Neuroimmunology and Neurovirology

Question 1

Inflammation and Pro-inflammatroy mediators

Answer 1

o Protective response initiated by the organisms to eliminate the injurious stimuli
o Only bad if it becomes chronic inflammatory
o Triggered by pro-inflammatory mediators such as cytokines (IL-1)
 Released by activated macrophages and other immune cells
 Induce production of pro- and anti-inflammatory cytokines, chemotaxis, leukocyte adherence, activation of fibroblast
 Responsible for the systemic effects of inflammation (ex: fever, loss of appetite, increased heart rate)

Question 2

Sickness Behavior

Answer 2

o Systemic inflammatory adaptive response to infection
o Triggered by peripheral release of pro-inflammatory cytokines (IL-1) act on brain areas
 Hypothalamus – fever, loss of appetite, sleep disturbance
 Amygdala – depressive symptoms
o Due to the innate ability of the brain to recognize immune molecular signals

Question 3

Brain Regulates the Immune Response to Stop Inflammation

Answer 3

o SNS – inhibit inflammation at a regional level through innervation of immune organs
o HPA axis – release of anti-inflammatory glucocorticoids
o Immune system – cells that released pro-inflammatory cytokines will release anti-inflammatory cytokines

Question 4

CNS Immune Cells: Microglia

Answer 4

o Main cell type of innate immune system in the brain
o Highly ramified/branched cells that are vary active surveying brain even in “resting state”
o Able to recognize different sorts of stimuli and respond to it in various ways (plasticity model)
 Maintained through neuron-derived signals even in quiescent state
 Very sensitive to any disturbance  change their morphology and upregulate expression of wide range of cell antigens during activation
o Activated during systemic infections and release of pro-inflammatory cytokines
o Activated microglia recruit/interact with T cells from periphery to activate adaptive immunity

Question 5

CNS Immune Cells: Astrocytes

Answer 5

o Most abundance cell in human brain
o Functions: support the BBB, nutrients to nervous tissues, maintenance of extracellular ion balance, role in repair and scarring process
o Active in innate immunity – promote local inflammation and tissue repair
o Very resistant to inflammatory stimuli
o Can be targeted or infected by several pathogens
o Activated by cytokines, especially during tissue damage
 Demarcating the lesion area, promote BBB repair, neuronal survival by providing neurotrophic support

Question 6

Pro-inflammatory Cytokines in the Brain: Interleukin-1 (IL-1)

Answer 6

o Interleukin family has 11 members but IL-1 (alpha and beta) are best known
o Expressed by neurons and glial cells in very low concentration in normal brain
o Produced by microglial cells in response to injurious stimuli
o Fundamental messengers that tune and modulate the immune response
o Mediates sickness behavior and endocrine changes during an immune response
o Role in learning and memory, sleep pattern, modulation of synaptic plasticity
o Implicated in neurodegeneration
 IL-1 increases after ischemic, hypoxic, excitotoxic, and traumatic insults
 Elevated in several neurodegenerative disease (response to ongoing CNS damage)
 Exogenous IL-1 exacerbates injury
 Blocking IL-1 reduces neuronal loss after injury

Question 7

Neuroimmunological Disease: Multiple Sclerosis

Answer 7

o Most common disabling condition and demyelinating disorder in young adults
o Chronic disease of the CNS – progresses to disability in majority of cases
o Affects the brain, spinal cord, and optic nerve
o Symptoms: weakness in limbs, clumsiness, stiffness and gait disturbances, bladder dysfunction, fatigue, visual disturbances, cognitive deficits, depression
o Pathology: immune system is triggered to see CNS myelin as foreign
 Inflammatory phase: autoimmune disease with massive inflammatory response
 Neurodegenerative phase: axonal loss, neurodegeneration

Question 8

MS Inflammation and Demylination Phase

Answer 8

o Demyelination results in reduced support for the axons as well as redistribution of ion channels, destabilization of axonal membrane potentials, reduced excitability, and conduction block
o High levels of inflammation in white matter but not in the cortex
o Axons initially adapt and restore conductivity (remission state) but eventually degenerate
o Preserving oligodendrocytes and promoting remyelination is important therapeutic goal

Question 9

MS Neurodegeneration Phase - White Matter

Answer 9

o Axonal and neuronal loss are responsible for the persistent neurological dysfunction
o Axons might degenerate due to loss of trophic support from oligodendrocytes more than demyelination itself
o Inflammation seems to be the cause of the initial degenerative process in the white matter

Question 10

MS Neurodegeneration Phase - Grey Matter

Answer 10

o Cortical demyelination occurs without significant influx of immune cells
o Activated microglial cells might be responsible for it
o Prominent feature in most MS patients – early and progressive
o Common in areas that have extensive cortico-cortico connections
o Not dependent on white matter lesion
o Possible that it precedes white matter lesions

