Immunology of MS Flashcards
MS cause: Inside out - outside in
Inside out, outside in hypothesis
Inside out: Maybe something goes wrong with the cells in CNS, eg. Oligodendrocytes, and some kind of cytodegeneration occurs, and they trigger immune system to clean it up = get autoimmunity. BYSTANDER ACTIVATION.
Immunological explanation:
something goes wrong in the brain = 1st step, which leads to release of target Ags, immune system creates a response against it, probably via molecular mimicry, autoreactive cells are produced and cause tissue damage in brain attacking the Ag.
Ex. MS patients dying shortly after the onset of relapse is chosen. When they look at this patients’ brains, there were no lymphocytes. So they thought huge cytodegeneration happened, and immune response is triggered afterwards. *But patients with a lot of infiltration of immune cells are also seen with huge lesions, so it’s discussed.
Outside-in: There’s a problem with immune system & they recognize auto-Ags, and it leads to cytodegeneration/lesion formation.
*something goes wrong in periphery & cells get activated by molecular mimicry = 1st step, lymphocytes get active and attack myelin.
Ex. Molecular mimicry with EBV or Measles, first step!
EAE model = definition
Experimental Autoimmune Encephalomyelitis)
Mice are immunized for myelin. (with injecting myelin + adjuvant, that causes severe inflammation, gets autoimmune cells). Mice getting paralyzed, can’t move their legs. = patients also end up on a wheelchair. These mice also have similar lesions, which ends up causing paralysis.
If you transfer T-cells of active EAE animals, disease can be transferred to a naïve animal, they can cause demyelination of CNS on their own. (passive transfer EAE)
Passive transfer EAE / spontaneous EAE
If you transfer T-cells of active EAE animals, disease can be transferred to a naïve animal, they can cause demyelination of CNS on their own. (passive transfer EAE)
mice express the receptor of autoreactive T cells as a transgene = happens rarely
Myelin + myelin proteins
Produced by oligodendrocytes, essential for rapid conduction of impulses, supports axonal survival/growth/protection.
Proteins: %50 of myelin proteins are proteolipid protein (PLP) & Myelin basic protein (MBP) %30 + MAG MOG minority. You stain for PLP/MBP while checking myelin in tissues in IHC as well.
T helper cells in MS
TH1/ TH17
*MS is a Th1 mediated disease, secretion of TNF + IFN gamma = cytokine profile can be seen in serum and CSF
• Tregs are reduced
• Th17 mediates tissue damage, secretion of IL17 leading to damage
• Chemokines/pro-inflammatory mediators are secreted
• Autoreactive T cells recognize myelin proteins, eg. PLP, MBP, MOG, MAG and others, and those T cells can be found on patients, although in low concentrations.
• PLP 184-209 is a strong candidate gene for MS, its known to be pathogenic in mice, it’s an immunodominant part of the PLP, found on the extracellular surface of myelin sheet (also accessible from Abs), causes T cell reactivity related with MS
Th1 and 17 responses are seen very early steps, even in CIS (Clinically Isolated Syndrome) patients before MS development only with 1 attack, high TH1 and TH17 levels are already high.
CD4 + CD8 T cells
human EAE comparison
• Predominantly autoreactive T cells that recognize myelin are CD4
• Their transfer can transfer the disease itself in EAE model to another mice
• Actually there’s more CD8 T cells observed in MS, because they clonally expand in CNS. CTLs promote vascular permeability, as their numbers increase you get more damage, they can really destroy axons, because they are really cytotoxic.
IRL: Both CD8 and CD4, CD8 is more, in EAE: only CD4.
B cells in MS
• They can produce Abs that recognizes myelin
• Important in crosstalk, antigen presentation, cytokine production, ectopic lymphoid follicle formation* in meninges = seen more in progressive stages
they can have a direct effect like activation, inhibition with cytokines. = complex.
• B cells can also clonally expand in CNS
• Oligoclonal IgG bands in CSF can be seen – used for diagnosis in old times, now mostly MRI is done
• Inflammation in CNS attracts B cells, their homing, survival and maturation is provided by cytokines secreted in CSF
• They can make Abs against oligodendrocytes, and probably other CNS cells
• In progressive phase of MS = there’s follicle like aggregates (germinal center like structures) in meninges* = contributes to ongoing neuron degeneration
• If you deplete them with Rituximab/Ocrelizumab = Anti-CD20 = great positive effect in therapy of MS
Innate immunity in MS
Macrophage/monocyte/microglia
Macrophages come to neuron, eat the myelin from axons.
Has M1 M2 types: pro-inflammatory and anti-inflammatory.(Phagocytosing foamy macrophages)
Monocyte travels from the blood vessel into a tissue, becomes a macrophage, and macrophages go to myelin. Very critical in MS, if you deplete them in EAE model, clinical signs of MS is lost.
Microglia
Microglia are the resident macrophages
Consist of 10-15% of the cells found in the brain
First line of defense in brain infection
key player in neuroinflammation, again M1, M2.
Increasing M2 is good therapy for MS.
M1 M2 differences:
Roles / cytokines secreted / surface receptors
Proinflammatory M1:
Antigen presentation - cytotoxicity - neurodegeneration
secretes IL-1beta, TNFalpha, IL-6, ROS, NO
Has costimulation, CCR receptors, HLA-DR.
Antiinflammatory M2:
Immunoregulation - phagocytosis - repair - survival
Secretes IL-10, IL-4, TGFbeta.
Why there’s chronic inflammation? When inflammation becomes chronic - lipid mediators!
Normal response: Cardinal signs of inflammation, swelling, heat, redness etc. This cardinal signs are controlled by lipid mediators. Eg. Prostoglandins are important in early stages of inflammation.
Cut on skin = barrier breaks down = bacteria enter = vessels get dilated, so that neutrophils etc. can arrive to side of infection = trap/eliminate bacteria, neutrophils die and they are removed by macrophages (efferocytosis)
If it goes normal, there’s complete resolution + tissue recovery.
Lipids mediate both vasodilation and trafficking of immune cells. Lipid mediators make sure that you will have cardinal signs of resolution, and makes sure the immune response never gets over reactive & leading to chronic inflammation.
Lipid mediators processed at onset of inflammation (during start edema stage). = proinflammatory mediators. Then it’s followed with edema, recruitment of neutrophils, then monocytes/macrophages that all contribute to clean the infection. Then class switch on mediators occur = proresolving mediators. Arachidonic acid = inflammatory EPA and DHA = resolving , Omega 3 is really important in their mediating EPA.
If you have proper lipid mediators, you will get a balanced response and complete resolution. = Tissue is protected, and whole inflammatory response is controlled. Defects in this system lead to excessive response, and no resolution = chronic inflammation
Lipidomics PC analysis show that MS relapse patients, controls, and progressive patients all have different lipid mediators! First set of biomarkers that can clearly differentiate MS subtypes. MRI can’t.
EAE model: If you treat mice with one of the lipid mediators = clinical signs can be suppressed around %30-40. (blue line) = Boosting own resolution response of body to regain homeostasis, good therapy addition to block inflammation in clinic.
