B Cells 9 Flashcards
what is the purpose of tolerance?
prevents immune system from destroying host tissue
why do we need tolerance?
many random rearrangements used to create B and T cell receptors could be SELF-REACTIVE, so tolerance prevents them from circulating in bloodstream
where does T cell development occur?
initially develop in the bone marrow, then mature in thymus
what are developing T cells called?
thymocytes
how do T cells mature?
by a rigorous selection process
what are the 2 regions of the thymus?
- cortex
- medulla
what are the 4 cell types in the thymus?
- cortical epithelial cells
- medullary epithelial cells
- thymocytes
- macrophages
which regions of the thymus are thymocytes and macrophages in?
both cortex and medulla
what type of cells are T cell precursors when they enter the thymus?
Double Negative cells –> don’t express CD4 or CD8
describe how CD4 and CD8 receptor expression changes during development in the thymus and which regions of the thymus each step occurs in
- double negative –> cortex
- double positive (both CD4 and CD8) –> cortex
- single positive (1 of CD4 or CD8) –> medulla
- then leaves for circulation
which part of the thymus do T cell precursors enter?
cortex
what do T cells develop during development?
develop MHC restriction and undergo a process for self-tolerance
what is positive selection?
selects FOR thymocytes with receptors that can bind self-MHC molecules, resulting in MHC restriction
what is negative selection?
selects AGAINST thymocytes with high-affinity receptors for self-MHC/self-peptide complexes, resulting in self-tolerance
describe the process of positive selection and 3 possibilities
- cortical epithelial cells express high levels of MHC I and II
- double positive T cells browse peptide MHC on the surface of these cells
(1) if TCRs can’t bind –> die by neglect
(2) if TCRs bind too strongly –> cells die bc too reactive to a self-peptide
(3) if TCRs bind low-just right –> positive selection to single positive stage
what happens to the T cells that die due to improper binding?
macrophages in cortex clean up debris
what percent of T cells will die bc they can’t bind?
90-96%
what allows a double positive T cell to become a single positive T cell?
if TCR binds low to just right
what type of single positive T cell occurs when a T cell binds MHC II with its CD4?
Becomes single positive CD4+ T cell
what type of single positive T cell occurs when a T cell binds MHC I with its CD8?
Becomes single positive CD8+ T cell
why is negative selection necessary?
ensures self-tolerance
how does negative tolerance occur?
medullary epithelial cells express TF called AUTOIMMUNE REGULATOR (AIRE) which induces expression of many tissue-specific proteins in thymic epithelial cells which can be processed and presented on MHC I or II
then single positive T cells will browse self p:MHC on the surface of thymic epithelial cells
where does positive tolerance occur?
in cortex
where does negative tolerance occur?
in medulla
what is another name for negative selection?
central tolerance
what happens if single positive T cells don’t bind self-p:MHC?
cell survives –> not self-reactive
what happens if single positive T cells do bind self-p:MHC? 3 possibilities
- usually clonal deletion –> self-reactive T cells die
- clonal anergy –> self-reactive T cells inactivated
- clonal editing –> another chance at rearranging genes to make non-self reactive TCR
what is peripheral tolerance?
when self-reactive T cells escape negative selection in thymus
how does peripheral tolerance occur?
anergy occurs when there is strong self-antigen signaling thru TCR in absence of costimulation, maintained by T_Reg
why is only negative selection required for B cells?
no need for MHC restriction
where does B cell development occur?
mainly in bone marrow, completed in periphery (including spleen)
where does negative selection of B cells occur?
bone marrow
describe the 3 possible outcomes of negative selection of B cells
BCRs are tested against self-antigens
- clonal deletion of strongly autoreactive cells thru apoptosis
- receptor editing –> reactivate recombination machinery
- anergy
what self-peptides are used for negative selection of B cells?
there is no AIRE-equivalent –> use self-Ag that are soluble proteins in circulation or presented on stromal cells, i.e. anything that is nearby
any potentially self-reactive B cell that’s been activated requires …..
any potentially self-reactive B cell that’s been activated requires the activation from a T cell
during negative selection, where does receptor editing of potentially autoreactive receptors occur?
light chains
why do we need receptor editing? what 2 types of editing can be used?
a functional Ab may bind to self antigens –> must turn on recombination machinery as a “last-ditch effort” to salvage the rearrangement or inactivate the self-reactivity
can implement COMBINATORIAL and JUNCTIONAL diversity
what happens when B cells leave the bone marrow?
they are still immature –> go to the spleen for further maturation
what happens when B cells leave the spleen?
they are mature and migrate to the lymphoid follicles
- express high levels of IgM/IgD on surface
- negative selection –> peripheral tolerance
- recirculate btwn blood and lymphoid organs
what is the half-life of mature B cells in periphery?
4.5 months
what are the 3 results of central tolerance
- clonal deletion
- receptor editing
- clonal anergy
what are the 3 results of peripheral tolerance?
- anergy
- deletion
- immune regulation
what are the 2 results of defects in tolerance?
- organ-specific autoimmunity
- systemic autoimmunity
what is organ-specific autoimmunity?
predominant injury of an organ or tissue
what is systemic autoimmunity?
injury of many different tissues
what are the 2 mechanisms of autoimmunity?
- cell-mediated autoimmunity
- Ab-mediated autoimmunity
what is cell-mediated autoimmunity (4)
- mostly T cell mediated
- transferable by T cell transfer
- sensitive to thymectomy
- MS, T1D
what is Ab-mediated autoimmunity? (3)
- mostly Ab-mediated
- transferable by serum
- lupus
