b-cell tolerance-[整理版].ppt

B-cell tolerance: mechanisms and implications Contents Introduction It is essential that tolerance be imposed on the B-cell as well as the T-cell repertoires. The main reasons for this are: (a) the spectrum of functional activities performed by B-cells that include not only antibody production, but also antigen presentation and secretion of pro-inflammatory and anti-inflammatory cytokines ; (b) the fact that the B-cell repertoire is generated in two stages: in the first, V(D)J recombination occurs within the bone marrow (BM) to create the ‘pre-immune repertoire’, while the second involves somatic hypermutation (SMH) of immunoglobulin (Ig) variable region genes within germinal centres (GCs) following antigen stimulation and provision of co-stimulatory signals from T-cells and/or external pathogens Introduction In each case, the primary goal is to diversify the repertoire of B-cell specificities against foreign antigens, although the random nature of both V(D)J recombination and SMH inevitably leads to the appearance of cells expressing anti-self B-cell receptors (BCR) within both repertoires. tolerance Introduction Multiple overlapping mechanisms of tolerance at several checkpoints in B-cell differentiation have evolved to deal with the ever-present threat of autoimmunity posed by the generation of self reactive B-cells. Decision between tolerance and immunity For B-cells, the decision between tolerance and immunity can still be explained within the framework of the two-signal hypothesis of Bretscher and Cohn. Decision between tolerance and immunity Decision between tolerance and immunity Mechanisms of tolerance Central tolerance Central tolerance Peripheral tolerance Only 10% of newly generated immature B-cells emerge from BM as transitional (T1 then T2) cells． tolerance mechanisms Multiple checkpoints of B-cell tolerance. Most self-reactive B-cells (90%) are eliminated by central de nov