In vivo Immune Response

Terminally differentiated B cells capable of secreting high affinity antibodies (aka plasma cells) arise following an extensive process of cell differentiation and activation that begins with hematopoietic stem cells (HSC) in the bone marrow.  Antigen-independent B cell development occurs in five discrete stages that are coupled with the sequential somatic recombination of the V, D, and J gene segments. Antigen-dependent B cell development takes place initially in the bone marrow and then in the periphery.

B Cell Development Pathway

  1. Hematopoietic stem cell – heavy chain and light chain genes are in germline configuration.
  2. Early pro-B cell – heavy chain undergoes D–J gene rearrangement.
  3. Late pro-B cell – heavy chain undergoes V–DJ rearrangement.
  4. Large pre-B cell – transient surface expression of IgM heavy chain with invariant pseudo light chain (pre-B cell receptor). Successful cell surface expression of pre-B cell receptor triggers allelic exclusion to prevent rearrangement of the second allele and also initiates pre-B cell proliferation, which results in different light chains matched with the same heavy chain in different daughter cells. Dividing cells are larger than resting cells, hence the name large pre-B cell.
  5. Small pre-B cell – light chain undergoes V–J rearrangement. Individual cells first attempt κ chain rearrangement.  If rearrangement of both κ alleles is unsuccessful, cells attempt λ chain rearrangement.
  6. Immature B cell – successfully rearranged heavy and light chains are expressed as IgM on the cell surface.  At this stage the cells are highly sensitive to antigen binding:  if they bind self-antigen in the bone marrow they die (negative selection).
  7. Mature naïve B cell – if the immature B cell survives, it matures in the bone marrow or spleen and expresses surface IgD and IgM, made from alternatively spliced transcripts.  Mature naïve B cells recirculate between blood, spleen, peripheral lymph nodes and other secondary lymphoid tissues (e.g. Peyer’s Patches in the gut) in search of cognate antigen.
  8. B Lymphoblast – antigen binding leads to alternative splicing to secrete Ig. The location of antigen encounter triggers isotype switching (gut microenvironmental signals lead to IgA, whereas lymph node signals lead to IgG). Somatic hypermutation is triggered in germinal centers in the follicles of secondary lymphoid tissues. CD4+ T cell help in germinal centers drives in vivo affinity maturation.
  9. Plasma cell – continuous antibody secretion, estimated at 2,000 IgM or 15,000 IgG molecules per second per cell. Alternative splicing yields some membrane-bound Ig, but most is secreted. Most plasma cells are incapable of proliferation, with their protein-synthesizing machinery dedicated entirely to making antibody. Although many die after several days, some survive in the bone marrow for months or years and continue to secrete antibodies into the blood.
  10. Memory B cell – a subset of B cells survive as long-lived memory B cells, which recirculate and can rapidly respond to antigen and differentiate into antibody-producing plasma cells.