In Vitro Studies Of Ipsc
A recent in vitro study using induced-pluripotent stem cells -derived midbrain neurons and T cells from PD patients was the first to show that PD patient-derived T cells can kill dopamine neurons directly. Sommer et al. determined that PD patients contain significantly higher Th17 cells than healthy controls . The PD patient-derived Th17 cells exerted cytotoxic effects on neurons by releasing IL-17A, a cytokine detected by IL-17R expressed on neurons . The iPSC in vitro cultures lacked glia, which express MHC-II and can potentially interact with Th17 cells. In addition, T cells were activated non-specifically, and so the antigen specificity of Th17 cells remains unclear . While the study indicates that PD-derived T cells can directly kill dopaminergic neurons, the omission of professional antigen presenting cells, antigenicity, and neuronal specificity in the cultures in this initial study overlooks the role of multiple relevant in vivo factors important for disease progression. Moreover, the mode of action that garners specific vulnerability of dopaminergic neurons and avoids unaffected neurons was not resolved in this study. Nevertheless, the study indicates Th17 cells may participate in PD-related neuronal death.
Immune Cells And Autoimmunity In Pd
To date, numerous immune cells have been shown to be responsible for driving PD progression. DCs and microglia are two types of mammalian immune cells that act as the first and main forms of active immune defense in the CNS . They act first as APCs and then activate T cells to initiate the immune system to identify and attack extrinsic antigens. In essence, these immune cells lie at the intersection of the immune response and the neurodegenerative processtwo primary aspects of CNS autoimmune disorders. DCs, the famous APCs , serve as messengers between the innate and adaptive immune systems and can induce and even maintain self-tolerance . It is the differentiation/maturation rather than the haematopoietic origin or subset classification of DCs that determines their tolerogenic or immunogenic functions. Immature DCs can inhibit alloantigen-specific T cell responses to reverse autoimmune diseases in murine models but simultaneously induce antigen-specific T cell tolerance . The maturation of DCs into professional APCs via the upregulation of MHC expression enables DCs to capture antigens successfully . Based on these phenomena, Platt et al. proposed a theory called regulatory mechanisms by DCs for immune responses against self-antigens. They concluded that the failure of DCs to control T cells via Treg differentiation and effector T cell clonal deletion leads to a direct attack on self-antigen-harboring target cells .
Availability Of Data And Materials
All the data is underlying the present study from the National Health Insurance Research database and Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan. Local interested researchers or cooperators can obtain the data through formal application to the Ministry of Health and Welfare, Taiwan.
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Factors Associated With Recurrent Falls In Parkinson’s Disease
Seven studies were identified which examined potential factors associated with recurrent falls . Six of these studies reported univariate and/or multivariable regression analyses , with four studies aiming to identify models which can be used to predict future recurrent fallers . One study aimed primarily to identify variables explaining fall frequency in fallers with PD.
Examination of these studies revealed that a history of a previous fall or falls was a significant factor associated with recurrent falls in all six of the studies that included it in their analysis . It was also found to be a predictor of future recurrent fallers in three of the four studies which aimed to predict recurrent fallers .
Disease severity as measured by Hoehn and Yahr stage or by the Unified Parkinson’s Disease Rating Scale was found to be significantly associated with recurrent falls in five of the seven studies . It also predicted future recurrent fallers in half of the studies which aimed to identify predictive variables . One study found that the relative risk of recurrent falls was 13.4 for people with Hoehn and Yahr stage 1 to 2.5 and was greater than 100 for people at stage 3 to 4 .
Unplugging The Main Lines
The removal of red meat from the diet of a patient with Parkinson disease has a sound basis. Having the highest intake of iron increases the risk of Parkinson disease almost as much as having a first-degree relative with the disease. The effect seems to be compounded by high intakes of manganese.9
However, the risk of Parkinson disease from high iron intake pales in comparison with the risk from extended constipation. One study10 found that between 60% and 80% of patients with Parkinson disease suffered from extended constipation and that the constipation preceded any motor symptoms by as much as 20 years. Not surprisingly, the constipation was often compounded by a lack of thirst that worsened throughout the patients lifetime.
