Organ-specific immunity: BRAIN - Disease Flashcards
This deck contains the lectures about viral encephalitis, bacterial meningitis, models to study MS and the immunopathogenesis of MS
1
Q
What is encephalitis?
A
An acute inflammation of the brain parenchyma
2
Q
What is the most common cause of encephalitis?
A
Viral infection
3
Q
What are the symptoms of viral encephalitis? (6)
A
- Fever
- Headache
- Behavioral changes
- Altered level of consciousness
- Focal neurologic deficits
- Seizures
4
Q
Which common human viruses can cause viral encephalitis? (3)
A
- Predominantly: herpesviruses
- Rare: Entero/Paramyxoviruses
- Very rare: influenza viruses
5
Q
Which zoonotic viruses can cause viral encephalitis? (3)
A
- Arboviruses
- Rabiesvirus
- Nipahvirus
6
Q
What are the two main routes of viral entry into the CNS?
A
- Hematogenous
- Migration via peripheral nerves
7
Q
Which viruses take the hematogenous entry route into the CNS?
A
Entero- and Arboviruses
8
Q
Which viruses take the peripheral nerve entry route into the CNS?
A
Herpes- and Rabies virus
9
Q
What are the three mechanisms of neurovirulence?
A
- Cytopathic effect
- Antiviral immune responses
- Exacerbated immune response due to viral infection of microglia
10
Q
What is the cytopathic effect of a virus?
A
Direct death of virus-infected neurons
11
Q
Which viruses cause mild meningitis? (2)
A
- Enteroviruses
- Measles virus
12
Q
Which viruses cause fatal encephalitis?
A
- Arboviruses
- Herpes Simplex
13
Q
What are the major Arbovirus families causing encephalitis? (3)
A
- Flaviviridae (West-Nile virus)
- Togaviridae
- Buyaviridae
14
Q
Which human herpes viruses are neurotropic?
A
Alphaherpesviruses
15
Q
Which two clinical manifestations of herpes simplex viruses are there?
A
- Herpetic stromal keratitis
- Herpes labialis
16
Q
Why is getting herpes labialis bad luck?
A
This is an opthalmic branch latency manifestation
17
Q
What is meningitis?
A
Inflammation (swelling) of the protective membranes covering the brain and spinal cord
18
Q
Which three divisions can be made when considering meningitis?
A
- Acute/chronic
- Infectious/non-infectious
- Bacterial/viral/fungal/protozoa
19
Q
Which two pathogens are the predominant causes of bacterial meningitis?
A
- S. pneumonia
- N. meningitidis
20
Q
What are the initial clinical features of acute bacterial meningitis? (5)
A
- Headache, fever
- Nausea, vomiting
- Photophobia
- Neck stifness
- Altered mental status
21
Q
What is petechiae? During which kind of meningitis do you see this?
A
- Pinpoint-sized spots of bleeding under the skin or mucous membranes
- N. meningitidis
22
Q
Describe the immunopathogenesis of community-acquired bacterial meningitis (3)
A
- Attachment and interaction with nasopharyngeal epithelium
- Survival in bloodstream
- Crossing of blood-brain barrier
23
Q
Which factors affect the intravascular survival of bacteria that cause meningitis? (2)
A
- Capsule
- Acquisition of iron from transferrin
24
Q
What are the most frequent systemic complications of bacterial meningitis? (3)
A
- Cardiorespiratory failure
- Hyponatremia
- Disseminated intravascular coagulation
25
What are the most frequent neurological complications of bacterial meningitis? (6)
- Cerebrovascular complications
- Meningo-encephalitis
- Seizures
- Hearing loss
- Brain oedema
- Hydrocephalus
26
What are the major intracranial complications in bacterial meningitis? (3)
- Posterior brain ischemia
- Brain infarction
- Obliteration cerebral artery
27
What is the treatment for (suspected) bacterial meningitis?
Antibiotics in combination with dexamethasone
28
What is MS (multiple sclerosis)?
Most common inflammatory disease of the CNS
29
What are risk factors for MS? (4)
- EBV
- Smoking
- Vitamin D
- Genetics/HLA --> especially MHC-II
30
Which HLA-molecule is mostly associated with development of MS?
HLA-DRB1*15:01
31
How do you diagnose MS? (3)
- Clinical profile (RR-MS or (S/P)P-MS)
- Cerebral/spinal cord MRI
- Presence of oligoclonal bands/ increased IgG index supportive
32
How do you treat MS? (3)
- Symptomatic/supportive
- Disease modifying drugs
- Steroids
33
What are the three clinical representations of MS?
- Relapsing-remitting MS
- Secondary-progressive MS
- Primary-progressive MS
34
What are the characteristics of relapsing-remitting MS?
