L4-5: Tolerance Flashcards
Central B cell tolerance mechanisms
By deletion:
Immature B cells undergo apoptosis if there is a too strong interaction between BCR and self-Ag/high avidity ligand. This requires strong cross-linking of BCR with multiple epitopes. This occurs through pro-apoptotic molecule Bim and reduced expression of BAFF receptor important for B cell survival.
By anergy:
Soluble self-Ag produces less receptor cross-linking. The cell survives and migrates into the periphery but has reduced surface IgM and is therefore poorly responsive. Low expression of CXCR5 and BAFF receptor mean it is unlikely to get T cell help and therefore upregulate CD86.
However, immature B cell can undergo light chain rearrangement. If the new BCR is not reactive, B cell survives.
Bim mode of action
BIM can sequester BCL-2 away from BAX and BAK, allowing BAX and BAK interaction which causes release of cytochrome C into cytosol, initiating apoptosis
Molecule that attracts B cells to the B cell follicle
CXCL13
Key issue with ignorant B cells
Can potentially become self-reactive if foreign antigen resembling self antigen causes proliferation of antibodie e.g. as in Guillain-Barre syndrome induced by Campylobacter jejuni that generates Ab that cross-react with peripheral nerves
Peripheral B cell tolerance
Mature naive B cell encounters Ag in the periphery. It needs two signals to respond: signal 1 from Ag and signal 2 via T cell help (CD40 as well as interleukin cytokines). Signal 1 alone leads to cell death.
Advantage of requiring two signals for B cells to respond
In order to have an autoreactive B cell response, you need to an autoreactive T cell as well as B cell.
Molecule and receptor responsible for attracting B cell to B cell follicle
CXCL13 binds CXCR5 expressed on B cells
Molecule and receptor responsible for attracting activated B cell to T cell zone, as well as keeping T cell and DC in this area
CCL19/21 expressed highly in the T cell zone attracts CCR7
B cell activation process in lymph nodes
Mature naive B cell enters the lymph node through HEV and is attracted towards the B cell follicle by CXCL13. Upon encounter with Ag, CXCL13 is downregulated and CCR7 is upregulated which causes it to migrate towards the T cell zone.
Central thymic tolerance
A thymocyte first develops in the cortex then migrates into the medulla. In the cortex, if the T cell receives no signal from the cortical thymic epithelial cell, it will die by neglect. If it is a weak signal and a weak affinity for self-peptides it will be positively selected.
Upon migration into the medulla, a strong recognition of MHC + peptide between T cell and mTEC or DC cell will result in negative selection and cell will die by bim-induced apoptosis.
A moderate signal will result in induction of Foxp3 and Treg development
Where do self-Ag come from?
expressed by cells (thymocytes, endothelial cells, DC) or expressed from the blood as soluble Ag
Role of AIRE
AIRE is expressed by medullary thymic endothelial (mTEC) cells and regulates thymic expression of tissue-specific Ag. AIRE is responsible for generation of tissue specific Ag as well as the death of mTECs.
Induction of chemokine XCL1 by AIRE attracts DC to dying mTEC. DC cells process apoptotic mTEC cells and process and present self-Ag.
Peripheral T cell tolerance
Strong stimulation of signal 1 alone leads to upregulation of Bim and inhibitory molecules like PD-1, and downregulation of TCR signalling, IL-7R, Bcl-2.
Stimulation of signal 1 (TCR-MHC+peptide) and signal 2 (CD28-CD80/86) results in upregulation of BclXL, IL-7R is less downregulated, and increased IL-2 production
