PATHOPHYSIOLOGY During the primary antibody response, B cells in the bone marrow produce immunoglobulin M (IgM) and immunoglobulin

D (IgD) antibodies of low avidity. This process occurs largely in an antigen-independent way (pro-B cells, pre-B cells). Once IgM B cells are engaged with antigens, B cells start the secondary antibody repertoire generation by undergoing 2 genetic alterations; class-switch recombination (switching from IgM to IgG, IgA, or IgE) and somatic hypermutation (introduction of point mutations in the V regions of the Ig genes, the antigen-biding sites, resulting in an expansion of the antibody repertoire to generate high-affinity antigen-specific antibodies). The secondary antibody repertoire generation is antigen and T-cell dependent and occurs in peripheral lymphoid organs, mainly through the interaction between CD40L (CD154) expressed on activated CD4+ T cells and CD40 expressed on B cells.