Neuroinflammation Flashcards
How can a microbe affect CNS function (Direct)?
Direct:
-Invasion of parenchyma of brain
(like Viral encephalitis, Cerebral abscess)
-Invasion of supporting structures of brain (VZV large-vessel vasculopathy)
How can a microbe affect CNS function (indirect)?
- Immune-mediated CNS damage
(Acute disseminated encephalomyelitis, Infection-triggered antibody-associated, Immune reconstitution inflammatory syndrome (IRIS)) - Infection-triggered metabolic catastrophes (Reye’s syndrome or in adults Kapila syndrome, Acute necrotising encephalopathy)
- Toxin-mediated diseases (Tetanus)
- Consequence of systemic sepsis (Septic encephalopathy)
Causes of acute viral encephalitis worlwide
Enteroviruses:
Poliovirus
Coxsackie virus
Echovirus
Hepatitis A
Herpesviruses:
HSV types 1 & 2
VZV
Diagnosis of Acute Encephalitis:
Lab & Imaging
-Imaging Modalities
-Electroencephalography
-CSF Analysis
What is the first line treatment for HSV?
Aciclovir triphosphate is a competitive inhibitor of viral DNA polymerase
What is the commonest in the US and 2nd commonest in UK cause of bacterial meningitis
Pneumococcal meningitis
What is the first line treatment for Pneumococcal meningitis?
High dose intravenous antibiotics
+ Steroids
Emerging Neuroviral Infections
Newly evolved virus e.g. EV 71 (1970s)
Environmental changes e.g. WNV in USA; Tick-borne encephalitis in UK
Virus crossing species barrier e.g. Nipah or bird ‘flu (H5N1)*
What are the 3 types of Glia cells in the brain?
1.
Oligodendrocytes
- Astrocytes
- Microglia
What are microglia?
Resident inflammatory cells of the CNS (Innate Immune System)
What do Oligodendrocytes do?
They form myelin sheaths around axons in the CNS for efficient signal conductance
What do Astrocytes do?
- Regulation of synaptic connectivity
- Maintenance of ionic/neurotransmitter homeostasis in the extracellular milieu
- wound healing/limiation of inflammation
How many clusters of microglia are there in the human brain?
9
What does the cell morphology depend on?
location = reflecting function
Name 4 functions of microglia:
- Clearing of apoptotic cells
- Neuron protection
- Synaptic pruning
- Tissue maintenance
What signals is microglia sensitive to?
PAMPS & DAMPS (dying, stressed neuronal cell)
PRRs (eat me signal)
What does the ramified microglia morphology imply?
High plasticity:
- change in shape
- change of secretion
- change of behaviour
Type of microglia reponses:
- Phagocytosis (engulf)
- Chemotaxis (move towards areas of damage)
- Cytokines & Chemokines (release)
- Complement and coagulation factors (produce and activate for elimination of pathogens)
Microglia M1 vs M2 activation
M1: Pro-inflammatory (classically activated)
M2: Anti-inflammatory (alternatively activated)
When does Immune activation occur in the brain
- Dementia
-Depression - Schizophrenia/Psychosis
When does immune activation occur in the periphery?
Obesity/Metabolic
Ageing
Infections
Autoimmune diseases
e.g. arthritis, diabetes
Which diseases are oligodendrocytes involved in?
- MS, MSA, Charcot-Marie-Tooth, Leukodystropgies, brain injury
[possibly schizophrenia & bipolar disorder]
Which diseases are astrocytes involved in?
AD, epilepsy, ALS, SCA, PD, HD, stroke, focal cerebral ischaemia, hepatic encephalopathy, brain injury
Which diseases are Microglia involved in?
AD, CJD, Batten’s disease, PD, ALS, HD, brain injury
What happens if microglia are activated in AD?
- Microglia surround plaques, neurofibrilary tangles and damage neurons
- Change morphology from ramified to amoeboid
- Increase in number (proliferation)
- Correlate with disease markers > neuronal cell death and emergence of behavioural symptoms
What is Inflammatory risk gene (immune) TREM2
TREM2 stands for Triggering Receptor Expressed on Myeloid Cells 2.
Function: It encodes a protein that is primarily expressed on microglia. TREM2 is involved in regulating the function of microglia, including their response to injury, inflammation, and the clearance of cellular debris.
Mutations in the TREM2 gene have been linked to an increased risk of developing neurodegenerative diseases, such as Alzheimer’s disease.
What is TNFα?
Tumor Necrosis Factor-α is a pro-inflammatory cytokine produced by various immune cells in response to infection, inflammation, or injury.
Dysregulation of TNF-alpha has been implicated in the pathogenesis of various inflammatory and autoimmune diseases. Additionally, elevated levels of TNF-alpha have been observed in neurodegenerative disorders, including Alzheimer’s disease.
