B-Cell Development
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B-Cell Development

B lymphocytes are a population of white blood cells that express clonally diverse cell surface Ig (immunoglobulin) receptors, recognizing specific antigenic epitopes. B cells express immunoglobulin (Ig) molecules on their outer surface and secrete them into the extracellular space. Secreted Ig is known as antibody which serves as effector molecules that neutralize microbes. Both the light- and heavy-chain genes are encoded by gene segments that are genetically rearranged during a process known as V(D)J recombination. Heavy chains are made up of three gene segments—variable (VH), diversity (DH) and joining (JH) where as light chains only have a V and J segment. Antigen-dependent diversity is generated by somatic hyper mutation in the periphery in a manner dependent on activation-induced cytidine deaminase (AID); during this process, mutations in the Ig genes are accumulated at rate of up to 106 times the normal background rate B cells are subsequently selected for enhanced affinity for the eliciting antigen( Ref. 3 ).

B cell development starts in bone marrow with the commitment of hematopoietic stem cells (HSCs) to the B cell lineage and ends with formation of mature B cells in peripheral secondary lymphoid organs (e.g., the spleen). The first developmental stage exhibiting commitment to the B cell lineage is called pro-B and is characterized by rearrangement of the Ig heavy chain. In the pro-B stage Iga (CD79a) and Igb (CD79b) are expressed at the cell surface in association with chaperon proteins such as calnexin. Surface expression of this receptor marks the transition to the pre-B stage. Marrow stromal cell–derived interleukin-7 (IL-7) is a non-redundant cytokine for B-cell development that promotes V to DJ rearrangement and transmits survival/proliferation signals (Ref.1). In the pre-B stage, the light chain V and J fragments are recombined, and, again, successful assembly of the mature form of the BCR marks the transition to the immature stage. Pro-B and pre-B stages are thus characterized by waves of VDJ recombination followed by waves of proliferation. To achieve this pattern, the expression of the two main enzymes responsible for VDJ rearrangement, the recombinase associated genes 1 and 2 (RAG1 and RAG2), are tightly regulated during the cell cycle; they are highly active in G0 and degraded before entrance into S phase (Ref.4 ).

At this point of development and before leaving for periphery, alternative mRNA splicing of the heavy chain gene transcript produces IgD, as well as IgM, as membrane bound Ig. Transition to the mature stage happens if the BCR of the immature/transitional B cell does not find its cognate antigen after several days of bone marrow and peripheral trafficking. But once encountering an antigen, B cells become activated and differentiate into memory B cells or plasma cells. These dynamic processes occur in the germinal center (GC) and extrafollicular areas (Ref. 3 ). In the GC, B cells proliferate rapidly and can undergo isotype switching and somatic hypermutation (SHM). SHM is thought to be critical for selecting B cells with increasing BCR (or antibody) affinity and specificity for the immunizing antigen, and these B cells can be differentiated into memory B cells or plasma cells (Ref.7 ).