MS: Immunology Flashcards
DOI: 10.1126/science.aav7188
- Studied genes associated with MS
- 48% explanation for MS heritability
- Implicates microglia, B cells, T cells, NK cells, and myeloid cells.
- MHC was the first loci to be identified, with multiple HLA effects
Describe pathophysiology of MS
- MS is primarily considered an inflammatory,
autoimmune demyelinating disease of the
CNS, widely held as being initiated by T and B
lymphocytes - Neurodegeneration is also recognised to play
a fundamental role since the early stages - Exact cause of the pathological process
remains unknown
Describe immunopathology of lesions in the CNS
- Perivascular cuffs and intra-parenchymal
infiltrates of inflammatory cells, mostly CD4+
and CD8+ T cells - B-cells are found in perivascular and meningeal
locations where they can aggregate or form
part of ectopic lymphoid follicles - Myelin-laden macrophages in and around
lesions
List the inflammatory events early in MS
- T-lymphocyte infiltration is seen during the very early stages of lesion formation; during active demyelination only few T-cells are found in the brain parenchyma.
- B-lymphocytes may also be found in small numbers.
- The majority of inflammatory cells in the MS lesion are monocytes and macrophages
How do immune cells become activated?
Lymphocytes require activation to migrate
into tissues, including CNS
• The events leading to pathological
immune activation in MS are unclear
• Possible mechanisms induce infection or
cross-reactivity with microbial, especially viral
antigen(s)
Describe the possible role of EBV in MS pathogenesis
- EBV almost exclusively infects B cells and uses the B-cell differentiation program to establish a persistent, usually asymptomatic, latent infection in humans.
- Using in situ hybridisation and immunohistochemistry, B cells infected with EBV were detected in post-mortem brain tissue (Serafini et al JEM 2007; JNEN 2010) controversial
Describe the role of the adaptive immune system in MS
- IFNγ producing cells
- Epigenetically imprinted by T-bet, require IL-12 for differentiation
- Express Homing Receptors CCR5 and CXCR3
- Tailored to the elimination of microbes, intracellular pathogens and viruses
- Increased clinical activity in MS patients correlated with expression of
- IFNγ and Il-12 in the CNS and CSF
- MS was exacerbated by the administration of IFNγ
- Experimental Autoimmune Encephalomyelitis (EAE) is induced by adoptive transfer of TH1 cells.
- CNS-infiltrating T cells in EAE were found to secrete IFNγ; Il-12p40 was detected in inflammatory lesions
- IFNγ released by Th1 induces MHC class II expression in the CNS, triggers production of chemokines that attract macrophages and monocytes and activates macrophage function
- IL-17A and IL17F producing cells; also produce IL22 and GM-CSF
- Epigenetically imprinted by RORγt, require IL-23 for differentiation into pathogenic cells
- Other signalling involved in their differentiation: IL-6, TFG-β, IL-1β, IL-21
- Express Homing Receptors CCR6 and CCR4
- Increased numbers of IL-17 transcripts and of IL-17 producing CCR6+ cells are detected in post mortem brain lesions of MS patients, in particular in chronic compared with either acute lesions or control
- EAE mice deficient in Il-12,IFNγ and TNF (Th1-mediated inflammation) anyway develop severe EAE.
- Il-23-deficient mice are completely resistant to EAE
- Transfer of Th17 cells seemed to induce more severe EAE than transfer of Th1
Part 2
- Frequency of CD8+ T cells recognizing myelin proteins is higher in the peripheral blood of patients with MS as compared to healthy controls
- CD8+ T cells are easily demonstrated at the edge of the inflammatory lesions and in the perivascular regions in post-mortem brain tissue of patients with MS and T cell receptor analysis of the CD8+ T cells found in
the lesion revealed clonal expansion of this population - MS lesion likely to be initiated by CD4+ T cells whereas amplification and damage is mediated by CD8+ T cells. CD8+ cells can, in some conditions, directly attach to and damage axons
- EAE mediated by CD8+ T cells has been described and transgenic mice overexpressing the co-stimulatory molecule B7-2 (CD86) on microglia develop disease mediated mainly by CD8+ T
- Mucosa associated invariant T cells present in the gut also of interest
Describe the roles of B cells
- Source of pathological antibodies (IgG oligoclonal bands) found in the vast majority of MS patients’ CSF (Freedman et al 2005). IgG recognize components of myelin, axons or neurons contributing to demyelination or axonal damage (Goverman 2009).
- Can act as antigen-presenting cells for T cells specific for CNS antigens (Goverman 2009). The collaboration between CNS antigen-specific B and T cells was responsible for an aggressive form of autoimmune disease in a mouse model of MS (Krishnamoorthy, Lassmann et al 2006).
Ig are a component of the demyelinating plaques (Lucchinetti et al
2000) and of the B cell infiltrates detected in the MS post- mortem brain
(Magliozzi et al 2007).
Can have immuno-regulatory function (Transitional B cells) producing
suppressive cytokines IL-10 and influencing regulatory T cell activity and
possibly modulating the mechanisms leading to axonal injury (Blair et al
2010, Lee-Chang et al. 2011)
Describe the roles of B cells in MS
In MS lesions (and CSF) there are clonally expanded B cells
• Ectopic B cell follicles develop in meninges of patients with SPMS
• BAFF (B cell activating factor, also named BLyS), a member of the TNF family, is overexpressed in MS tissue (astrocytes)
• Subpial B cell follicles can re-stimulate inflammatory T and B cells
• secretion of inflammatory mediators diffusing to the brain cortex
Describe the roles of NK cells
- Cytotoxic lymphocytes of the innate immune system
- Roles: i) host defense against intracellular pathogens and tumors
ii) Regulation of adaptive immunity and control the
homeostasis of other immune cells
ii) antiviral response, homing to liver, mucosal tissues, uterus, pancreas, joints and brain - Express the natural cytotoxicity receptor NKp46
- Produce IFN-γ (cytotoxic)
- Human NK cells express CD56
Describe role of NK cells in EAE
In EAE, become fully activated and proliferate in the CNS even before the arrival of T cells. CNS-infiltrating NK cells up-regulate the inhibitory receptor NKG2A and produce large amounts of CCL2 (chemo-attractant
for microglia)
What is EAE?
Inflammatory model of MS
