B cell differentiation

A key question in cell biology is how cells control the equilibrium of the various organelles to maintain their shape. Even more challenging is how they adjust their architecture to comply with new functions. A spectacular example of such a transformation is the differentiation of B-lymphocytes to plasma cells. B-lymphocytes express immunoglobulins (Ig) on their surface as clonal antigen receptors but do not secrete antibodies. These cells have a small cytoplasm, with scarce endoplasmic reticulum (ER) cisternae. Upon binding of specific antigen to the B cell receptor, or by stimulation with mitogens, B cells proliferate and differentiate into plasma cells, each of which secretes thousands of antibodies per second. In IgM secreting plasma cells the components of secreted polymers are the secretory form of µ heavy chains (µs), light and J chains. This massive Ig production correlates with a highly developed secretory machinery, most being ER, like in other professional secretory cells.

We set out to investigate how B-lymphocytes reorganize their machineries to become cells that are professional secretors. How does the transformation from dormant B-lymphocytes to plasma cells unfold? To analyze the relationship between organelle reshaping and Ig secretion, we performed a dynamic proteomics study of B lymphoma cells undergoing in vitro terminal differentiation. By clustering proteins according to temporal expression patterns, it appeared that B cells anticipate their secretory role in a multi-step process. On the first day of activation, mitochondrial and cytosolic chaperones showed highest expression, whereas metabolic enzymes peaked at the third day. ER resident proteins linearly increased during differentiation, accompanied by proteins involved in the redox balance. We witnessed a sharp increase in IgM synthesis only after two days of activation. We conclude that the transformation from dormant B cells to secretory plasma cells is a multi-step process. Upon activation, B cells carefully prepare for their role as plasma cells well before IgM secretion starts. First the cell ensures that metabolic capacity and the secretory machinery have expanded enough to accommodate the launch of bulk IgM production.

van Anken E, Romijn EP, Maggioni C, Mezghrani A, Sitia R, Braakman I & Heck AJ Sequential waves of functionally related proteins are expressed when B cells prepare for antibody secretion. Immunity 2003;18:243-53. pdf supplementary data

Currently, we are developing novel proteomics methods to further analyze the series of events during B cell differentiation.

• The B cell differentiation crew
  Ineke Braakman
  Eelco van Anken (alumnus)
  Chantal Christis
  Claudia Maggioni (alumna)