Adaptive Immunity For Therapeutic Gain In Pd
It is likely that the adaptive immune systems response to disease in the CNS is similar in a range of neurodegenerative diseases. Thus, therapeutic strategies aimed at modulating the immune response during disease may be applicable to several neurodegenerative diseases. Here we will discuss recent approaches taken to modulate the adaptive immune system for disease therapy.
Tracing The Origin And Progression Of Parkinsons Disease Through The Neuro
Study Rationale: While inflammation of the brain caused by immune cells has been implicated in Parkinsons disease , it is unknown whether these cells attacking the brain initiate the disease. Moreover, there is new evidence that bacteria in the gut may actually trigger the immune system leading to disease initiation via the peripheral nerves that connect the gut with the brain. Our studies will integrate cutting-edge technologies in humans and pre-clinical models to determine whether the disease is mediated by immune cells recognizing alpha-synuclein, a key brain protein implicated in PD.
Hypothesis: We hypothesize that in a subset of cases, PD is initiated by an autoimmune event involving recognition of alpha-synuclein in the gut, and that interactions between the immune system and the peripheral and central nervous systems establish the disease in the brain.
Impact on Diagnosis/Treatment of Parkinsons Disease: This work will reveal fundamental mechanisms that account for the initiation and progression of PD, uncovering disease- and tissue-specific profiles of autoreactive T cells and overall T cell surveillance that will lead to the discover of perturbed immune pathways in PD with potential application in the development of immunomodulatory therapies.
Leadership
Yale University
Project Outcomes
Neuro-immune Interactions | 2020
How Parkinsons Disease Affects The Autonomic Nervous System And The Heart
In PD, there are two major reasons why the automatic control of the cardiac system is impaired. First, areas of the brain that control this system often contain Lewy bodies and have undergone neurodegeneration. In addition, the autonomic nervous system itself is directly affected by Lewy body-like accumulations and neurodegeneration. This means, when the baroreceptors in the heart and carotid artery sense a drop in blood pressure and try to generate a signal to the heart and blood vessels to increase the blood pressure, the message may not get through. This results in neurogenic orthostatic hypotension , or drops in blood pressure upon standing due to autonomic nervous system dysfunction. There are no medications that can cure nOH by restoring the autonomic nervous system in PD. nOH however, can be treated. Read more about nOH and its treatments here.
Structural problems of the heart such as coronary artery disease or cardiomyopathy are not thought to be part of the pathology of PD, although of course, could co-exist with PD.
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How Does The Immune System Affect Parkinson Disease
- Details
Think about the hobbies you have. It may be running or weight lifting, playing music or drawing. Now, think about your work. Does it involve writing or typing? Do you have to drive to get there every day?
Many of our jobs and hobbies require fine motor skills and coordinated movement, and most of the time, we dont even think about it. We are able to type on our computers, go for a morning run and do the chores around the house without having to concentrate too much on our coordination. Unfortunately, this is not the reality for people living with Parkinsons disease. To them, the simplest tasks may be impossible to complete.
Parkinsons disease is a debilitating neurodegenerative disease that causes progressive problems with movement due in part to the aggregation of a protein called a-synuclein in the brain. It is often defined by tremors even at rest, rigidity, bradykinesia or slow movement, and postural instability. As the disease progresses, the more severe the symptoms become, eventually resulting in the patient being unable to do much of any tasks requiring movement on their own. By 2030, its predicted that 1.2 million people in the U.S. will have this disease. Thats 1.2 million people who will have a debilitating disease that cannot be cured.
In the meantime, Schonhoff said to take care of your brain by eating right and getting regular exercise . So, put down the bowl of chips and get up and move! Your brain is counting on you.
Could Lrrk2 Function In Immune Response Relate To Pd Etiology
A recent study by Mutez and collaborators shows alterations in the transcriptional profile of blood mononuclear cells from PD patients with LRRK2 mutations. In particular, they observed dysregulated interleukin signaling and TGF- signaling, further supporting the notion that PD also involves neuroinflammatory processes and peripheral immune infiltration . Moreover, these observations imply that analyzing selected pathways that become altered in peripheral cells may help to identify and delineate the early stages of PD, using dysregulated genes as molecular markers.
