MS: Immunology Flashcards
List the types and locations of key cells in MS lesions
CD4+/CD8+: perivascular cuffs and intra-parenchyma
B-cells: (aggregated or as ectopic lymphoid follicles) perivascular and meningeal
Macrophages: (laden w/ myelin) in + around lesions
Main cells implicated in MS pathology?
- Th1
- Th17
- Anti-inflam CD4+ helper cells (Th2 and T-Reg)
- Cytotoxic CD8+ cells
- M1/M2 microglia
- (and macrophages)
Describe the cell pathology in the early stages of MS
MAJORITY of INFLAMMATORY CELLS: monocytes + macrophages
T-lymphocytes infiltration in early stages (only a few in parenchyma during active demyelination)
B-lymphocytes in small numbers
Mechanisms through which autoimmunity is prevented (regulatory)?
NORMALLY:
- NK T-cell upregulation -> kills less tolerant T-cells
[infection] -> DCs present interact w/ T-cells -> regulatory cytokines (IL-10 + TGF-b) -> tolerance to self
Th1 -> can also maintain tolerance
Mechanisms for induction of autoimmunity (pro-inflammatory)?
[in response to virus/bacteria] -> DCs activate and prime lymphocytes -> already-autoreactive T-cells OR induce autoreactive T-cells
Bystander activation: T-cell receptor independent immune cell activation (no DCs making contact)]- cytokines induce autoreactive T-cells
Cross-reactivity w/ self peptides in susceptible T-cells (response to self by accident since they look similar)
What is the bystander effect?
T-cell receptor independent immune cell activation (no DCs making contact)
Cytokines -> T-cell activation -> response against self
EBV histochemistry w/ MS
Immunohistochemistry shows detection of B-cells infected w/ EBV in post mortem MS brain tissue
EBV and MS epidemiological studies
~100% seropositivity for EBV in MS compared to 90% in healthy
AND
much higher MS risk w/ higher anti-EBNA IgG titres than lower
Role of EBV in MS?
Infects B-cells (persistent latent infection)
NB: events leading to immune activation in MS are unclear
1/4:
Describe the cellular events events in early MS (up to and including T-cell activation)
APC (DC) presents autoreactive antigen on CD4 T-cell -> CD4 differentiates
- > proinflammatory: CD4 Th1 and CD4 Th17
- > anti-inflammatory: CD4 Th2 and CD4 Treg
Response is amplified by CD8 cells (cytotoxic and MAIT)
2/4:
Describe cellular events after T-cell activation
Activated T-cells extravasate into blood parenchyma
[DCs further activate pro-inflam T-cells -> increased damage]
Entry into CNS via BBB or blood-CSF barrier
3/4:
Cellular events of MS after T-cells in brain
B-cells migrate into parenchyma and differentiate into plasma cell -> Ig production -> inflammation
[IgG oligoclonal bands]
Macrophages produce reactive-oxygen-species (ROS) -> axonal damage
Microglia primed to M1 (pro-infl) or M2 (anti-infl)
4/4:
Cellular events of MS in neurons
Neuronal death -> neurodegradation
Inflammation -> immune cell infiltration -> inflamm + cyotoxic damage -> axonal/neuronal damage
other mechanisms: loss of synapses, Wallerian degeneration (retrograde + anterograde)
Proinflammatory effects in early MS?
Extravasation of autoreactive cells -> induces M1 microglia -> neurotoxic mediators -> neuronal death -> protein debris -> DC capture antigens and go to lymph nodes -> vicious cycle
TH1:
What t.factor induces it’s Dx?
What does it produce?
What are its homing receptors?
- Requires IL-12 for - differentiation from naive T
- Produces IFN-gamma
- CCR5 and CXCR3
[MS activity correlates w/ IFN-g]
TH17:
What t.factor induces it’s Dx?
What does it produce?
What are its homing receptors?
Requires IL-23
Produces IL-17
CCR6 and CCR4
[increased IL-17 producing cells in MS lesions] and [IL-23 deficient mice are resistant to EAE]
Anti-inflammatory effects in early MS
Induction of M2 microglia -> maintain tolerance in CNS
Relevance of Th2 in MS?
Produce anti-inflammatory cytokines (IL-4, IL-5, IL-13)
What does Th2 and T-Reg produce?
Th2 Produce: IL-4, IL-5, IL-13 (all anti-inflammatory)
T-Reg produces: TGF-b and IL-10
[NB: CD25 component of IL-2 receptor has been identified- essential for T-reg development]
Location of CD8 cytotoxic T-cells and mucosal-associated invariant (MAIT) T-cells in MS
CD8 Cytotoxic: found at the edge of lesions and in perivascular areas
MAIT: gut lymphocyte found in post mortem MS brain tissue]- can infiltrate CNS in MS
NK cells:
What do they produce?
What is their receptor?
Produce IFN-gamma
Express CD56 receptor
Desrcibe M1 microglia features (and how it’s triggered)
Injured neurons release pro-inflam mediators -> M1
M1 -> phagocytosis + cytokine release -> neuronal death (MS lesion
Regulatory CD8+ T-cell examples?
- CD57+
- CD103+
Genetic susceptibility to MS?
GWAS shows relationship w/ MS and HLA class II immune genes: IL-7R, IL-24-alpha. CD58
- Gut microbiome influences autoimmunity
- Dietary fatty acids influence GI T-cell differentiation: long chain FA -> Th1/Th17; short chain FA -> Treg
CSF in MS
- oligoclonal bands (>90% of MS cases)
- increased leukocytes
- increased protein in CSF
Comorbidities for MS?
MS associated w/ increased incidence of other AI conditions (esp thyroiditis) and asymp. auto-Ab
Mechanisms for MS treatment
Immune-modulatory
no regenerative/neuroprotective therapies
MS treatment and indications?
- immunomodulatory (1st line): injectables (IFN-b, GA); orals (dimeth fumarate, teriflunomide)
- acute relapse: high-dose corticosteroids
- block immune cell entry: to CNS- Natalizumab, in periph- Gylenia
- Modulate/neutralise immune cells- Daclizumab
- Immunosuppress/depleting- Alemtuzumab
- RRMS: autologous haematopoetic stem cell transplant (AHSCT)
