Differentiation of pro-B cells results in a productive IGH V-D-J rearrangement and expression of the pre-B cell receptor (pre-BcR), composed of an Ig heavy μ chain and the surrogate light chain corresponding to the VpreB and Cλ-like (λ5 in the mouse) polypeptides. Receptor feedback inhibits further V-D-J rearrangements of IGHV genes and promotes proliferation. During this phase the surrogate light chain gene (VpreB and Cλ-like (λ5)) transcription appears to be repressed. Cessation of pre-B cell proliferation culminates in the induction of light chain gene (kappa or lambda) rearrangements and the generation of immature IgM+ B cells.
Immature B cells that are not reactive to autoantigens are selected and mature into antigen-responsive, resting B cells. (OCA-B/OBF-1) is a B cell specific coactivator that interacts with the POU domain transcription factors Oct1 and Oct2 which recognize the functionally essential octamer.
Upon encountering cognate antigen, a naïve B cell is stimulated to proliferate via signalling through its BcR, surface IgM (sIgM). The antigen is endocytosed, proteolytically processed, and presented to T helper (Th) cells. Extensive interactions of antigen-reactive B cells with cognate Th cells and follicular dendritic cells the result in the formation of germinal centers in secondary lymphoid tissue. Clonal proliferation of B cells in germinal centers is accompanied by differentiation involving isotype switch recombination and somatic hypermutation of Ig genes. The process culminates in the generation of memory B cells or Ig-secreting plasma cells.
The transcription factors regulating B cell proliferation and differentiation can be divided into three functional groupings :
A bHLH transcription factor, ABF1, expressed in activated B lymphocytes can bind E box motifs in Ig gene enhancers either as a homodimer or as a heterodimer with E2A proteins. Expression of Id3, a negative regulator of E2A proteins, appears to selectively inhibit Ig isotype switching. E2A complexes could potentially regulate isotype switching by binding to enhancer elements at the 3' end of the IGH locus.
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