Neuroinflammation Flashcards
- Unique Aspects of the CNS in Terms of Injury and Repair
Physical Environment: The CNS is enclosed within a rigid, bony structure (skull and vertebrae) and surrounded by cerebrospinal fluid (CSF), which provides mechanical protection.
Blood-Brain Barrier (BBB): The CNS has a closed vascular system, limiting immune cell entry and reducing inflammation but also restricting repair mechanisms.
Limited Regeneration: Neurons are largely post-mitotic, meaning they have a limited capacity to regenerate after injury.
High Metabolic Demand: Despite being only ~2% of body mass, the CNS consumes ~20% of oxygen and relies heavily on glucose metabolism.
Functional Specialization: Different CNS regions have specific functions, meaning damage can lead to highly localized deficits.
Response to Injury: Unlike other tissues, the CNS has limited regenerative capacity. Instead of full repair, injuries often result in gliosis (formation of glial scars by astrocytes).
Normal Functions of Astrocytes and Microglia
Astrocytes:
Maintain homeostasis of the extracellular environment, including ion and neurotransmitter balance.
Form part of the BBB through their end-feet interactions with blood vessels.
Provide metabolic and structural support to neurons.
Participate in synaptic regulation and neuroplasticity.
Microglia: The CNS’s Resident Macrophages
Act as the primary immune cells of the CNS, constantly surveying the environment.
Participate in synaptic pruning and remodeling during development.
Respond to injury by adopting an activated state to clear debris and secrete inflammatory mediators.
Structure and Function of the Blood-Brain Barrier (BBB)
Structure:
Comprised of endothelial cells with tight junctions, forming a nearly impermeable barrier.
Astrocyte end-feet contribute to additional support and selective permeability.
Pericytes help regulate blood flow and barrier integrity.
`Function:
Prevents entry of pathogens, toxins, and large molecules (e.g., antibodies).
Allows passage of small, hydrophobic, and essential nutrients (e.g., oxygen, glucose).
Active transport mechanisms regulate the entry of crucial molecules like glucose and amino acids.
Some regions, such as circumventricular organs, have higher permeability to allow for neuroendocrine communication.
Changes in Astrocytes and Microglia Associated with Neuroinflammation
Astrocytes:
Become reactive, proliferating and forming glial scars (gliosis).
Secrete cytokines and chemokines that contribute to inflammation.
Alter their metabolic and neurotransmitter regulatory functions, potentially exacerbating pathology.
Microglia:
Shift from a surveillance state to an activated state, releasing pro-inflammatory molecules.
Can contribute to neuronal damage if chronically activated.
May transition to different activation states (e.g., M1-like pro-inflammatory vs. M2-like anti-inflammatory).
microglia
Primary immune cells of the CNS: Constantly monitor the brain’s microenvironment for signs of injury, infection, or dysfunction.
Synaptic pruning and remodeling: During development, microglia remove unnecessary synaptic connections, helping refine neural circuits.
Response to injury: When activated, they shift from a resting (spindly) state to a larger, more amoeboid shape, secrete inflammatory mediators, and help clear cellular debris.
Morphological changes: In response to injury or infection, microglia:
Enlarge their cell bodies.
Shorten and thicken their processes.
Increase cytokine production to signal other immune responses.
Highly dynamic: They can return to a resting state once the inflammatory trigger is resolved, though chronic activation is linked to neurodegenerative diseases.
Unique mobility: Microglia can move toward areas of injury (chemotaxis).
Congregation: They cluster in regions of damage, where they help clear debris and modulate the inflammatory response.
Neurodegenerative diseases?
In Alzheimer’s disease, microglia cluster around amyloid plaques but may fail to clear them efficiently, contributing to disease progression.
In multiple sclerosis, microglia contribute to demyelination by producing inflammatory molecules.
CNS is Different from Other Organs
The central nervous system (CNS) has unique characteristics that set it apart from other organs, particularly in terms of immune response and injury repair.
Resolution – not always a good outcome
-In most tissues, resolving inflammation leads to healing and restored function.
-However, in the CNS, resolution may lead to gliosis (scarring by astrocytes) rather than true tissue regeneration, potentially impairing neural function.
Avoid response to mild injury?
-The CNS aims to minimize immune responses to mild injuries to prevent unnecessary damage.
-Unlike other organs, excessive inflammation in the brain can be harmful, leading to bystander damage to neurons, which are post-mitotic and difficult to replace.
Why the CNS Avoids Excessive Immune Responses
The CNS is considered “immune-privileged”, meaning it limits immune responses to avoid inflammation-induced neuronal damage.
