Immunology of Multiple Sclerosis

Question 1

Give 3 immunopathological features of multiple sclerosis

Answer 1

1) Perivascular cuffs and intraparenchymal infiltrates of inflammatory cells
2) B cells in perivascular and meningeal locations, where they aggregate or form ectopic lymphoid follicles
3) Myelin-laden macrophages in and around lesions

Question 2

Which inflammatory cells are most predominant in inflammatory lesions?

Answer 2

Macrophages

Question 3

Describe macrophages in an active MS plaque

Answer 3

Foamy, containing numerous lipid droplets from myelin breakdown products

Question 4

Which cells are exclusively infected by EBV?

Answer 4

B cells

Question 5

In Ascherio & Munch’s 2000 study, what percentage of MS patients tested seropositive for EBV, and what percentage of healthy controls?

Answer 5

100% of MS patients, 90% of controls

Question 6

In Munger et al’s 2011 study on military personnel, how much higher was the MS risk with an anti-EBNA titer >320 compared to <20?

Answer 6

36x higher

Question 7

Which interleukin do pro-inflammatory CD4 T helper Th1 cells require for differentiation?

Answer 7

IL-12

Question 8

Name two homing receptors expressed by pro-inflammatory CD4 T helper Th1 cells

Answer 8

CCR5 and CXCR3

Question 9

Describe the relationship between IFN-gamma, IL-12, and MS disease activity

Answer 9

Increased clinical activity correlates with increases in IFN-gamma and IL-12 in both the CNS and CSF

Question 10

Name the mouse model of MS

Answer 10

Experimental autoimmune encephalomyelitis (EAE)

Question 11

Describe how Th1 cells induce inflammation

Answer 11

Th1 cells release IFN-gamma, inducing MHC class II expression in the CNS. This results in chemokine production which attracts and activates macrophages and monocytes

Question 12

Which interleukin do pro-inflammatory CD4 T helper Th17 cells require for differentiation into pathogenic cells?

Answer 12

IL-23

Question 13

Which molecule epigenetically imprints Th17 cells?

Answer 13

RORyT

Question 14

Name 2 homing receptors expressed by Th17 cells

Answer 14

CCR6 and CCR4

Question 15

Describe the effect of IL-23 deficiency on mice

Answer 15

It renders them completely resistant to experimental autoimmune encephalomyelitis

Question 16

Describe the relationship between Th17 cells and MS

Answer 16

Increased numbers of IL-17 producing CCR6 cells are found in the brain lesions of MS patients post-mortem - especially in chronic lesions

Question 17

Name 3 anti-inflammatory cytokines secretes by CD4 T helper Th2 and T-reg cells

Answer 17

IL-4, IL-5, IL-13

Question 18

Describe the action of Th2 cells

Answer 18

They slow down or prevent inflammation

Question 19

Where are CD4 CD25 T-reg cells generated?

Answer 19

The thymus

Question 20

Name two molecules secreted by CD4 CD25 T-reg cells

Answer 20

IL10 and TGF-beta

Question 21

Describe the relationship between CD4 T-reg cells and MS

Answer 21

CD4 T-reg cells have impaired function in MS, with a decreased ability to inhibit the activation of myelin-specific T cells

Question 22

Describe the relationship between cytotoxic CD8 T cells and MS

Answer 22

CD8 T cells are found with higher frequency in the peripheral blood of MS patients than healthy controls - especially around the edges of inflammatory lesions and perivascular regions.

Question 23

Describe the theorised role of CD4 and CD8 T cells in MS lesion formation

Answer 23

It is theorised that lesions are initiated by CD4 T cells, with amplification and damage mediated by CD8 T cells. In some conditions, CD8 cells can directly attach to and damage axons

Question 24

Describe the role of CD8 T cells in the EAE mouse

Answer 24

CD8 cells mediate the process of disease formation

Question 25

What are mucosa-associated invariant T cells (MAIT cells)?

