What is immunity
ability to resist an tumour or infection caused by intra- and extracellular bacteria (Mycobacteria, streptococcus pneumoniae), parasites (Trypanosoma, Leishmania), viruses (influenza) or fungi (candida)
Immune system consists of (classification by development)
1) molecules
e. g. antibodies, complement, cytokines
2) cells
e. g. lymphocytes, dendritic cells, macrophage and granulocytes
3) organs/tissues
What is made from CMP but are not leukocytes?
CMP… common myeloid progenitor
erythrocytes and platelet
What are the drived from CLP?
CLP… common lymphoid progenitor
Lymphocytes! e.g. B lympho, T lympho, Natural Killer Cells and Innate Lymphoid Cells
What is the newest lymphocytes discovered?
Innate Lymphoid Cells
It is a cell resident and control immune homeostasis
Where are immune cells produced?
- Primary lymphoid organs: where immune cells are produced
e. g. bone marrow and thymus胸腺 - Secondary lymphoid organs: where lymphocytes are activated
e. g. spleen, lymph nodes and mucosal associated typhoid tissue like the gut associated lymphoid
tissue: tonsils, appendix and Peyer‘s patches
This separation of primary and secondary allows immune system to not always be active
Division of immune system
natural/innate By NK cells and derivatives of common myeloid progenitor
specific/adaptive (humoural or T cell mediated)
Pathogen recognised by natural vs specific
Natural: receptors encoded in germline: Patter Recognition Receptor (can also recognise stress cells and tumour cells)
Specific: receptors generated randomly; B-Cell Receptor or TCR for antigen
Receptor specificity by natural vs specific
Natural: broad; Pathogen-Associated Molecular Patterns
Specific: narrow; only know particular epitope (part of antigen)
PAMP
Pathogen-Associated Molecular Patterns used for natural immunity and TCR
Life duration by natural vs specific（ここまで）
Natural: die after work; no expansion after contact with antigen or pathogen
Specific: productional expansion stimulated by antigen proliferation by cloning
PAMPs and DAMPs
Pathogen-associated molecular pattern molecules (PAMPs): derived from microorganisms and recognized by pattern recognition receptor (PRR)-bearing cells of the innate immune system as well as many epithelial cells
Damage-associated molecular pattern molecules (DAMPs); cell-derived and initiate and perpetuate immunity in response to trauma, ischemia, and tissue damage, either in the absence or presence of pathogenic infection
example of pattern recognition receptors
Fx: detects antigen of antigen presenting cells
Toll-like receptors
localised @ plasma memb
ligands: various such as RNA virus, fungus etc…
How does IS know what to do upon antigen presenting cells arrive?
- PAMP (invader) couple with Pattern Recognition Receptor on the dendritic cells
- Intracellular signalling by microbes leading to corresponding MHC to be present on the surface of dendritic cells
- antigen presented on MHC signal naive Th cells
This leads to 3 separate ordered signals - (general) antigen recognition; not necessary but sufficient to activate lymphocytes
- (general) interaction with APC; necessary to activate lymphocytes
- (specific) secretion of APC (e.g. cytokines) tell Th the type of infection
For T cell, 2nd signal come from APC
For B cell, from Follicular Helper T cells
Helper T vs cytotoxic T
Helper •Stimuli for B cell growth and differentiation •Macrophage activation, CTL activation •Stimuli for eosinophils •MHC Class II restricted Marker: CD3+ CD4+
Cytotoxic •Lysis of virus-infected cells, tumor cells, allografts •Macrophage activation •MHC class I restricted Marker: CD3+ CD8+
How does IS deactivate?
Regulation (/ending) of immune system is done by regulatory cells produced in the thymus.
Regulatory (suppressor) cells have different pathway but can suppress all immune system (e.g. Th, monocytes) activation
Overall, what causes the difference: healthy or diseased
Imbalance of either pro-inflammatory and anti-inflammatory / effector and regulatory / neurotoxic and neurotrophic
The ‘immune privilege’ of the CNS
- The concept of immune privilege refers to the observation that tissue grafts 移植片 placed in certain anatomical sites can survive for extended periods of time.
- Essential for damage restriction during inflammation in the CNS (a organ with poor regenerative capacity).
- Immune privilege is partly maintained by:
• the lack of a specialized lymphatic drainage
• the absence of dendritic cells
• the low expression levels of MHC Class I and II
• the presence of the blood-brain barrier (BBB)
Three ways of immune cells (e.g. leukocytes) entering brain
- Blood to CSF: leukocyte pass through the fenestrated blood vessels of choroid plexus to CSF
- Perivascular to CSF: through perivascular or virchow-Robin space (where meningeal blood vessel branch into the subarachnoid space)
- (classic) blood to brain parenchyma: through postcapillary venule of BBB via glia limitans
In the classic BBB migration model
- Capillary > post capillary> through endothelial cell> perivascular> glia limitans > CNS parenchyma
- Immune cells get activated in the perivascular space
Natalizumab
Potential drug for MS (by reducing relapse and progression)
Commercial name: Tysabri
VLA4Ab blocks migration of leukocytes from blood to PV space
Downfall of Natalizumb
Some users suffered from Progressive Multifocal Leukoencephalopathy
- caused by John Cunningham virus
- 70-90% of population are infected
- Infection may initiate in the tonsils/ GI tract and persist in the brain and other organs (kidney, tonsils)
- Inside the CNS, JC virus infects primary oligodendrocytes, causing virus-induced killing of oligodendrocytes and demyelination.
Interaction of T cells with neurons
- Neurons do not express MHC class I (?) or class II molecules (with the exception of Neurons, all somatic nucleated cells express MHC Class I on their surfaces)
- Induction of MHC class I genes in neurons of the CNS requires signals by proinflammatory cytokines, in particular IFN-gamma, and the blockade of electric activity.
How can infected neurons be killed?
- In a antigen-dependent way: CD8 interact with MHC1 present on the neuron
- Antigen-independent way: CD4 interact with both the APC microglia via MHC2 and neuron via TRAIL which initiates apoptosis