Relapse periods (clinical symptoms) that go away again
35
What are the characteristics of secondary-progressive MS?
- Patients start of with RR-MS
- Then: less and less of the relapses, more of a steady decline of neurological functions
36
What are the characteristics of primary-progressive MS?
- Patients do not start with RR-MS first
- A fairly steady, gradual change in functional ability over time without any remissions
37
What are the pathological hallmarks of MS? (3)
- Demyelination --> loss of the myelin sheet
- CNS inflammation --> influx of peripheral immune cells
- Neurodegeneration --> loss of axons, synapses and neurons
38
Can you cure MS with a stem-cell transplantation?
No
39
Describe the dominant MS phenotypes across for a younger- and older age
- Younger age: mostly attacks of neurological disability --> make new MRI lesions
- Older people: Not that many attacks, more prominent progression of disability --> very resistant to almost any drug
40
Which different tests can you do across the lifespan?
- Bloodwork
- Genetics
- CSF analysis
41
What do you need to bear in mind about post-mortem autopsy?
These are performed really at the end of MS --> will not really learn you a lot about how the immune system drives the start of disease
42
Which lesions drive relapsing-remitting MS?
New inflammatory lesions in white matter
43
What is EAE particularly suitable for?
To study inflammatory white matter lesions
44
What drives axonal degeneration in inflammatory white matter lesions?
Influx of extracellular Ca2+ through a leaky membrane
45
What drives progressive MS?
- Brain atrophy
- Neurodegeneration
46
What drives cortical neurodegeneration in progressive MS?
- Microglial activation
- Meningeal inflammation
47
Which cells are the central cells in MS?
Memory B cells are the niche for MS
48
What is the lymphocyte distribution in the normal blood?
- Mostly CD4+
- Some CD8+
- Lots of naïve cells
- Lots of B cells
49
What is the lymphocyte distribution in the CSF?
- No naive cells in your CNS
- Central memory cells most prominent in CSF
- Hardly any B cells found
50
What do T cells in the CNS prevent?
Neurotropic viruses
51
Phenotypic adaptations during normal immune surveillance are depend on..?
Border organ such as the choroid plexus and meninges
52
Where does the expression of CD69 mostly occur?
CSF and white matter
53
What are the three options for the start of an MS-attack?
- Antigens from the periphery
- Activation of CNS patrolling immune cells
- Presentation of CNS antigens in the periphery
54
After initiation of an MS-attack, what happens next? (3)
- APC with peptide ends up in cervical lymph node
- Interaction with naive or memory populations
- Migrate out of LN Into bloodstream and move to border BB-barrier to infiltrate
55
Disease modifying therapies for MS can act on the sequence of events in the lymph nodes. Describe the sequence of events on which these drugs can act.
- Activation
- Clonal expansion
- Migration
- Depletion
- Trafficking intro CNS
56
Which event is the most logical target for disease modifying therapies in MS?
Depletion
57
Do you see lesions in the grey matter in E-MS?
Far less pronounced
58
Which kind of lesions do you see more at the start of MS?
Far more white matter inflammation than grey matter inflammation
59
Which three factors mediate the recovery after an MS attack?
- Resolving inflammation
- Remyelination of lesions
- Compensation for loss of function - using larger brain networks
60
About ⅘ patients (when they die) still have active lesions in the CNS. Which cells populate these lesions?
MHC class II positive cells → not driven by cells infiltrating from the periphery
61
True or False: "Lesions from people with advanced MS show higher numbers of T cells present in the context of these lesions"
True. These cells ended up in the PVS once and kept contributing by making pro-inflammatory mediators
62
True or False: "The majority of lesions from people with advanced MS do not contain B cells." + Explain what this does to the prognosis.
False. Many of them do contain B cells, which continuously produce immunoglobulins --> prognostic unfavorable factor.
63
What is a likely driver of the ongoing antibody synthesis during progressive MS?
Local interaction of CD4+ T cells and B cells
64
What are the 2 stages of axonal degeneration?
1: Focal swelling and 2: fragmentation
65
What is the EAE model?
A mouse model in which an autoimmune response is induced against myelin, by injecting myelin protein with immune activators
66
What predicts axonal fate?
Ca2+
67
What is the source of increased Ca2+?
Extracellular influx
68
What drives cortical pathology?
The immune cells in the meninges (meningial inflammation) that stimulate and activate the microglia
69
What is the phenotype of MS2 (MS specific) microglia that is not found in other neurodegenerative diseases?
High branching, low homeostatic markers and low inflammatory markers (HLAII low)
70
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What is the CMI?
A chronic meningeal inflammation model to study cortical pathology in progressive MS
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