Immunology of Multiple Sclerosis Flashcards
Describe the evidence supporting a role of the immune system in the pathogenesis and clinical course of MS Discuss the interactions between the adaptive and innate immune system in the context of MS pathophysiology Critically evaluate and discuss the relationship between inflammation and neurodegeneration in the context of MS pathogenesis, clinical evolution, and therapeutic needs
Give 3 immunopathological features of multiple sclerosis
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
Which inflammatory cells are most predominant in inflammatory lesions?
Macrophages
Describe macrophages in an active MS plaque
Foamy, containing numerous lipid droplets from myelin breakdown products
Which cells are exclusively infected by EBV?
B cells
In Ascherio & Munch’s 2000 study, what percentage of MS patients tested seropositive for EBV, and what percentage of healthy controls?
100% of MS patients, 90% of controls
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?
36x higher
Which interleukin do pro-inflammatory CD4 T helper Th1 cells require for differentiation?
IL-12
Name two homing receptors expressed by pro-inflammatory CD4 T helper Th1 cells
CCR5 and CXCR3
Describe the relationship between IFN-gamma, IL-12, and MS disease activity
Increased clinical activity correlates with increases in IFN-gamma and IL-12 in both the CNS and CSF
Name the mouse model of MS
Experimental autoimmune encephalomyelitis (EAE)
Describe how Th1 cells induce inflammation
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
Which interleukin do pro-inflammatory CD4 T helper Th17 cells require for differentiation into pathogenic cells?
IL-23
Which molecule epigenetically imprints Th17 cells?
RORyT
Name 2 homing receptors expressed by Th17 cells
CCR6 and CCR4
Describe the effect of IL-23 deficiency on mice
It renders them completely resistant to experimental autoimmune encephalomyelitis
Describe the relationship between Th17 cells and MS
Increased numbers of IL-17 producing CCR6 cells are found in the brain lesions of MS patients post-mortem - especially in chronic lesions
Name 3 anti-inflammatory cytokines secretes by CD4 T helper Th2 and T-reg cells
IL-4, IL-5, IL-13
Describe the action of Th2 cells
They slow down or prevent inflammation
Where are CD4 CD25 T-reg cells generated?
The thymus
Name two molecules secreted by CD4 CD25 T-reg cells
IL10 and TGF-beta
Describe the relationship between CD4 T-reg cells and MS
CD4 T-reg cells have impaired function in MS, with a decreased ability to inhibit the activation of myelin-specific T cells
Describe the relationship between cytotoxic CD8 T cells and MS
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.
Describe the theorised role of CD4 and CD8 T cells in MS lesion formation
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
Describe the role of CD8 T cells in the EAE mouse
CD8 cells mediate the process of disease formation
What are mucosa-associated invariant T cells (MAIT cells)?
A subtype of CD8 T cells with a pro-inflammatory slant which originate in the gut mucosa
Name two substances produced by MAIT cells
IL-17 and IFN-gamma
Name a CNS homing receptor expressed by MAIT cells
CCR6
Describe the relationship between diet and CNS autoimmunity proposed by Haghikia et al
Long-chain fatty acids promote the pro-inflammatory T cell phenotypes, whereas short-chain fatty acids favour regulatory T lymphocytes
Describe Cekanaviciute et al’s findings on the link between gut bacteria and MS
Gut bacteria from MS patients affects T cells and exacerbates symptoms in mouse models of MS
Describe the actions of CD57 CD8 regulatory T cells
They suppress CD4 T cell proliferation
Describe the actions of IgG antibodies in MS
They recognise components of myelin, axons, or neurons, contributing to demyelination or axonal damage
Which antibody type are oligoclonal bands?
IgG
Describe how B cells have an immune regulatory function
Transitional B cells produce suppressive cytokines like IL-10 and influence regulatory T cell activity
Describe three roles of B cells in MS
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
Where are B cell follicles found in MS?
Perivascular and meningeal lesions. Ectopic B cell follicles develop in the meninges of patients with secondary progressive MS
How do subpial B cell follicles perpetuate inflammation in MS?
They can re-stimulate inflammatory T and B cells, as well as secreting inflammatory mediators that diffuse to the brain cortex
How are astrocytes involved in B cell activation in MS?
They overexpress B cell activating factor - BAFF
Name 3 functions natural killer cells are involved in
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
Describe the role of natural killer cells in the EAE mouse
They become fully activated and proliferate in the CNS even before T cell arrival,producing large amounts of CCL2 - a chemoattractant for microglia
Name 2 receptors expressed by natural killer cells
NKp46 and CD56
Describe the difference in CD56bright natural killer cells in healthy individuals and MS patients
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
Which cells form the first line of CNS defence?
Microglia
What leads to the induction of M1 phenotype microglia?
Tissue injury, neurodegeneration, or autoimmunity, leading to release of pro-inflamamtory mediators from injured neurons
Describe the role of M1 phenotype microglia in MS
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
How are M2 phenotype microglia sustained in MS patients?
By Th2 or T-regulatory cells secreting IL-4, which favours the production of neurotrophic factors
State the steps of the adhesion cascade
Endothelial tethering, rolling, the triggering of adhesion by adherin surface molecules, and extravasation into the CNS
Describe the route into the CNS from the blood through the blood-CSF barrier
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
Define the Virchow-Robin space
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
Describe the typical leukocyte count in the CSF of MS patients
Often mildly increased but can be normal, and mainly consisting of T cells (80%)
What percentage of MS patients have oligoclonal bands in their CSF?
Over 90%
