Figure 1.

B cell development in the bone marrow and periphery. (A) In the bone marrow, B cells develop from Common Lymphoid Progenitor cells to naïve B cells expressing a functional B cell receptor (BCR) in a series of developmental steps. Firstly, expression of lymphocyte specific RAG complexes triggers Pro-B cell development by initiating the recombination of the D and J segments of the Immunoglobulin heavy chain (IgH) and expression of surrogate light chains. Further differentiation of Pre-B cells leads to the rearrangement of the complete IgH and also Ig light (IgL) gene. Immature B cells with functional BCRs receive stimulatory signals completing naïve B cell development in the bone marrow. (B) In response to antigens, naïve B cells develop further into effector B cells in peripheral lymphoid organs such as the spleen (shown) or lymph nodes (not shown). In the spleen, germinal centers (GCs) that are specialized structures that contain follicular dendritic cells and T follicular helper cells are formed. A GC contains a light zone (LZ) and a dark zone (DZ). The marginal zone surrounds the GC. Naïve B cells take up antigen presented by follicular dendritic cells in the LZ. BCR signaling induces B cell proliferation in the DZ and triggers AID somatic hyper mutation (SHM) of the BCR. B cells expressing newly formed clones (e.g. clones 1 and 2) re-enter the LZ to take up antigen from follicular DCs and present these via major histocompatibility complex (MHC) II to T follicular helper cells. Clones (e.g. clone 1) that do not receive T cell help via CD40-CD40 L signaling axis fail to differentiate and survive. Clones that receive T cell help (e.g. clone 2) differentiate to antibody secreting plasma cells or long-lived memory cell or re-enter the DZ for further SHM and class switch recombination (CSR). Loss of function mutations for genes involved and that cause PID are indicated in red.