IMMUNE SYSTEM AND NEURODEGENRATIVE DISEASES

PRESENTED TO : D M ISHA OLIVE KHAN

LECTURER, NORTH SOUTH UNIVERSITY

PRESENTED BY

SADIA SHAHID KASHFI 141 1340 046

CONTENTS • NEUROIMMUNE SYSTEM• IMMUNE PRIVILEGE • COMPONENTS OF NEUROIMMUNE SYSTEM• NEUROINFLAMMATION• MICROGLIA IN NEURODEGENERATION• NEURODEGENERATIVE DISEASES• PARKINSON’S DISEASE• MULTIPLE SCLEROSIS

NEUROIMMUNE SYSTEMThe neuroimmune system is a system of structures and processes involving the biochemical and electrophysiological interactions between nervous system and immune system which protect neurons from

pathogens.

IMMUNE PRIVILEGEThe CNS has developed strategies to limit the entry of immune elements. This so-called phenomenon of ‘immune privilege’ was recognized in the mid-20th century by Sir Peter Medawar who was awarded the Nobel Prize with Sir Frank Macfarlane Burnet in 1960 for the discovery of acquired immune tolerance.

COMPONENTS

• Microglia

• Astrocytes

• Oligodendrocytes

NEUROINFLAMMATION Neuroinflammation is a

process in which the

brain responds to

infections, diseases and

injuries through release

of proinflammatory

molecules. These

responses are mediated

by glial cells of the CNS

ACTIVATION OF GLIAL CELLS The magnitude of microglial activation depends on extrinsic and intrinsic conditions: • the type of insult,• potency of the stimulus, • distance from the stimulus, • immediate microenvironment, • “primed” (sensitized) state of microglia that

have been exposed to prior and existing stimuli.

MICROGLIA IN NEURODEGENERATION

NEURODEGENERATION

NEURODEGENERATIONNeurodegeneration is an umbrella term for the progressive loss of structure of function of neurons.

Neurodegeneration can be found in many different levels of neuronal circuity ranging from molecular to systemic.

NEURODEGENERATIVE DISEASES

Neurodegenerative disorders such as• Parkinson’s • Alzheimer’s • Huntington’s • Multiple Sclerosis • Amyotropic Lateral Sclerosis

PARKINSON’S DISEASE

Parkinson's disease is a neurodegenerative brain disorder that progresses slowly in most people. Most people's symptoms take years to develop, and they live for years with the disease.

In short, a person's brain slowly stops producing a neurotransmitter called dopamine. With less and less dopamine, a person has lessand less ability to regulate their movements, body and emotions.

CAUSES OF PARKINSON’S DISEASEPD is basically caused by the progressive impairment or deterioration of neurons in an area of the brain known as the substantia nigra. When functioning normally, these neurons produce a vital brain chemical known as dopamine.

A lack of dopamine results in abnormal nerve functioning, causing a loss in the ability to control body movements.

FACTORS OF PARKINSON’S DISEASE• Genetic factors: The vast majority of Parkinson's cases are not directly inherited.

• Environmental factors: These include the insecticides permethrin and beta-hexachlorocyclohexane (beta-HCH), the herbicides paraquat and 2,4-dichlorophenoxyacetic acid and the fungicide maneb.

MECHANISM OF PARKINSON’S DISEASE

• microglia has two alternative activation phenotypes, termed the M1 (pro-inflammatory) phenotype and the alternative M2 (anti-inflammatory) phenotype.

• These different activation statuses of microglia are characterized by secretion of different arrays of cytokines. It has been demonstrated that LPS/IFN-γ treatment induces M1 activation, while IL-4/IL-13 treatment triggers M2 activation in microglia.

• The classical M1 activation of microglia is featured by the production of pro-inflammatory cytokines, including TNF-α, IL-1β, IL-6, IL-12, and other cytotoxic molecules such as superoxide, NO and reactive oxygen species (ROS), contributing to the amplification of the pro-inflammatory responses during injuries and infections.

MECHANISM OF PARKINSON’S DISEASE

• Conversely, M2 microglia plays an immunosuppressive role by antagonizing the classic M1 microglia and promoting tissue repair.

• The M2 microglia produces a variety of cytokines with anti-inflammatory property, such as IL-4, IL-13, IL-10, and TGF-β.

• The different activation forms of microglia can be distinguished by their characteristic gene expression pattern.

• Expression of Arg1, FIZZ1 and Chi3l3 may be regulated by cytokines, since their levels are significantly increased in primary cultured microglia or the striatal and frontal cortical regions of mouse brain following IL-4 stimulation.

TREATMENTS OF PARKINSON’S DISEASE

To date, there's no standard treatment for the disease – the treatment for each person with Parkinson's is based on his or her symptoms. Though some medications available to treat the symptoms of Parkinson’s, although none actually reverse the effects of the disease.

TREATMENTS

Following medications are currently available to treat Parkinson’s:– Carbidopa/Levodopa therapy– Dopamine Agonists– Anticholinergics– MAO-B Inhibitors– COMT Inhibitors– Other medications

MULTIPLE SCLEROSIS

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system (CNS) in which lymphocytes infiltrate and attack myelin, leading to demyelination and neuronal degeneration

MULTIPLE SLCEROSIS

CAUSES OF MULTIPLE SCLEROSIS

While the cause (etiology) of MS is still not known, scientists believe that the interaction of several different factors may be involved. Immunologic factorsEnvironmental factorsInfectious factors Genetic factors

Activation of myelin

autoreactive T lymphocytes

Migration of activated T cells

across BBB

Inflammatory response against

myelin

Demyelination and subsequent

neural degeneration

STAGES

•T-cell activation requires several steps –T-cell receptor (TCR) on a naïve T cell recognizes and binds to an antigen, which is found on the major histocompatibility complex (MHC) of an antigen-presenting cell (APC) –Antigen binding delivers the first signal to the T cell and the APC expresses a second, costimulatory signal leading to activation •Activated T cells drive the inflammatory response against myelin antigens in the CNS

Activation of myelin auto-reactive T-lymphocytes

MIGRATION ACROSS THE BLOOD BRAIN BARRIER

• Migration of activated lymphocytes across the BBB is mediated by adhesion molecules, chemokines, and matrix metalloproteinases (MMPs)

• Upregulation of adhesion molecules encourages interaction between T cells and the BBB

• Chemokines attract myelin-specific T cells across the BBB into the CNS

• MMPs degrade the extracellular matrix and basement membrane, compromising the BBB

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INFLAMMATORY RESPONSE AGAINST MYELIN

• B cells produce oligoclonal immunoglobulins, which are found in the CSF of MS patients

• B cells may have a direct impact on demyelination through secretion of pathogenic antibodies against oligodendrocytes

• Macrophages and microglial cells produce cytotoxins

TREATMENT WITH TYSABARI

TREATMENTS OF MULTIPLE SCLEROSIS

REFERENCES • Thomas & Flint Beal, Parkinson's disease, Human

Molecular Genetics 2007, Vol 16, Review Issue 2, 183-194

• Bar-Or A. The immunology of multiple sclerosis. Semin Neurol. 2008;28:29-45.

• http://shodhganga.inflibnet.ac.in/bitstream/10603/4780/6/06_chapter%201.pdf

• Mechanisms of Neurodegenerative DisordersPart 2: Control of Cell Death

Benjamin Wolozin, MD, PhD; Christian Behl, PhD

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