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Peripheral Humoral Immune Response Is Associated With The Non
- 1Department of Neurology, Qilu Hospital, Shandong University, Jinan, China
- 2Department of Neurology, Henan Provincial Peoples Hospital, Peoples Hospital of Zhengzhou University, Zhengzhou, China
Background: Non-motor symptoms are common in Parkinsons disease and can even be used as part of the supportive criteria for diagnosis. Chronic inflammation is involved in every stage of PD. Disorders of the immune system affect the peripheral blood. Whether the humoral immune response is associated with the non-motor symptoms of PD remains unknown.
Methods: MannWhitney tests and Bonferroni correction were used to compare the serum levels of IgG, IgA, IgM, C3, and C4 between 180 sporadic PD patients and 187 healthy controls. Multiple regression models were conducted to assess the associations among these indicators of humoral immunity and the clinical features of PD patients.
Results: Male PD patients had lower levels of C3 and C4 than healthy controls and lower levels of C3 than female PD patients . Patients suffering from attention/memory problems had significantly lower levels of IgA and C3 than those without these problems . In addition, serum IgG levels were negatively associated with mood/cognition problem scores and were positively associated with gastrointestinal tract problem scores . Serum C3 levels were negatively associated with being male, age, and sleep/fatigue problem scores .
Parkinsons And Difficulty Sleeping
More than 75 percent of people with Parkinsons disease report sleep problems. You may experience restless sleep, where you wake up frequently during the night.
You may also experience sleep attacks, or episodes of sudden sleep onset, during the day. Talk with your doctor about treatment methods, such as taking an over-the-counter or prescription sleep aid to help you regulate your sleep.
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How Parkinsons Disease Affects The Body
Life with Parkinsons is challenging, to say the least. This progressive disease starts slowly, and because theres currently no cure, it gradually worsens how you think and feel.
Giving up may seem like the only solution, but it certainly isnt. Thanks to advanced treatments, many people are able to continue living healthy, productive lives with Parkinsons.
Take a glance at this infographic to get a visual picture of how Parkinsons can affect everything from your memory to your movement.
How Does Parkinsons Disease Affect The Body
Recognising the signs
A combination of signs can help a doctor make an early diagnosis. If Parkinsons disease is diagnosed early, the chances of being able to treat and manage the condition are greater. Individual signs may not be an indication of Parkinsons disease. Some signs such as loss of smell could be caused by an infectious illness, or joint stiffness by conditions like arthritis.
Parkinsons is most commonly diagnosed with a very physical examination and assessment of a persons medical history. There are very specific markers for diagnosis which doctors use to assess for possible Parkinsons disease. These markers have a lot to do with a combination of very specific signs and symptoms and if recognised early enough, can be better managed.
1. Primary motor symptoms
2. Secondary motor symptoms
Other motor symptoms include:
Some individuals may also experience the following:
- Hunched over / stooped posture – When standing, the body may begin to slouch or lean inwards, causing a hunched over appearance.
- Impaired gross motor coordination
- Impaired fine motor dexterity and motor coordination
- Difficulties with swallowing or chewing
- Cramping
- Production of excess saliva and drooling
- Sexual dysfunction
- Dystonia
- Akathisia
3. Non-motor symptoms
Symptoms that do not involve physical movement or coordination, and often precede motor problems, can include:
Symptoms are initially mild, even if they develop suddenly, and typically affect one side of the body at first.
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What Is Parkinsons Disease
Parkinsons disease is a progressive disease. It starts slowly, often with a minor tremor. But over time, it can affect everything from speech to gait to cognitive abilities.
While treatments are becoming more advanced, theres still no cure for Parkinsons disease. An important part of a successful Parkinsons treatment plan is recognizing and managing secondary symptoms those that affect day-to-day life.
Here are a few of the more common secondary symptoms and what you can do to help manage them.
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Neuroinflammation As A Key Player In Pd
Microglia are macrophages resident in the brain and represent the first line of defense of innate immune system. While most of microglia functions are protective, there is mounting evidence that chronically activated microglia and astrocytes contribute to PD and that peripheral inflammation increases microglia activation with consequent damage of the nigrostriatal dopaminergic circuit .
