Clinical consequences of defects in B-cell development

Abstract

Abnormalities in humoral immunity typically reflect a generalized or selective failure of effective B-cell development. The developmental processes can be followed through analysis of cell-surface markers, such as IgM, IgD, CD10, CD19, CD20, CD21, and CD38. Early phases of B-cell development are devoted to the creation of immunoglobulin and testing of B-cell antigen receptor signaling. Failure leads to the absence of B cells and immunoglobulin in the blood from birth. As the developing B cells begin to express a surface B-cell receptor, they become subject to negative and positive selection pressures and increasingly depend on survival signals. Defective signaling can lead to selective or generalized hypogammaglobulinemia, even in the presence of normal numbers of B cells. In the secondary lymphoid organs some B cells enter the splenic marginal zone, where preactivated cells lie ready to rapidly respond to T-independent antigens, such as the polysaccharides that coat some microorganisms. Other cells enter the follicle and, with the aid of cognate follicular T cells, divide to help form a germinal center (GC) after their interaction with antigen. In the GC B cells can undergo the processes of class switching and somatic hypermutation. Failure to properly receive T-cell signals can lead to hyper-IgM syndrome. B cells that leave the GC can develop into memory B cells, short-lived plasma cells, or long-lived plasma cells. The latter ultimately migrate back to the bone marrow, where they can continue to produce protective antigen-specific antibodies for decades.

Figure 1

B cell development illustrated as a linear progression through developmental checkpoints. Proper assembly of the B cell antigen receptor complex is required. The expression pattern of key surface molecules during this process is marked by bars. Also illustrated are the developmental checkpoints at which loss of function (Δ) of selected transcription factors can influence B cell development.

Figure 2

Schematic morphology of the spleen (A) and the germinal center reaction (B). The white pulp consists of a central artery surrounded by T cells; the marginal zone and the follicles. Antigen-specific B cells and T cells interact at the border of the follicle. The B cells differentiate into centroblasts and undergo clonal expansion in the germinal center dark zone.