LYMPH NODES - pediagenosis
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Thursday, September 24, 2020



The encapsulated tissue of the lymph nodes acts as a filter for lymph draining the body tissues (Figure 6.15a). The lymph, which will contain any foreign antigens present in the tissues, enters the subcapsular sinus (space) via the afferent lymphatic vessels. The subcapsular sinus constitutes a continuous area beneath the capsule that surrounds the entire lymph node and, together with the trabecular sinuses which pass through the body of the lymph node, allow larger antigens to either be engulfed by the resident macrophages lining the subcapsular and medullary sinuses, or to pass unimpeded to the efferent lymphatics (Figure 6.12 and Figure 6.15b). The resident macrophages, together with dendritic cells that have taken up antigen in the tissues and arrive via the afferent lymphatics, can both act as APCs for T‐cells in the lymph node.

Figure 6.15 Lymph node. (a) Human lymph node, lowpower view. GC, germinal center; LM, lymphocyte mantle; MC, medullary cords; MS, medullary sinus; PA, paracortex; SF, secondary follicles; SS, subcapsular sinus. (b) Diagrammatic representation of section through a whole node. Each lymph node is served by several afferent lymphatic vessels but usually has only one efferent lymphatic vessel. (c) The conduit networks that permeate the lymph node parenchyma are composed of collagen bundles enclosed by fibroblastic reticular cells. The networks are filled with lymph and act to transport small antigens and chemokines to different areas of the lymph node. (d) Secondary lymphoid follicle showing germinal center surrounded by a mantle of small Blymphocytes stained by antihuman IgD labeled with horseradish peroxidase (brown color). There are few IgDpositive cells in the center but both areas contain IgMpositive Blymphocytes. (e) The differentiation of Bcells during passage through different regions of an active germinal center. Macrophages engulf apoptotic Bcells in the basal light zone. Plasma cell precursors leave the germinal center before reaching full maturity, whereas memory Bcells can either leave the germinal center or enter the mantle zone. FDC, follicular dendritic cell; Mø, macrophage.

Naive B‐cells, irrespective of their antigen specificity, are able to use their complement receptors to transport immune complexes from the subcapsular sinus to specialized follicular dendritic cells (FDCs) for subsequent presentation to antigen‐specific B‐cells. The FDCs have very elongated processes that make intimate contact with B‐lymphocytes. FDCs, unlike nearly all the other cells of the immune system, are not derived from bone marrow hematopoietic stems cells but instead arise from multipotent mesenchymal stem cells. They are functionally very clearly distinct from interdigitating dendritic cells, being nonphagocytic and lacking MHC class II and molecules required for T‐cell co‐stimulation such as CD80 and CD86.

Within the lymph node parenchyma there are extensive conduit networks composed of collagen fibers ensheathed by μm diameter channels (Figure 6.15c). Lymph containing small antigens (below approximately 70 kDa), chemokines, and other low molecular weight substances passes through the channels of the conduit system to permeate the lymph node. Because the FRCs do not form a complete seal around the channels, both dendritic cells and lymphocytes are able to extend protuberances into the conduits, thereby both accessing the antigen‐containing lymph and receiving chemokine signals. What is so striking about the organization of the lymph node is that the T‐ and B‐lymphocytes are very largely separated into different anatomical compartments, a process directed to a large extent by chemokines. Lymph node stromal cells (and to a lesser extent interdigitating dendritic cells) secrete CCL19 and CCL21 in the paracortex that is deposited locally on the surface of the HEVs and FRCs, thereby attracting CCR7‐bearing T‐cells along a network of reticular fibers. In contrast, CXCL13 produced by stromal cells in the cortex attracts CXCR5‐positive B‐cells, which can traffic along a network of FDC processes.