Question 11

MS Treatments

Answer 11

– NO CURE
o Medications that suppress the immune system and anti-inflammatory
o Palliative (pain control) medications that control symptoms

Question 12

HIV-associated Neurocognitive Disorder (HAND)

Answer 12

o 50% of HIV individuals will develop neurocognitive disorders
o Early event in children; late event in adults
o Source of great morbidity – limited survival in its most severe form

Question 13

HIV Virus and Invasion of the CNS

Answer 13

o Trojan Horse Theory – HIV passes through blood brain barrier through infected monocyte
o Another Theory – virus uses GP120 protein on its envelop to bind to soluble transporters in blood brain barrier
o Retrovirus with high replication rate and high frequency of mutations
o Invasion of CNS occurs early after infection but productive infection is limited and delayed
o Brain may serve as a reservoir for HIV-1
o HIV antigen and nucleic acid mainly restricted to macrophages, microglia, and some astrocytes
 Cell must express CD4 and a co-receptor for virus to invade; BUT neurons do NOT express CD4receptor so virus cannot invade yet neurons still die somehow?
• Maybe excess release of pro-inflammatory cytokines  become toxic to neurons
• Maybe affect astrocytic function  unable to provide growth factors to neurons
• Maybe GP120 protein on virus is lose and they can then bind to microglial cells causing activation OR GP120 protein is internalized by the neuron

Question 14

HIV-associated Neurocogntive Disorders Classification

Answer 14

o Asymptomatic neurocognitive impairment – subclinical decline in cognition
o Minor neurocognitive disorder – mild decline in cognition and impairment in everyday function
o HIV associated dementia – significant decline in cognition and everyday function; subcortical dementia

Question 15

Clinical Mannifestation of HIV-associated Neurocognitive Disorders

Answer 15

o Motor – slowed movements, clumsiness, ataxia (lack of limb coordination), gait changes
o Cognitive – inattention, reduced concentration, slowing of processing, short and long term memory loss, agnosia, visual-spatial impairment
o Psychiatric – irritability, apathy, depression, anxiety, dulled personality, agitation

Question 16

Neuropathology of HAND

Answer 16

o Presence of dendritic and axonal damage causing cognitive decline
o Infected microglia and macrophages and astrocytosis (many astrocytes)
o Neuronal loss in cortex via apoptosis
o Enlarged ventricles due to subcortical atrophy

Question 17

Prions

Answer 17

– Proteinaceous infectious particle
 Cause transmissible spongiform encephalopathy (TSE) “mad cow” disease
o Encoded by Pmp gene on chromosome 20
o Glial cell membrane protein that is highly expressed in the brain and immune system
 Developmentally regulated
o Functions: required for peripheral myelin maintenance; involved in synaptic plasticity in neonatal hippocampus
o 2 forms
 Normal version = cellular prion protein (PrPc)
 Misfolded, infectious version (PrPSc) – same amino acids but different shape

Question 18

Prion Disease across Species

Answer 18

o Humans – Creutzfeldt Jakob Disease (CJD), Gerstmann Straussler Syndrome (GSS), Fatal Familial Insomnia, Kuru
o Cattle – Bovine Spongiform Encephalopathy
o Sheep – Scrapie
o Deer/Elk – Chronic Wasting Disease

Question 19

Prion Propagation

Answer 19

o PrPC – soluble, sensitive to proteases
o PrPSc – resistant to proteases and accumulates in lysosomes/endosomes by forming insoluble aggregates in lymphoid tissues before entering the brain  BAD version

Question 20

Creutzfeldt Jakob Disease

Answer 20

– 85% of all prion diseases
o Sporadic, familial, or iatrogenic (due to medical procedure)
o Symptoms: very rapid cognitive decline, causing dementia; speech impairment; jerky movments; ataxia; changes in gait and posture; seizures
o Causes spongiform appearance of brain tissue and widespread neurodegeneration
o Astrocytosis occurs but NO inflammation
o Amyloid plaques form of aggregates of PrPSc
o Cortex is area most affected

Question 21

Prion Differences from Bacteria and Viruses

Answer 21

o Do not contain nucleic acid; NO DNA or RNA
o Extremely resistant to heat and chemicals
o Difficult to decompose biologically; survive in soil for many years

Question 22

Prion Controversy

Answer 22

o DNA and RNA are only substances known to replica in body tissues; so how do prions make copies of themselves without DNA or RNA
 Protein-only hypothesis – PrPSc is transmitted between species and results in the other species having the amino acid sequence of the protein  NO immune response
o TSEs may be caused by unidentified slow-acting virus
o Small virus may accompany a prion and work together to cause disease