A factor contributing to constipation is the extreme anxiety common among patients with Parkinson disease. Many are anxious long before they show motor symptoms. The addition of progressive disease worsens underlying anxiety. As many as 40% of patients with Parkinson disease experience clinically significant anxiety, and few are treated.11
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First Direct Evidence That Abnormal Protein In Parkinsons Disease Triggers Immune Response
New York, NY Researchers have found the first direct evidence that autoimmunityin which the immune system attacks the bodys own tissuesplays a role in Parkinsons disease, the neurodegenerative movement disorder. The findings raise the possibility that the death of neurons in Parkinsons could be prevented by therapies that dampen the immune response.
The study, led by scientists at Columbia University Irving Medical Center and the La Jolla Institute for Allergy and Immunology, was published today in Nature.
The idea that a malfunctioning immune system contributes to Parkinsons dates back almost 100 years, said study co-leader David Sulzer, PhD, professor of neurobiology . But until now, no one has been able to connect the dots. Our findings show that two fragments of alpha-synuclein, a protein that accumulates in the brain cells of people with Parkinsons, can activate the T cells involved in autoimmune attacks.
It remains to be seen whether the immune response to alpha-synuclein is an initial cause of Parkinsons or if it contributes to neuronal death and worsening symptoms after the onset of the disease, said study co-leader Alessandro Sette, Dr. Biol. Sci., professor in the Center for Infectious Disease at La Jolla Institute for Allergy and Immunology in La Jolla, Calif. These findings, however, could provide a much-needed diagnostic test for Parkinsons disease and could help us to identify individuals at risk or in the early stages of the disease.
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New Research Gives Further Evidence That Autoimmunity Plays A Role In Parkinsons Disease
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A new study co-led by scientists at the La Jolla Institute for Immunology adds increasing evidence that Parkinsons disease is partly an autoimmune disease. In fact, the researchers report that signs of autoimmunity can appear in Parkinsons disease patients years before their official diagnosis. The research could make it possible to someday detect Parkinsons disease before the onset of debilitating motor symptomsand potentially intervene with therapies to slow the disease progression. The Parkinsons Foundation supports this research.
Investigating Parkinsons As An Autoimmune Disease
At the University of Montreal, Professor Louis-Eric Trudeau investigates the earliest potential causes of Parkinsons disease, at the cellular level. His project is funded by the Saucier-van Berkom Parkinson Quebec Research Fund with contributions from Parkinson Newfoundland & Labrador, in the amount of $49,748.00 for 1 year. He is exploring the possibility that Parkinsons is a form of autoimmune disease, caused when the immune system attacks the axon terminals in our brain cells. Those extremities release the chemical messengers that communicate with other cells, and damage to such terminals may disrupt the dopamine-producing brain cells that are key to Parkinsons.
The death of the brain cells that produce dopamine, the chemical messenger that signals other cells involved in motor control, triggers the symptoms of Parkinsons disease. But researchers still dont know exactly what causes those dopamine-producing cells to die.
Trudeau, a neuroscientist, investigates the possibility that an autoimmune attack on those dopamine cells is the culprit.
Trudeau and his immunologist colleague, Michel Desjardins, are studying the role of the portion of cells called axon terminals. These terminalsthe root-like extremities of cellsrelease the chemical messengers that send communication signals. Trudeau believes the death of these terminals, before the death of the dopamine cells themselves, is where the trouble starts.
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Implications For Diagnosis And Therapeutics
Understanding the extent of the role of the immune response in the pathogenesis of PD opens up new avenues of diagnosis and treatment for patients. Identifying people who are carriers of HLA alleles that place them at risk for -syn-specific T cells to be monitored can help early diagnosis and treatment of PD. In addition, -syn-specific T cells could be use as early biomarkers of the disease, identifying autoimmunity to self proteins prior to the onset of motor symptoms. Large-scale, longitudinal studies monitoring -syn reactivity and the development of PD would need to be conducted before establishing T cells as PD biomarkers.