Answer 25

A subtype of CD8 T cells with a pro-inflammatory slant which originate in the gut mucosa

Question 26

Name two substances produced by MAIT cells

Answer 26

IL-17 and IFN-gamma

Question 27

Name a CNS homing receptor expressed by MAIT cells

Answer 27

CCR6

Question 28

Describe the relationship between diet and CNS autoimmunity proposed by Haghikia et al

Answer 28

Long-chain fatty acids promote the pro-inflammatory T cell phenotypes, whereas short-chain fatty acids favour regulatory T lymphocytes

Question 29

Describe Cekanaviciute et al's findings on the link between gut bacteria and MS

Answer 29

Gut bacteria from MS patients affects T cells and exacerbates symptoms in mouse models of MS

Question 30

Describe the actions of CD57 CD8 regulatory T cells

Answer 30

They suppress CD4 T cell proliferation

Question 31

Describe the actions of IgG antibodies in MS

Answer 31

They recognise components of myelin, axons, or neurons, contributing to demyelination or axonal damage

Question 32

Which antibody type are oligoclonal bands?

Answer 32

IgG

Question 33

Describe how B cells have an immune regulatory function

Answer 33

Transitional B cells produce suppressive cytokines like IL-10 and influence regulatory T cell activity

Question 34

Describe three roles of B cells in MS

Answer 34

1) They are the source of IgG oligoclonal bands - pathological antibodies - in the CSF 2) They act as antigen-presenting cells for T cells targeting CNS antigens 3) They are a component of demyelinating plaques

Question 35

Where are B cell follicles found in MS?

Answer 35

Perivascular and meningeal lesions. Ectopic B cell follicles develop in the meninges of patients with secondary progressive MS

Question 36

How do subpial B cell follicles perpetuate inflammation in MS?

Answer 36

They can re-stimulate inflammatory T and B cells, as well as secreting inflammatory mediators that diffuse to the brain cortex

Question 37

How are astrocytes involved in B cell activation in MS?

Answer 37

They overexpress B cell activating factor - BAFF

Question 38

Name 3 functions natural killer cells are involved in

Answer 38

1) Host defence against intracellular pathogens and tumours 2) Regulation of adaptive immunity and homeostasis of other immune cells 3) The antiviral response - homing to certain tissues, including the brain

Question 39

Describe the role of natural killer cells in the EAE mouse

Answer 39

They become fully activated and proliferate in the CNS even before T cell arrival,producing large amounts of CCL2 - a chemoattractant for microglia

Question 40

Name 2 receptors expressed by natural killer cells

Answer 40

NKp46 and CD56

Question 41

Describe the difference in CD56bright natural killer cells in healthy individuals and MS patients

Answer 41

In healthy individuals, CD56bright NK cells are a regulatory population. However in MS, they are less efficient at suppressing the proliferation of autoreactive CD4 T cells

Question 42

Which cells form the first line of CNS defence?

Answer 42

Microglia

Question 43

What leads to the induction of M1 phenotype microglia?

Answer 43

Tissue injury, neurodegeneration, or autoimmunity, leading to release of pro-inflamamtory mediators from injured neurons

Question 44

Describe the role of M1 phenotype microglia in MS

Answer 44

They contribute to lesion development through phagocytosis, TNF-alpha secretion, production of the oxidative free radicals ROS and RNS, and by promoting neuronal death. They also promote antigen presentation to CD4 T cells

Question 45

How are M2 phenotype microglia sustained in MS patients?

Answer 45

By Th2 or T-regulatory cells secreting IL-4, which favours the production of neurotrophic factors

Question 46

State the steps of the adhesion cascade

Answer 46

Endothelial tethering, rolling, the triggering of adhesion by adherin surface molecules, and extravasation into the CNS

Question 47

Describe the route into the CNS from the blood through the blood-CSF barrier

Answer 47

Immune cells must pass from the blood to the choroid plexus, which produces CSF. From there, they pass into the subarachnoid space, into the pia, and from there into the brain

Question 48

Define the Virchow-Robin space

Answer 48

Perivascular spaces, also known as Virchow-Robin spaces, are pial-lined interstitial fluid-filled spaces in the brain that surround perforating vessels. They are virtual spaces unless occupied by immune cells

Question 49

Describe the typical leukocyte count in the CSF of MS patients

Answer 49

Often mildly increased but can be normal, and mainly consisting of T cells (80%)

Question 50

What percentage of MS patients have oligoclonal bands in their CSF?

Answer 50

Over 90%