Proinflammatory cytokines, such as IFN-, TNF, and IL-1 coordinate the action of microglia and PD patients have been found to possess elevated levels of TNF and IFN- in cerebrospinal fluid and postmortem brain tissue .
Innate Immunity In Pd: Microglia Activation
Microglial cells are the principal actors of innate immunity in the CNS responsible for the protection and restoration of neurons . They can be activated by various external or internal insults such as neuronal dysfunction, trauma or certain toxin. Also, a wide range of molecules including viral or bacterial proteins, -syn, cytokines and antibodies are able to induce the activation of microglia . Consequently, microglial cells produce different molecular mediators with chemotactic and immunomodulatory functions. One of them is tumor necrosis factor which in PD plays important roles contributing to the regulation of synaptic plasticity . PD brains are characterized by the presence of HLA-DR+ microglial cells and raised levels of CD68, an activation marker for microglia and macrophages, having a direct relation with -syn aggregations and the duration of disease . Moreover, an increased expression of MHC-II molecules in microglial cells has been observed in chronic neuroinflammation but not in the CNS of healthy subjects . Individuals with single nucleotide polymorphism at MCH-II locus are prone to develop PD, which indirectly proves the importance of adaptive immunity in these patients .
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Problems With The Immune System
The immune system protects our bodies from foreign invaders, such as bacteria and viruses. There are a number of autoimmune conditions that are caused when the immune system mistakenly attacks and damages healthy cells in the body.
Previous studies have suggested that certain genetic factors, which control how our immune system behaves, are linked to an increased risk of Parkinson’s.
This research, for the first time, suggests that the immune system in people with Parkinson’s may respond to a protein called alpha synuclein, which is known to be involved in the condition.
The researchers suggest that changes in the alpha synuclein protein could activate the immune system, causing it to start attacking dopamine producing brain cells.
Adaptive Immunity And The Cns
Even under normal conditions, activated T and B lymphocytes patrol the CNS in low numbers, whereas naïve lymphocytes are excluded . Although fewer activated T cells infiltrate the normal CNS than other tissues , this may be owing to the low level of adhesion molecules expressed on endothelial cells under normal conditions , whereas increased expression of adhesion molecules leads to increased lymphocyte infiltration. When cytokines such as interleukin -1 and tumor necrosis factor – are secreted by activated glia in the brain, or are present in circulating blood, permeability of the BBB is increased and the expression of cellular adhesion molecules on microvascular endothelial cells are up-regulated . Activated T cells and B cells are then able to extravasate and migrate to the site of neuronal injury in increased numbers .
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Increased Falls And Loss Of Balance
Parkinsons disease can alter your sense of balance and make simple tasks like walking seem more dangerous. When youre walking, be sure to move slowly so your body can rebalance itself. Here are some other tips to avoid losing your balance:
- Dont try to turn around by pivoting on your foot. Instead, turn yourself around by walking in a U-turn pattern.
- Avoid carrying things while walking. Your hands help your body balance.
- Prepare your home and remove any fall hazards by arranging furniture with wide spaces between each piece. The wide spaces will give you ample room to walk. Position furniture and lighting so that no extension cords are needed and install handrails in hallways, entryways, stairwells, and along walls.
Parkinsons And Decreased Range Of Movement
Exercise is important for everyone, but its especially important for people with Parkinsons disease. Physical therapy or exercise can help improve mobility, muscle tone, and range of motion.
Increasing and maintaining muscle strength may be helpful as muscle tone is lost. In some cases, muscle strength can act as a buffer, countering some of the other effects of Parkinsons. Additionally, massage can help you reduce muscle stress and relax.
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Parkinson Disease Shown To Induce Immune Imbalance In The Blood Indicating Possible Benefit Of Immune Modulation
Researchers uncovered that patients with Parkinson disease could benefit from immune modulation as an alternative treatment, due to the conditions influence on immune imbalance, according to study findings.
Researchers uncovered that patients with Parkinson disease could benefit from immune modulation as an alternative treatment, due to the conditions influence on immune imbalance, according to findings of a study published in the journal Movement Disorders.
