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Flashcards in MS: Immunology Deck (28)
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1

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

2

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)

3

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

4

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

5

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)

6

What is the bystander effect?

T-cell receptor independent immune cell activation (no DCs making contact)

Cytokines -> T-cell activation -> response against self

7

EBV histochemistry w/ MS

Immunohistochemistry shows detection of B-cells infected w/ EBV in post mortem MS brain tissue

8

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

9

Role of EBV in MS?

Infects B-cells (persistent latent infection)

NB: events leading to immune activation in MS are unclear

10

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)

11

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

12

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)

13

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)

14

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

15

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]

16

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]

17

Anti-inflammatory effects in early MS

Induction of M2 microglia -> maintain tolerance in CNS

18

Relevance of Th2 in MS?

Produce anti-inflammatory cytokines (IL-4, IL-5, IL-13)

19

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]

20

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

22

NK cells:

What do they produce?
What is their receptor?

Produce IFN-gamma

Express CD56 receptor

23

Desrcibe M1 microglia features (and how it’s triggered)

Injured neurons release pro-inflam mediators -> M1

M1 -> phagocytosis + cytokine release -> neuronal death (MS lesion

24

Regulatory CD8+ T-cell examples?

- CD57+

- CD103+

25

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

26

CSF in MS

- oligoclonal bands (>90% of MS cases)
- increased leukocytes
- increased protein in CSF

27

Mechanisms for MS treatment

Immune-modulatory

(no regenerative/neuroprotective therapies)

28

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)

29

Comorbidities for MS?

MS associated w/ increased incidence of other AI conditions (esp thyroiditis) and asymp. auto-Ab