Multiple Sclerosis - Mechanisms Flashcards
What can CD4+ T Cells differentiate into?
Th17 cells
Treg cells
Th1 Cells
Th2 Cells
What cells mediate MS?
T Cells
What specific T cells are implicated in MS Pathogenesis?
CD4+ T-Cells
What is the process in which T-Cells traverse the BBB?
Extravasation
1- Selectin binds weakly to glycosylated proteins on surface
2- T cells roll along until intergrin-Icam interaction
3-Tcell squeezes through wall (Diapedesis)
4-Migration through tissue down cytokine gradient
What chemokine is the first wave of MS dependant on?
CCR6 expressed by Th17
CCR6:CCL20 binding promotes Th17 movement across BBB
In EAE, injection of activated T cells falls short of full MS pathology. How?
Injection of T cells in EAE only results in inflammation and does not result in demyelinated lesions typically seen in MS
How do the classes of MHC differ?
Major histocompatability complex 1 (MHC 1) are presented by any cells type and present any internal (self) peptide
MHC 2 - presented by specialed immune cells such as macrophage, dendritic cells, B cell and present peptides from internalised invader
What is the TCR ligation to APC signal transduction pathway?
Phosphorylation of PKC
Influx of intracellular Ca2+
Upregulation of DNA binding proteins/transcription factors
T Cell activation and proliferation
How is the EAE model produced?
Sensitisation/injection of various CNS antigens (such as MBP), myelin-specific antibodies or T cells activated against CNS antigens
How are autoreactive T cells activated?
Potentially by molecular mimicry
- 129 viral/bacterial peptides match structural motif of MBP antigenic determinant
What is the second wave of MS (prior inflammation)?
Immunosurveillance performed by Th17 cells in subarachnoid space
Restimulation of Th17 by MBP-presenting APC
Activation of BBB
Large scale invasion by inflammatory T cells
How does demyelination occur in EAE?
Adding anti-MOG (or other CNS protein) autoantibodies promote demyelination
Activate complement system and attrct Macrophage/microglia
Macrophages strip myelin from axons and generate ROIs, secrete TNF-alpha and protein-degrading enzymes
IL-3 targeted to astrocytes promotes macrophage recruitment and demyelination
T cell activation of what cells induce demyelination before secondary influx of macrophage/microglia?
Plasma cells which secrete autoantibodies which bind to myelin and recruit complement system/membrane attack complex to the myelin
What is needed to causes Relapsing Remitting EAE alongside CD$+ TCR recognising MOG?
Commensal Microbiota in the gut
How is gut microbiota said to be related to MS?
Composition of gut microbiota influences production of serotonin in the gut, influencing serotonin-mediated regulating of systemic immune function. Also involved in complex interactions with immune cells influencing immune responses in periphery and CNS