B‐cell areas

The follicular aggregations of B‐lymphocytes are a prominent feature of the outer cortex of the lymph node. In the unstimulated node they are present as spherical collections of cells termed primary follicles, but after antigenic challenge they form secondary follicles that consist of a corona or mantle of concentrically packed, resting, small IgM+ IgDB‐cells surrounding a pale‐staining germinal center (Figure 6.15d,e). This structure contains large, usually proliferating B‐blasts (activated B‐cells with increased amounts of cytoplasm), a minority of T‐cells, scattered macrophages, and a network of FDCs. The formation of germinal centers is dependent upon B‐cell expression of the Bcl‐6 transcription factor which, among other roles, regulates B‐cell activation and differentiation. Germinal centers constitute sites of B‐cell proliferation, class switching, somatic hypermutation, and the generation of memory B‐cells and the precursors of plasma cells.

On priming with a T‐dependent antigen (i.e., antigen for which the B‐cells require cooperation from T‐helper cells), the FDC network within the germinal center becomes colonized by specific B‐cells undergoing exponential growth. These proliferating cells form what is called the dark zone (because it stains more heavily with histological stains). This coloration is due to the dense packing of the lymphocytes with the production of around 104 B‐cells that are referred to in this location as centroblasts. Recruitment of B‐cells to the dark zone of the germinal center is dependent on the local production of the CXCL12 chemokine detected by CXCR4 on the B‐cells. The centroblasts displace the original resting B‐cells that now form the mantle that surrounds the germinal center. These highly mitotic centroblasts in the dark zone express high levels of CXCR4 and low levels of CD86. Differentiation into centrocytes involves transit into a less densely packed area of the germinal center called the basal light zone, which is where most of the FDCs are found. This differentiation is accompanied by downregulation of CXCR4 and upregulation of CD86. At this stage there is very extensive apoptotic cell death of B‐cells with inappropriate specificity and/or affinity, giving rise to fragmented lymphocytes that are visible as phagocytosed “tingible bodies” within the macrophages, the disposal system for the dead cells. The higher affinity survivors undergo their final differentiation in the apical light zone. A proportion of those that differentiate down the memory cell pathway take up residence in the mantle zone; the remainder join the recirculating B‐cell pool. Other germinal center B‐cells in the apical light zone differentiate into a cell type called the plasmablast which has a well‐defined endoplasmic reticulum, prominent Golgi apparatus, and cytoplasmic Ig. Plasmablasts migrate to become antibody‐secreting plasma cells in the medullary cords, which project between the medullary sinuses (Figure 6.15b). This maturation of antibody‐forming cells at a different location (i.e., in the medullary cords of the secondary follicles rather than in the germinal center itself ) from that at which antigen triggering has occurred is also seen in the spleen, where plasma cells are found predominantly in the marginal zone. It is thought that this movement of cells acts to prevent the generation of high local concentrations of antibody within the germinal center, so avoiding neutralization of the antigen and premature shut­down of the immune response. We will look at germinal centers again in Chapter 8.

The remainder of the outer cortex is also essentially a B‐cell area with scattered T‐cells.


T‐cell Areas

T‐cells are mainly confined to the paracortex of the lymph node (Figure 6.15a,b). Techniques such as intravital multiphoton scanning laser microscopy allow observation of lymphocyte behavior within lymphoid tissue. T‐cells are seen to move rapidly and randomly within the paracortex, where they attempt to find an interdigitating dendritic cell (IDC) bearing “their” antigen. Should the TCR on the T‐cell recognize the cognate MHC–peptide, a stable binding occurs that is largely cemented by LFA‐1 on the T‐cell binding to ICAM‐1 on the IDC. An immunological synapse is generated and contact maintained for 8–24 hours in order to fully activate the T‐cell. As germinal centers develop, newly activated helper T‐cells can enter these structures to develop into T‐follicular helper (Tfh) cells. These T‐cells have upregulated their expression of the Bcl‐6 transcription factor leading to decreased CCR7 and increased CXCR5 chemokine receptor levels, They also have high levels of the CD28 family members PD‐1 and ICOS, and secrete cytokines such as IL‐4 and IL‐ 1 that direct the differentiation of germinal center B‐cells.

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