B-cell Activation and Development PDF

B- cell activation and development Prof Palmer - Surface Ig or mIg B cell development Antibody diversity The specificity of a particular antibody, i.e. what the antibody recognizes, is determined by the shape of its variable region a particular antibody will bind to...

B- cell activation and development Prof Palmer - Surface Ig or mIg B cell development Antibody diversity The specificity of a particular antibody, i.e. what the antibody recognizes, is determined by the shape of its variable region a particular antibody will bind to a protein that has a region with a complementary structure to the antibody’s own variable region. Diversity in the specificity of antibodies is initially generated at the earliest stages of B-cell development. While still at the B-cell progenitor stage in the bone marrow, B cells randomly rearrange their variable (V), diversity (D), and joining (J) genes to form the blueprint for the variable regions of their antibodies.  Diversity comes from the fact that there are multiple copies of the V, D and J genes that can be joined together in different combinations. In a majority of mammals, each antibody molecule is composed of both a heavy and light chain, which each have their own V and J genes to rearrange (only the heavy chain has D genes). Further diversity is added to the variable region genes by an enzyme called terminal deoxynucleotidyl transferase (TdT) that adds extra nucleotides between the V, D and J regions, changing the structure of the variable regions that will be produced. Allelic exclusion Where one allele is silenced For example after one allele is re-arranged the other is silenced Note if the productive allele produces an antibody that is not self tolerant this may be reversed  B cell receptor signal transduction Antigen-induced cross-linking of membrane immunoglobulin (IgM) on B cells leads to clustering and activation of Src-family tyrosine kinases and tyrosine phosphorylation of the immuno-receptor tyrosine- based activation motifs (ITAMs) in the cytoplasmic tails of the Ig-α and Ig-β molecules. This leads to docking of Syk and subsequent tyrosine phosphorylation events as depicted. Several signaling cascades follow these events, as shown, leading to the activation of several transcription factors. These signal transduction pathways are similar to those described in T cells. B cell migration to spleen To complete development, immature B cells migrate from the bone marrow into the spleen as transitional B cells, passing through two transitional stages: T1 and T2. Throughout their migration to the spleen and after spleen entry, they are considered T1 B cells. Within the spleen, T1 B cells transition to T2 B cells. T2 B cells differentiate into either follicular (FO) B cells or marginal zone (MZ) B cells depending on signals received through the BCR and other receptors. Once differentiated, they are now considered mature B cells, or naïve B cells. B cell activation B cell activation occurs in the secondary lymphoid organs (SLOs), such as the spleen and lymph nodes. After B cells mature in the bone marrow, they migrate through the blood to SLOs, which receive a constant supply of antigen through circulating lymph. At the SLO, B cell activation begins when the B cell binds to an antigen via its BCR