest PD is a disease of protein aggregation and insufficient clearance by the proteasome/lysosome resulting in neuronal death. This death leads to low level inflammation as dead neurons are cleared by immune cells.
The model I cite may end up being incorrect but there is no doubt it is the current consensus model in the field making a discussion of it unbiased, current, and factual."

Protein aggregation and defects in autophagy seem to be responsible for generating immune responses, and we have a working model that incorporates all these factors. we hope to publish it soon,

As a long time follower, and at times participant, in Neurotalk and the old Braintalk, a comment made on this thread reminded me of the old days *edit* Let a thousand flowers bloom someone said.
In any event, during my LDN journey, I read all the papers I could find by Dr's Hong and Liu on neuroinflammation. I found them to be interesting and probably relevant to PD. My wife was taking LDN for about 7-8 years (she was Dxd about 10 years ago). Thought she was holding off progression but she said it wasn't. She stopped about 2 years ago and is now dealing with falls and on/off. I have no idea if LDN or DXM can slow the progression of PD but it seems Dr. Hongs rodents showed a significant reduction in neuroinflammation when on either of these drugs.

John