Lymph nodes. The earliest event during lymph-node development is the formation of lymph sacs by endothelial-cell budding from the larger veins during.
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ORGANOGENESIS OF LYMPHOID TISSUES Reina E. Mebius The development of lymphoid organs depends on the correct expression of several molecules within a defined timeframe during ontogeny. Although this is an extremely complex process, with each secondary lymphoid tissue requiring subtly different signals, a common framework for lymphoid development is beginning to emerge. Drawing on studies of lymph nodes, Peyer’s patches and nasal-associated lymphoid tissue, an integrative model of lymphoid-tissue development, involving adhesion molecules, cytokines and chemokines, which emphasizes the role of interactions between CD3–CD4+CD45+ ‘inducer’ cells and VCAM1+ICAM1+ stromal ‘organizer’ cells is presented. LYMPHOTOXIN
(LT). This protein belongs to the tumour-necrosis factor family and can be produced as a secreted homotrimer, LTα3, or as a membrane-bound heterotrimer, LTα1β2. The heterotrimer LTα1β2 binds to the lymphotoxin-β receptor (LTβR).
Department of Molecular Cell Biology, VU University Medical Center, v.d. Boechorststraat 7, 1081 BT, Amsterdam, The Netherlands. e-mail: r.mebius.cell@ med.vu.nl doi:10.1038/nri1054
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| APRIL 2003 | VOLUME 3
The inflammatory lesions in the autoimmune diseases rheumatoid arthritis, Sjögren syndrome and Hashimoto thyroiditis are often organized into distinct B-cell areas, surrounded by other haematopoietic cells, such as T cells and dendritic cells (DCs)1–5. This degree of organization is reminiscent of the distinct B- and T-cell areas that are seen in secondary lymphoid organs, such as lymph nodes, Peyer’s patches and the lymphoid compartment of the spleen, the white pulp. Chemokines and adhesion molecules, as well as cytokines, are thought to be instrumental in the development of both lymphoid organs and inflammatory lesions. Genetic studies in mice have shown that various genes are mandatory for lymphoid-organ development, and from these mice, much can be learned about the organogenesis of lymphoid tissues, as well as the induction of inflammatory lesions (TABLE 1). A common developmental programme seems to underly the organogenesis of lymph nodes, Peyer’s patches and nasal-associated lymphoid tissue (NALT), whereas the organogenesis of the more complex spleen, which consists of red and white pulp, involves different genes. Once these organs are formed, similar processes occur for the organization of lymph nodes, Peyer’s patches, NALT and the splenic white pulp. As lymph nodes, Peyer’s patches and NALT best resemble the ectopic lymphoid aggregates that are seen at sites of inflammation, I discuss recent insights into the molecular and cellular events in the organogenesis of these
lymphoid tissues. Together, these studies lead to a general model of the order and consequence of expression of genes that seem to have crucial roles in the organogenesis of lymphoid tissues. In addition, this model should allow the characterization of mechanisms that lead to the development of ectopic lymphoid tissue during inflammatory reactions. Development of lymphoid organs
Lymph nodes. The earliest event during lymph-node development is the formation of lymph sacs by endothelial-cell budding from the larger veins during embryogenesis (FIG. 1). Subsequently, connective tissue protrudes into these lymph sacs, establishing the first anlagen of the lymph nodes. The lymph sacs give rise to the lymphatic vasculature by sprouting of lymphatic vessels6–11. On the basis of expression of the homeobox gene Prox1, which is restricted to lymphatic endothelium, lymph sacs in mice start to form around embryonic day (E)10.5 and the lymphatic network is finished by E15.5 (REF. 12) (FIG. 1). The early formation of lymph-node anlagen has been visualized by immunostaining of embryos, showing that the first clusters of interleukin-7 receptor-α (IL-7Rα)expressing cells occur between E12.5 and E13.5, with an order of appearance from the anterior to posterior side of the embryo13. Signalling through IL-7Rα has been shown to induce expression of LYMPHOTOXIN-α1β2 www.nature.com/reviews/immunol
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Table 1 | Summary of mutant mice with defective lymphoid organogenesis Mice
Formation of: LN
PP
NALT
Ltα –/–, Ltβ r –/–, Nik –/–, aly/aly, Rela × Tnfr –/–
–
–
+
Nfκ b2 –/–, Relb –/–
+*
–
N.D
29,83,84
Ltβ
18,19,23
–/–
References
20–22,80–82,86
CLN, MLN
–
+
Light –/– × Ltβ–/–
