B cells take their time: sequential IgG class switching over the course of an immune response?

B cells are unique in their capability to modify their immunoglobulin (Ig) molecules during an immune response. Affinity maturation is established by somatic hypermutations (SHMs) and selection for antigen binding. Furthermore, through class switch recombination (CSR), the Ig constant regions can be changed from IgM into IgD, IgE, one of the two IgA, or one of the four IgG isotypes. In this issue of Immunology and Cell Biology, Jackson et al.1 show a relationship between the extent of affinity maturation and Ig subclass usage through large-scale sequence analysis of IgA and IgG transcripts. SHM levels in variable regions were increased in transcripts switched to more downstream-located IgG constant regions, that is, IgG3 IgG1>IgG2>IgG4 occurs with increasing levels of SHMs. (c) Model for sequential IgG switching in secondary germinal center responses, where primary IgG memory B cells re-enter a germinal center in a secondary response, undergo additional SHMs and switch to a more downstream IgG subclass.3 (d) IgA and IgG subclass distributions in transcripts derived with consensus primers in previous studies.5, 6, 8 Ig subclass distributions were compared between children and adults using the χ2 test.