B Cell Differentiation - Creative Diagnostics

B Cell Differentiation

It takes about 1 or 2 weeks for original B cells to become mature B cells, during which they randomly rearrange their Ig genes to generate Ag-specific B-cell receptors (BCRs) capable of recognizing a wide variety of Ags. Each B cell produces a single species of antibody, each with a unique antigen-binding site. The sequence of expression of cell surface receptor and adhesion molecules which allows for differentiation of B cells, proliferation at various stages, and movement within the bone marrow microenvironment. Immature B cell leaves the bone marrow and undergoes further differentiation. When a naive or memory B cell encounters antigen in an environment and the aid of a T cell, BCRs stimulation induces B cell differentiation into an antibody-secreting effector cell. Such cells make and secrete large amounts of soluble (rather than membrane-bound) antibody, which has the same unique antigen-binding site as the cell-surface antibody that served earlier as the antigen receptor. Effector B cells can begin secreting antibody while they are still small lymphocytes, but the end stage of their maturation pathway is a large plasma cell, which continuously secretes antibodies at the astonishing rate of about 2000 molecules per second. Plasma cells seem to have committed so much of their protein-synthesizing machinery to make an antibody that they are incapable of further growth and division. Although many die after several days, some survive in the bone marrow for months or years and continue to secrete antibodies into the blood.It is a general rule in adaptive immunity that naive antigen-specific lymphocytes are difficult to activate by antigen alone. Naive T cells require a co-stimulatory signal from professional antigen-presenting cells; naive B cells require accessory signals that can come either from an armed helper T cell or, in some cases, directly from microbial constituents. Antibody responses to protein antigens require antigen-specific T cell help. B cells can receive help from armed helper T cells when antigen bound by surface immunoglobulin is internalized and returned to the cell surface as peptides bound to MHC class II molecules. Armed helper T cells that recognize MHC complex then deliver activating signals to the B cell. Thus, protein antigens binding to B cells both provide a specific signal to the B cell by cross-linking its antigen receptors and allow the B cell to attract antigen-specific T cell help. These antigens are unable to induce antibody responses in animals or humans who lack T cells.

After several days, the primary focus of proliferation begins to involute. Many of the lymphocytes comprising the focus undergo apoptosis. However, some of the proliferating B cells differentiate into antibody-synthesizing plasma cells and migrate to the red pulp of the spleen or the medullary cords of the lymph node. The differentiation of a B cell into a plasma cell is accompanied by many morphological changes that reflect its commitment to the production of large amounts of secreted antibody. Plasma cells have abundant cytoplasm dominated by multiple layers of rough endoplasmic reticulum.

The purpose of the germinal center reaction is to enhance the later part of the primary immune response. Some germinal center cells differentiate first into plasmablasts and then into plasma cells. Plasmablasts continue to divide rapidly but have begun to specialize to secrete antibody at a high rate; they are destined to become nondividing, terminally differentiated plasma cells and thus represent an intermediate stage of differentiation. These plasma cells will migrate to the bone marrow, where a subset of them will live for a long period of time. Plasma cells obtain signals from bone marrow stromal cells that are essential for their survival. These plasma cells provide a source of long-lasting high-affinity antibody.

Other germinal center cells differentiate into memory B cells. Memory B cells are long-lived descendants of cells that were once stimulated by antigen and had proliferated in the germinal center. These cells divide very slowly if at all; they express surface immunoglobulin, but do not secrete antibody at a high rate. Since the precursors of memory B cells once participated in a germinal center reaction, memory B cells inherit the genetic changes that occurred in germinal center cells, including somatic mutations and the gene rearrangements that result in isotype switch. The signals that control which differentiation path a B cell takes, and even whether at any given point the B cell continues to divide instead of differentiating, are unclear.