Currently, new treatment avenues targeting the immune system are being tested on PD patients. Sargramostim is a human recombinant granulocyte-macrophage colony-stimulating factor approved by the Food and Drug Administration for the recovery of patients receiving bone marrow transplantation and cancer therapies . It functions by promoting myeloid recovery and inducing Treg responses . In a preliminary randomized, double-blind phase 1 clinical trial, Sargramostim-treated patients showed modest improvements after 6 and 8 weeks of treatment and increases in Treg numbers and function compared to PD patients receiving placebo . Further clinical investigation will shed light on the potential of immunomodulatory drugs for treatment of PD.
Autoimmunity As A Trigger Of Axonal Dying
The death of the brain cells that produce dopamine, the chemical messenger that signals other cells involved in motor control, triggers the symptoms of Parkinsons disease. But researchers still dont know exactly what causes those dopamine-producing cells to die.
At the University of Montreal, Professor Louis-Eric Trudeau, a neuroscientist, investigates the possibility that an autoimmune attack on those dopamine cells is the culprit.
Trudeau and his immunologist colleague, Michel Desjardins, are studying the role of the portion of cells called axon terminals. These terminalsthe root-like extremities of cellsrelease the chemical messengers that send communication signals. Trudeau believes the death of these terminals, before the death of the dopamine cells themselves, is where the trouble starts.
Using dopamine-producing brain cells from genetically modified mice, Trudeau and his team are exposing dopamine cells directly to immune cells. Then they closely study the axon terminals of those dopamine cells to see what happens in an immune attack.
This project is focused on trying to develop a better understanding of why the terminals are affected, Trudeau says. This is a relatively new field in Parkinsons disease looking at the possibility that this disease is at least in part an autoimmune disease, in some ways like Multiple Sclerosis .
The immune system can be relatively easily targeted for treatment, Trudeau says.
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What Is Parkinsons Disease
Parkinsons disease is a progressive neurological disorder. The first signs are problems with movement.
Smooth and coordinated bodily muscle movements are made possible by dopamine, a substance in the brain. Dopamine is produced in a part of the brain called the substantia nigra.
In Parkinsons, the cells of the substantia nigra start to die. When this happens, dopamine levels are reduced. When they have dropped 60 to 80 percent, symptoms of Parkinsons start to appear.
Some of the early symptoms of Parkinsons can begin several years before motor problems develop. These earliest signs include:
- problems with attention and memory
- difficulty with visual-spatial relationships
Early signs of Parkinsons disease may go unrecognized. Your body may try to alert you to the movement disorder many years before movement difficulties begin with these warning signs.
The exact cause of Parkinsons is unknown. It may have both genetic and environmental components. Some scientists believe that viruses can trigger Parkinsons as well.
Low levels of dopamine and norepinephrine, a substance that regulates dopamine, have been linked with Parkinsons.
Abnormal proteins called Lewy bodies have also been found in the brains of people with Parkinsons. Scientists do not know what role, if any, Lewy bodies play in the development of Parkinsons.
While theres no known cause, research has identified groups of people who are more likely to develop the condition, which include:
Genetic Regulation Of Autoimmunity In Pd
In addition to these observations, DJ-1 has also been reported to affect the development of natural Tregs and induced Tregs . Mature Tregs with normal function, which modulate not only adaptive immunity but also innate immunity, are pivotal for maintaining thymic function, peripheral immune self-tolerance and immune system homeostasis. nTregs are generated in the thymus, while iTregs are derived from naïve CD4+ T cells encountering antigens in the peripheral organs. Both cell types are generally immunosuppressive through the suppression or downregulation of effector T cell proliferation . Their self-check function successfully prevents excessive effector cell reactions. On the other hand, the abnormal proliferation of both types of Tregs leads to the failure of self-/non-self-discrimination, resulting in autoimmune disease . Evidence reported by Singh et al. has demonstrated that DJ-1, one of the most classical key players responsible for PD pathogenesis, is strongly linked with neuroimmunology and multiple autoimmune responses in PD . In addition, DJ-1-deficient animal models have shown compromised iTreg induction, cell cycle progression, and cell survival and proliferation. DJ-1/ iTregs are more proliferative, more susceptible to cell death signals and deficient in cell division compared with wild type counterparts, as analyzed by flow cytometry and Western blotting.
