Mechanisms of Tolerance Flashcards
what is immunogenic tolerance?
permits immune attack on non-self and tolerance of self-Ag
1st step of central tolerance of B cells
B cell develops BCR in bone marrow via random selection of V,D, J regions
what is negative selection?
removal of self reactive B cells
which cells undergo negative selection?
BCR+ B cells aka immature B cell (with IgM)
how are self-Ag presented to B cells?
surface bound self-Ag is expressed on bone marrow stromal cells to the IgM+ B Cells OR self-Ag released from bone marrow to be soluble
what occurs to make the B cell apoptose?
strong binding to multivalent self-Ag (on bone marrow cells) with crosslinking of BCR (multiple BCRs bind to multiple spots)
what occurs to make the B cell anergic?
strong binding to soluble self-Ag without crosslinking of BCR (weaker signal)
what is anergy?
self reactive B cells (soluble selfAg) survive andenter the periphery as an anergic naive mature B cell (IgM- IgD+)
what is an anergic naive mature B cell
self reactive B cell that can produce cytokines but cannot proliferate to become a plasma cell and is UNRESPONSIVE to Ag in the periphery
what occurs to make the B cell survive?
no recognition of self Ag, and cell enters the periphery as naive mature B cell (IgM+, IgD+)
what occurs if there is strong BCR binding to multivalent or soluble self-Ag? (other than anergy or death)
persistent RAG1/2 expression
what does RAG1/2 do?
is a recombinase, rearranges L chain DNA to generate a new BCR specificity (basically it makes a new BCR and tests it again)
what if B cell does not recognize self-Ag?
native mature B cell (IgM+ IgD+)
what happens once negative selection has occurred?
mature naive CXCR5+ B cells localize to follicles following CXCL13 gradient
what gradient makes mature naive B cells localize to follicles?
CXCL13
what is B cell positive selection?
promotion of a fraction of immature B cells to become mature B cells in secondary lymphoid tissues
what is a pro T cell?
a double negative T cell with no CD4 or CD8 and no TCR) that travels from the bone marrow to the thymus
first step of differentiation into a T cell
bone marrow stem cell –> pro-T cell
what occurs once the pro-T cell is in the thymus?
Pro-T cells rearrange the beta chain gene of TCR and express the protein on the surface becoming a Pre-T cell
second step of differentiation into a T cell
pro-T cell +beta chain TCR–> pre-T cell
what is a pre-T cell?
T cell with a recombined Beta chain of TCR
what occurs if beta chain rearrangement is successful?
alpha chain is rearranged
what occurs if both alpha and beta chains are both successfully rearranged?
TCR is fully made, inducing CD4 AND CD8 (BOTH) gene expression, making a double positive T cell (CD4+CD8+)
what is a DP T cell?
double positive T cell, a pre-T cell that has successfully recombined its alpha and beta chains to make a TCR, and has BOTH CD4 AND CD8 gene expression