How B cells can be stimulated to produce a humoral antibody response
• T cell-independent antigens: mitogens and bacterial polysaccharides have repeating structures that enable them to crosslink surface Ig (BCR) causing B-cell activation that results in a predominantly IgM response.
• T cell-dependent antigens: the majority of protein and glycoprotein antigens require T-cell help to mount a humoral response against them. The steps for this to occur are:
• Naïve T cells recognize antigen associated with MHC HLA class II molecules on APCs. The CD4+ T helper cell is activated and can provide help to a B cell for antibody production.
• The BCR of a B cell binds and internalizes the antigenic peptide for which it is specific. This antigen is often provided by FDCs that present antigen–antibody complexes on their surface to B cells entering into the primary lymphoid follicles in the secondary lymphoid organs (lymph nodes, spleen, MALT). The B cell processes the antigen and puts it on its surface in association with its MHC HLA class II molecules. The CD4+ T helper cell TCR will bind to this HLA class II-antigenic peptide complex. A second signal is then provided by CD40 on B cells binding to CD40L on activated CD4+ T helper cells. Other costimulatory activating pathways also exist (e.g., BAFF/BLYS, TACI, APRIL). Note that if a second signal is not provided, the B cell becomes anergic (unresponsive). Additionally, Tfh (CD4+, CXCR5+) are antigen-experienced T cells found in the B-cell follicles. They mediate antigen-specific naïve and memory B-cell activation which triggers germinal center formation through the Tfh cell secretion of IL-21 and IL-4.
• Within germinal centers, the activated B cell proliferates (clonal expansion). Each cycle of division leads to selection of cells with Ig receptors with the highest affinity for the antigen (affinity maturation). Cells with the highest affinity/specificity Ig receptors on their surfaces have their receptors crosslinked by antigen complexed on FDCs and are selected to differentiate into plasma cells or memory B cells. The CD40-CD40L costimulation is critical for Ig class-switching, antibody affinity maturation, and memory B-cell formation.
• In the primary immune response, there is first an IgM response occurring 4 to 10 days after antigen exposure. With clonal expansion, there is Ig class-switching to IgG and other isotypes. In the secondary immune response, memory B cells that actively circulate from blood to lymph in search of antigenic stimulation can mount a much quicker (1–3 days) humoral response with production of isotypes other than IgM. Memory B cells require less antigen and less T-cell help than naïve B cells due to the high affinity surface Ig receptors for their specific antigen.
• One activated B cell can generate up to 4000 plasma cells which can produce up to 10 12 antibody molecules per day.