The Blood-Brain Barrier (BBB) and the absence of classical lymphatic drainage restrict immune cell entry.
Some foreign antigens (such as viral particles or transplanted tissues) can be introduced into the CNS without triggering a strong immune response.
While this protects neurons, it also makes the CNS vulnerable to chronic infections (e.g., herpes virus) and autoimmune diseases (e.g., multiple sclerosis).
What is the Perivascular Space?
The perivascular space (also called Virchow-Robin space) is a small fluid-filled area around blood vessels in the brain that acts as a buffer zone between the CNS and the immune system.
It surrounds blood vessels before they fully penetrate into the brain tissue.
Immune cells, such as T cells, perivascular macrophages, and dendritic cells, can exist in this space without directly infiltrating the brain.
This allows for immune surveillance while still protecting neurons from excessive immune activity.
MS pathophysiology
several factos
- T cells mistakenly recognize myelin proteins as foreign.
These auto-reactive T cells are activated outside the CNS, probably due to:
Molecular mimicry: A virus or bacteria has a protein similar to myelin, confusing the immune system.
Genetic susceptibility: Some individuals have HLA-DR2 haplotypes, making their immune system prone to attacking myelin. - Once activated, these auto-reactive T cells produce inflammatory cytokines (like TNF-α and IFN-γ), which disrupt the BBB.
This allows immune cells (T cells, B cells, and macrophages) to enter the perivascular space, where they start attacking myelin. - Microglia and astrocytes upregulate MHC class I and II, allowing even more T cell activation inside the CNS.
MHC class I allows CD8+ cytotoxic T cells to recognize and attack oligodendrocytes.
MHC class II allows CD4+ helper T cells to further activate the immune response.
This amplifies the autoimmune response, bringing in even more T cells.
They also release metalloproteinases (MMP-2 and MMP-9), which break down the extracellular matrix, weakening the BBB.
This creates a vicious cycle—more immune cells enter, worsening inflammation and damage.
Perivascular Cuffing?
Perivascular cuffing is when immune cells (mainly T cells, macrophages, and some B cells) accumulate around blood vessels in the brain.
Normally, a few immune cells (T cells, macrophages) can be present in the perivascular space for immune surveillance.
However, in MS and other inflammatory conditions, large clusters of immune cells accumulate in an abnormal, pathological way.
This persistent immune cell buildup around blood vessels is called perivascular cuffing and indicates active inflammation and BBB breakdown.
It happens because T cells enter through leaky BBB regions but remain concentrated around blood vessels before fully infiltrating brain tissue.
Why is it important?
It is a hallmark of MS lesions and indicates that the immune system is actively attacking myelin near blood vessels.
It suggests that BBB breakdown precedes widespread brain infiltration.
Brain Structure and Protective Layers
Dura mater: The outermost and toughest meningeal layer, protecting the brain.
Falx cerebri: A fold of dura mater that separates the left and right hemispheres of the brain.
Tentorium cerebelli: Another dural fold, separating the cerebellum from the occipital lobes of the cerebrum.
The neocortex is the outermost layer of the brain, responsible for higher-order functions like cognition, sensory processing, and motor control.
It has a six-layer structure (cortical lamination), where each layer has distinct types of neurons and functions.
The outermost layer (Layer I) is mostly non-neuronal and contains dendrites and synaptic connections.
Cerebrospinal Fluid (CSF) Production and Flow
Choroid plexus: A specialized tissue in the ventricles that produces cerebrospinal fluid (CSF).
CSF Movement:
CSF circulates through the ventricles of the brain.
It flows into the arachnoid space (between the arachnoid mater and pia mater), where it cushions the brain and spinal cord.
CSF is eventually reabsorbed into the venous system via the arachnoid granulations.
White Matter vs. Gray Matter
Gray Matter:
Contains neuronal cell bodies, dendrites, and synapses.
Some myelin is present, but it is less concentrated than in white matter.
Found in the cortex, basal ganglia, and spinal cord horns.
White Matter:
Consists mostly of myelinated axons, which transmit signals between different brain regions.
Lacks neuronal cell bodies.
Located beneath the cortex and forms connections between different brain regions.
Astrocytes: Structure and Role in CNS
Nucleus: Astrocytes have a slightly larger and more diffuse nucleus compared to oligodendrocytes.
Darker Staining: Their nucleic acids stain darker than those in oligodendrocytes due to their role in gene expression and metabolic activity.
Astrocytes and Brain Injury Response
The brain has limited regenerative capacity due to the post-mitotic nature of neurons.
