Marshall E Kadin

Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, U.S.A.

Lymph nodes have a well-defined architecture including sinuses, cortical, paracor-tical, and medullary regions (Fig. 1). Sinuses are potential spaces lined by sinus histiocytes which are professional macrophages (Fig. 2). Cortical areas of the lymph node contain lymphoid follicles which bring developing B lymphocytes into contact with antigen expressing follicular dendritic cells (Fig. 3). Naïve B cells are concentrated in the dark staining mantle zone surrounding the germinal center (GC) (Fig. 3). These mantle zone lymphocytes are small to medium sized, have dense chromatin, and express surface immunoglobulin M (IgM) and immunoglobulin D (IgD).

During the immune response to antigens, mantle zone lymphocytes migrate into the follicle GC where they proliferate and mature in response to antigen which is corecognized by helper T lymphocytes (CD3+ and CD4+). Following antigen stimulation, B lymphocytes are transformed into centroblasts which undergo immu-noglobulin gene hypermutation. Centroblasts are large cells with vesicular nuclei with areas of chromatin clearing and one to several prominent nucleoli adjacent the nuclear membrane. Centroblasts undergo affinity maturation or apoptosis giving rise to the dark zone of the follicle (Fig. 4). Surviving centroblasts give rise to centrocytes which occupy the light or apical zone of the GC (Fig. 4). Centrocytes have elongated angular nuclei with diffuse chromatin and inconspicuous nucleoli.

The final step in B lymphocyte maturation is the development of plasma cells which are concentrated in the medullary cords of the lymph node. Plasma cells have an eccentric nucleus with coarsely clumped "cartwheel" chromatin, and lack prominent nucleoli. Plasma cells can accumulate large amounts of cytoplasmic immu-noglobulin which appears as pink globules known as Russell bodies. If the accumulated immunoglobulin indents the nucleus, it may appear as an intranuclear inclusion known as a Dutcher body (Fig. 5). Because of their high content of carbohydrates, both Dutcher and Russell bodies stain with the periodic acid Schiff (PAS) stain which is inhibited by diastase. This is especially prominent with IgM which has the highest carbohydrate concentration of Ig heavy chains. Plasma cells can accumulate in the medullary cords and can also exit the lymph node through efferent lymphatics, returning to the circulation through the thoracic duct (1,2).

Normal Lymph Node Architecture

Figure 1 Architecture of normal lymph node—round secondary follicles of containing developing B lymphocytes occupy the outer portion (cortex) and are separated by and external to paracortical T-zone. The central portion includes the medullary cords containing mature plasma cells and sinuses lined by specialized macrophages.

Figure 1 Architecture of normal lymph node—round secondary follicles of containing developing B lymphocytes occupy the outer portion (cortex) and are separated by and external to paracortical T-zone. The central portion includes the medullary cords containing mature plasma cells and sinuses lined by specialized macrophages.

Hematopoietic Cords
Figure 2 Lymph node with expanded sinuses containing pale-staining histiocyte/ macrophages.
Normal Centroblast And

Figure 3 (A) Reactive follicle outlined by mantle zone of dark staining lymphocytes surrounding germinal center with lighter staining centroblasts and centrocytes, and starry sky macrophages. (B) Silver stain outlining arborizing fibers of follicular dendritic cells.

Figure 3 (A) Reactive follicle outlined by mantle zone of dark staining lymphocytes surrounding germinal center with lighter staining centroblasts and centrocytes, and starry sky macrophages. (B) Silver stain outlining arborizing fibers of follicular dendritic cells.

Figure 4 Lymph node with follicles polarized by outer dark zones containing centroblasts and apoptotic bodies and paler staining apical portions containing predominance of centrocytes.

Figure 4 Lymph node with follicles polarized by outer dark zones containing centroblasts and apoptotic bodies and paler staining apical portions containing predominance of centrocytes.

Immunoblasts are also antigen-stimulated B or T lymphocytes which are found mainly in the interfollicular zone but may also occur in the GC. B immunoblasts are distinguished by abundant basophilic cytoplasm and large eccentric nuclei with a single prominent central nucleolus (Fig. 6). B immunoblasts may be immediate precursors to plasma cells.

T cells are concentrated in the interfollicular zone. The interfollicular zones have a diffuse dark-staining mottled appearance due to the presence of numerous small T lymphocytes and scattered pale-staining antigen presenting cells. The antigen presenting cells of the T zone include resident interdigitating reticulum cells (IDC), also known as T-zone histiocytes, and Langerhans cells (LC) which have migrated from the skin. Both IDC and LC have elongated finely grooved nuclei with pale chromatin, inconspicuous nucleoli, and a small rim of pale cytoplasm (Fig. 7). They cannot be distinguished at the light microscopic level. When examined with electron microscopy, only LC contain cytoplasmic Birbeck granules which are thought to arise from infoldings of the cell membrane (Fig. 7). Birbeck granules often have a "tennis racket'' appearance. Both LC and IDC stain for CD1a and for S100 antigens which are not expressed by professional macrophages. They are only capable of

mi sn

Figure 5 (A) Plasma cell with intranuclear inclusion (Dutcher body). (B) Periodic acid Schiff stain of Dutcher body.

Dutcher And Russell Bodies
Figure 6 Immunoblasts with basophilic cytoplasm, eccentric nuclei, and prominent central nucleoli.

microphagocytosis or pinocytosis and do not contain cellular elements. They are potent antigen presenting cells.

The T zones contain a mixture of naïve and memory T cells. Naïve T cells, not been previously exposed to antigen, circulate continuously between lymph nodes and blood. They express high levels of L-selectin, permitting their attachment and rolling on the surface of high endothelial venules in lymph nodes. The rolling T cells are activated by a secondary lymphocyte chemokine, 6-C-kine (SLC) expressed on the luminal surface of high endothelial venules (3). The T cells are then activated by chemokine receptor CCR7 which allows them to bind tightly through lymphocyte functional antigen 1 (LFA-1) to intercellular adhesion molecule 1 (ICAM-1) expressed on venules. The resultant flattening of T lymphocytes on the endothelial cell surface allows them to exit the venule and accumulate in T-cell-rich areas of the lymph node where they are exposed to resident IDC. They are also exposed to antigen presenting LC and dermal dendritic cells which migrate to lymph nodes through afferent lymphatics. If a naïve T cell encounters antigen for which it has specificity in a skin draining lymph node, it becomes activated and acquires the characteristics of a memory T cell, expressing cutaneous lymphocyte antigen (CLA). Memory T cells

Birbeck Granule
Figure 7 (A) Langerhans cells with elongated nuclei and abundant pale-staining cytoplasm with adjacent smaller lymphocytes. (B) Langerhans cell with Birbeck granule identified by electron microscopy.

have the capacity to migrate to the skin site where the antigen was first encountered, but also may retain the capacity to exit high endothelial venules in lymph nodes (reviewed in Ref. 4).

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