PD is a multisystem disease in which both the central and peripheral nervous systems are affected. The disease is characterized by the slow degeneration of the neurons in the brain due to the abnormal accumulation of a protein called -synuclein. While it is primarily seen as a brain disorder, the behavior of immune cells in the blood of affected patients is starkly different than in those without the disease. This evidence reveals a potential extension to usual research of PD-related changes on immune response, indicating a further impact on peripheral immune cells, such as monocytes, in addition to microglia in the brain.
Researchers from the Department of Biomedicine at Aarhus University sought to investigate this understudied aspect of PD-related changes in peripheral immune cells by examining their responsiveness to stimulation and their ability to release immunomodulatory molecules, which is linked to consequences for PD progression:
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Medicines For Parkinson’s Disease
Medicines prescribed for Parkinson’s include:
- Drugs that increase the level of dopamine in the brain
- Drugs that affect other brain chemicals in the body
- Drugs that help control nonmotor symptoms
The main therapy for Parkinson’s is levodopa, also called L-dopa. Nerve cells use levodopa to make dopamine to replenish the brain’s dwindling supply. Usually, people take levodopa along with another medication called carbidopa. Carbidopa prevents or reduces some of the side effects of levodopa therapysuch as nausea, vomiting, low blood pressure, and restlessnessand reduces the amount of levodopa needed to improve symptoms.
People with Parkinson’s should never stop taking levodopa without telling their doctor. Suddenly stopping the drug may have serious side effects, such as being unable to move or having difficulty breathing.
Other medicines used to treat Parkinsons symptoms include:
- Dopamine agonists to mimic the role of dopamine in the brain
- MAO-B inhibitors to slow down an enzyme that breaks down dopamine in the brain
- COMT inhibitors to help break down dopamine
- Amantadine, an old antiviral drug, to reduce involuntary movements
- Anticholinergic drugs to reduce tremors and muscle rigidity
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Peripheral Immunity In Parkinsons Disease: Evidence For Monocyte Involvement And Infiltration
The presence of -syn pathology in the periphery and the peripheral neuropathy in PD supports a more holistic affection of the nervous system in PD . This peripheral -syn pathology occurs early as it is also seen in RBD patients, prodromal PD . Since the antigenicity of -syn is true for both microglia and monocytes an innate immune response is expected to occur both in the brain and periphery, and their cross-talk will shape the integrated immune response in PD . Accordingly we have shown that, in RBD patients, TLR4 expression in blood monocytes directly correlated to the immune brain activation and indirectly to the dopaminergic neurotransmission as shown by PET , therefore supporting an early central and peripheral immune response, and a cross talk between brain and periphery that associates to the neurodegenerative event. However, it is unclear how much of this is exerted from the periphery or through recruitment and infiltration.
Changes in monocyte subpopulations in Parkinsons disease
Functional changes in monocytes in Parkinsons disease: abnormal activation, phagocytosis and proliferation
Super Foods To Boost The Immune System
With winter just around the corner, its time we all started to look after ourselves a little more. Avoiding germs is one thing, but we can also try and boost our immune systems by getting plenty of sleep and eating the right foods.
Here are nine foods well-known for their immunity-boosting qualities according to prevention.com.
1. YogurtProviding you can eat dairy without any side effects, the natural probiotics found in yogurt are great for keeping the gastrointestinal tract healthy and in order. Opt for ones without added sugar or sweeteners if possible.
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2. Oats and BarleyAdding oats to your diet in the winter is easy, you can start your day with a hot bowl of oatmeal and you can switch barley for rice with your evening meal. Both of these grains are gentle on the stomach and are high in antioxidants important for fighting off those winter bugs.
3. BeefBeef is full of zinc, which many of us are low in over the winter months. Zinc helps to form healthy white blood cells which are important in the fight against winter illnesses. To get the most out of beef aim for organic, grass-fed beef.
4. GarlicFor optimum garlic power, you should eat two cloves of raw garlic a day. However, if this sounds unpalatable then you can either take garlic capsules or use lots of garlic in your cooking. The allicin in garlic is great for helping to fight off colds and flu.
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