When injury occurs, astrocytes become chronically activated and form a glial scar.
Glial scars can help “wall off” damage, but they also inhibit neuron regrowth, leading to permanent disability or death.
No fibroblasts in the CNS: Unlike other tissues that rely on fibroblasts for healing, the CNS depends entirely on astrocytes for injury response.
Astrocytes and the Blood-Brain Barrier (BBB)
Astrocytes form part of the BBB via their foot processes, which surround blood vessels.
They help regulate what passes into the brain from the bloodstream.
If astrocytes become dysfunctional, BBB integrity is compromised, allowing harmful substances and immune cells to enter the CNS.
Astrocytes also play a role in immune surveillance, helping to maintain CNS homeostasis.
Astrocytes and CSF Interaction
Astrocytes are highly concentrated near brain surfaces, blood vessels, and in regions interacting with cerebrospinal fluid (CSF).
They help regulate ion balance, clear waste, and maintain structural integrity in these areas.
Areas of Greater Permeability – Circumventricular Organs (CVOs)
While most of the brain is protected by the BBB, some specialized areas, called circumventricular organs (CVOs), lack a complete BBB.
These regions allow for greater permeability so that the brain can monitor the bloodstream and regulate body functions.
Examples of CVOs:
Subfornical organ & area postrema: Help regulate thirst and detect toxins in the blood (important for vomiting reflex).
Median eminence & neurohypophysis: Allow hormones like oxytocin and vasopressin to enter the bloodstream.
CSF, ISF, and Glymphatics – Push or Pull?
CSF (Cerebrospinal Fluid) and ISF (Interstitial Fluid) help clear waste and transport nutrients in the brain.
The glymphatic system is a brain-wide clearance system that helps remove toxic proteins like amyloid-beta (linked to Alzheimer’s).
Push or Pull? → The question refers to how these fluids move:
“Push” (bulk flow): CSF movement is driven by pulsations from arteries and pressure gradients.
“Pull” (exchange and diffusion): Waste products are cleared via astrocytic channels and perivascular spaces.
This system is active during sleep, helping the brain detoxify overnight.
Viral Encephalitis and BBB Breakdown
Viral encephalitis is an infection that causes brain inflammation due to viral invasion.
The BBB breaks down, allowing viruses to enter the brain, often through the perivascular space (the space around blood vessels).
Once inside, viruses replicate, causing immune responses that worsen inflammation.
Multiple Sclerosis (MS) – Lesions
MS is characterized by plaques (lesions) in white matter, especially around the ventricles (periventricular regions), optic nerve, brainstem, cerebellum, and spinal cord.
These plaques are sites of demyelination, where oligodendrocytes (which produce myelin) are destroyed.
Periventricular diagnostics: MRI scans often show periventricular plaques, which help diagnose MS.
Perivascular Cuffing and Microglial Nodules
Perivascular cuffing:
When the BBB is compromised, immune cells (T cells, macrophages) accumulate around blood vessels to fight the infection.
This creates clusters of immune cells surrounding blood vessels, known as perivascular cuffing.
Microglial Nodules:
Microglia react to the infection by forming nodules (clumps of activated microglia).
These nodules surround infected neurons, trying to contain and remove the virus.
Seen in diseases like Japanese Encephalitis, where viral replication causes neuronal death and inflammation.
Cellular Response in MS Lesions
Death of oligodendrocytes → Leads to loss of myelin, slowing nerve conduction.
Reactive astrocytes → Become chronically activated, contributing to glial scarring (gliosis), which hinders repair.
Microglia become overactive → Produce inflammatory signals, worsening damage.
Foam macrophages = macrophages infiltrate from the blood.
- Macrophages engulf myelin debris in active MS lesions.
- These myelin-laden macrophages appear “foamy” under the microscope.
- They play a role in clearing debris but also contribute to inflammation.
Explain the difference between acute and chronic neuroinflammation with examples.
A1.
Acute neuroinflammation involves blood-brain barrier (BBB) breakdown and intense immune activation.
Examples: Encephalitis, Meningitis, Traumatic Brain Injury (TBI).
Chronic neuroinflammation has a partially or largely intact BBB, with ongoing low-level inflammation.
Examples: Multiple Sclerosis (moderately intact), Alzheimer’s Disease (largely intact).
What are the hallmark histological features of viral meningoencephalitis?
A2.
Perivascular cuffing of lymphocytes.
Microglial nodules, often composed primarily of microglia, not astrocytes.
Infiltration by monocytes/macrophages.
Virus detectable in neurons, endothelial cells, or glia by IHC or PCR.
