B Cell Differentiation Results in Maturation of the Antibody Response and Generation of Long-lived Plasma Cells and Memory B Cells

KEY CONCEPTS
- Mature B cells that emerge from the bone marrow and are recruited in the primary response express a B cell receptor (BCR) with only a moderate affinity for antigen.
- Toward the end of the primary response, B cells expressing BCRs with a higher affinity for antigen are selected and later revert back to a resting state to become memory B cells.
- Re-exposure to the same antigen triggers a secondary response through rapid activation and clonal expansion of memory B cells.
A primary antibody response is induced by activation of the mature naïve B cell through antigen-mediated BCR cross-linking. This leads to clonal expansion, but only to a limited extent. Vigorous proliferation of antigen-specific B cells requires engagement of other immune receptors. In particular, engagement of TLRs by MAMP molecules on microbial pathogens plays an important role in the early stage of the antibody response before specific T cell help is available. Early B cell response is accompanied by the differentiation of B cells into plasmablasts, which produce mostly unmutated IgM with a moderate intrinsic affinity, but high avidity, for antigen. These antibodies are identical to the BCR expressed by the B cell progenitor, the only difference being the C instead of the C terminal of the constant region. TLR engagement can also induce CSR and likely SHM as well as prime B cells for the cognate B-T engagement.
Engagement of CD40 expressed on B cell surface by CD40 ligand (CD154) expressed on T cells takes place at a later stage of the primary response. It induces high levels of CSR and SHM for the eventual generation of more specific IgG, IgA, and/or IgE antibodies. These are produced by plasma cells, which are terminal differentiation elements from B cells, and home into bone marrow niches to become long-lived, thereby contributing to the long-term immune memory. Alternatively, activated B cells can differentiate into memory B cells. These cells comprise a minor proportion of the B cells generated at the end of the primary response. They express mutated V(D)J gene segments coding for BCRs that display increased affinity for antigen and have generally undergone CSR. Memory B cells are typically “frozen” with respect to their V(D)J somatic mutations and IgH chain class. They are in a resting state, but are rapidly activated when they re-encounter the same antigen that induced their generation for a secondary antibody response. Upon re-exposure to the same antigen, they can mount a secondary response, rapidly and with vigorous clonal expansion. Activated memory B cells can differentiate into plasma cells producing large amounts of antibodies, thereby mediating a vigorous high-affinity memory or anamnestic response. Virtually all B cells recruited in an antigen-specific antibody response to undergo CSR and SHM (FIGURE 1) are “conventional” B cells, or B-2 cells. In addition to these cells, a separate set of B cells exists, referred to as B-1 cells. B-1 cells also undergo the V(D)J gene rearrangement and apparently are selected for expression of a particular repertoire of antibody specificities. They may be involved in natural immunity; that is, they may possess the intrinsic ability to respond in a T-independent fashion to many naturally occurring antigens, particularly bacterial components, such as polysaccharides and lipopolysaccharides. B-1 cells are the main source of natural antibodies. Natural antibodies are mainly IgM that bind a variety of microbial components and products as well as self-antigens. They are important components of the first line of defense against bacterial and viral infections and may provide the templates for high-affinity antiself autoantibodies that mediate autoimmune pathology.

FIGURE 1.B cell differentiation is responsible for acquired immunity. Initial exposure of mature B cells to antigen results in a primary response and generation of memory cells. Subsequent exposure to antigen induces a secondary response through
activation of the memory cells.