IMMUNOLOGY - Roitt I. - Mir 2000

Chapter 12. Ontogeny of the Immune System

GENERATION OF B MEMORY CELLS

Upon antigen activation (with T-Cell help), B Cells either mature into antibody-forming cells (AFCs) and subsequently reach The final stage of differentiation into plasma cells, or they develop into memory cells. Convincing evidence indicates that germinal centers in various peripheral lymphoid Tissues play a crucial role as the site for B memory cell generation (see Chapters 3 and 11). Here, B cells undergo active somatic hypermutation of antibody variable-region genes, resulting in the death of some cells (via apoptosis) while others survive. Antigen presentation by follicular dendritic cells within germinal centers ensures the survival of cells expressing high-affinity receptors for the foreign antigen.

This process deserves a more detailed description. Antigen-specific B cells colonizing primary lymphoid follicles are primed by antigen and transform into blasts. One or very few B-cell blasts enter the primary lymphoid follicles and form a germinal center (Fig. 12.21). The blasts proliferate rapidly, reaching approximately 10⁴ cells within 3–4 days. By day 4, they differentiate into centroblasts lacking surface IMMUNOGLOBULINS and migrate to the inner region of the secondary follicle, forming the dark zone of the germinal center. Centroblasts give rise to centrocytes, which re-express surface immunoglobulins and occupy the basal light zone of the germinal center. Immunoglobulin Class switching occurs during this stage. Hypermutation of antibody variable-region genes is thought to take place following stimulation by antigen presented by follicular dendritic cells (FDCs). Centrocytes remain in close contact with FDCs; their interaction is mediated by lymphocyte surface molecules LFA-1 (CD11a/CD18) and VLA-4 (α₄β₁-integrin, CD49d/CD29) and FDC-expressed ICAM-1 (CD54) and VCAM-1 (CD106) molecules. Effective interaction between centrocytes bearing high-affinity receptors for the FDC-presented antigen leads to the generation of activated cells that leave the secondary follicles either as immunological memory cells or as plasma cell precursors. Without FDC interaction, centrocytes undergo apoptosis.

Fig. 12.21. Germinal centers are sites of clonal proliferation, Ig class switching, somatic hypermutation of Ig receptor genes, and antigen-driven Selection. As shown in the diagram, a germinal center consists of three main zones: the dark zone, the basal light zone, and the apical light zone. These are populated predominantly by centroblasts, centrocytes, and secondary blasts, respectively. Primary B-cell blasts expressing surface immunoglobulin receptors (sIg⁺) enter the follicle and exit either as memory B cells or as AFCs. Antigen-presenting follicular dendritic cells (FDCs) are located primarily in the two deeper zones. Apoptotic cell death occurs mainly in the basal light zone, which also contains tingible-body macrophages. Blue squares represent iccosomes on FDCs. (From Roitt I.M. Essential Immunology, 7th edn. Oxford: Blackwell Scientific Press; 1991.)

Questions for Structure/133.html">Discussion

■ What factors are required for The Development of granulocytes from hematopoietic stem cells?

■ How does myeloid cell development differ from lymphoid cell development, and why must they differ?

■ What are the MAIN STAGES OF T-cell maturation in the Thymus?

■ What are the Similarities and differences between T- and B-cell maturation processes?

■ Why does cellular apoptosis play such a prominent role during lymphocyte differentiation?

■ What are the primary Functions of germinal centers?

Introduction/47.html">Further Reading

Anderson G., Moore N.C., Owen J.T.T. et al. 1996. Cellular interactions in thymocyte development. Annu. Rev. Immunol. 14: 73-99.

Karasuyama H., Rolink A., Melchers F. 1996. Surrogate light chain in B cell development. Adv. Immunol. 63: 1-41.

Kisielow P., von Boehmer H. 1995. Development and selection of T cells; facts and puzzles. Adv. Immunol. 58: 87-209.

Robey E., Fowlkes B.J. 1996. Selective events in T cell development. Annu. Rev. Immunol. 14: 675-705.

Wagner S.D., Neuberger M.S. 1996. Somatic hypermutation of immunoglobulin genes. Annu. Rev. Immunol. 14: 441-57.