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Clinical Features And Autoimmunity In Pd
-Synuclein participates in autoimmunity and is involved in the pathological progression of PD. -Syn, as the main disease-causing protein, first appears in the gut and is related to gut dysbiosis, which disturbs the intestinal immune system, leading to one of the main non-motor symptoms of PD: constipation. Then, this protein transmits to the dorsal motor nucleus through the vagus nerve and acts as a self-antigen targeted by effector T cells, B cells, and microglia. This autoimmunity attack finally results in the damage and death of DNs. SIBO, small intestinal bacterial overgrowth.
Pathogenic Protein Function In Autoimmunity
As discussed above, molecular mimicry and cross immunoreactions are two of the primary mechanisms through which autoimmunity is triggered. Molecular mimicry between herpes simplex virus 1 and human -syn was detected in PD patients in 2016. HSV1 infection could enhance the development of autoimmunity because autoreactive antibodies induced by HSV1 have the same response to the human -syn homologous peptide bound to the membrane of DNs and lead to DN destruction . These results also support the assumption that -syn participates in autoimmunity involved in the pathological progression of PD.
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What Is Niehs Doing
Unraveling the genetic and environmental underpinnings of autoimmune disease is a focus at NIEHS and the National Toxicology Program . Progress happens through multiple research efforts, such as:
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Evidence Of Autoimmunity In Parkinsons
Research by Columbia University and the La Jolla Institute for Allergy and Immunology in the United States has found evidence of the role that autoimmunity plays in Parkinsons disease. According to the study, the death of the neurons that cause this disease could be prevented by therapies that dampen the response of the immune system.
The researchers claim that two fragments of a protein that appears in the brain cells of people with Parkinsons, alpha-synuclein, can activate T cells. T cells play a role in autoimmune responses. Apparently, dopamine neurons, which play a role in the disease, are vulnerable to autoimmune attacks. This occurs because they have some proteins on the cell surface. These proteins help the immune system to recognise foreign substances. This confuses the T cells, which identify the neurons damaged by Parkinsons as invaders and attack them.
In the study, the researchers exposed 67 blood samples from patients with the disease and 36 healthy controls to alpha-synuclein fragments and other proteins found in neurons. In the blood of the controls, not much cellular immune activity was observed. However, in the patients samples, the T cells showed a strong response to the protein fragments.
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Deterioration Of Brain Cells In Parkinson’s Disease Is Slowed By Blocking The Bach1 Protein Preclinical Study Shows
Parkinson’s disease is the most common neurodegenerative movement disorder, afflicting more than 10 million people worldwide and more than one million Americans. While there is no cure for PD, current therapies focus on treating motor symptoms and fail to reverse, or even address, the underlying neurological damage. In a new…
Validation In Mouse Models
The new findings of Dr Michel Desjardins from the University of Montreal and Dr Heidi McBride of MNI, linking Parkinsons disease to autoimmune mechanisms, have been validated in a mouse model of Parkinsons disease where PINK1 or Parkin are absent.
Clinicians have shown that the immune system is activated in the brain of Parkinsons disease patients, said Dr Diana Matheoud, a postdoctoral fellow from the University of Montreal. Our study explains how an attack by the immune system may be responsible for the destruction of dopaminergic neurons during the disease. We are currently testing whether autoimmune mechanisms lead to the loss of dopaminergic neurons in mice, and developing systems to extend our study to human neurons.
Antigen presentation was not believed to play a direct role in Parkinsons disease, added McBride. While most laboratories are following the trail of the toxic mitochondria model, our path led us to observe Parkinsons disease from a different point of view. Our approach, centred on the immune system, led us down a different road where we were able to observe that autoimmunity is likely to play an important role in the progression of the disease.
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