Source: https://www.nature.com/articles/nri1669?error=cookies_not_supported&code=d61b9a82-2fae-475a-92b2-24be2b98e39c
Timestamp: 2019-04-23 20:11:22+00:00

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Reina Mebius completed a Ph.D. at Vrije Universiteit (Amsterdam, The Netherlands), where she studied the process of lymphocyte migration. During postdoctoral training, she continued to work in this field, in the laboratory of Irv Weissman, at Stanford University (Stanford, California, USA). In 1995, she returned to the Department of Molecular Cell Biology and Immunology at Vrije Universiteit. Her research focuses on the cellular and molecular aspects of lymphoid-organ development, the cell–cell interactions that are required for proper organization of lymphoid organs, the cellular interactions that occur in immune responses, and the early onset of inflammatory lesions.
Georg Kraal also works in the Department of Molecular Cell Biology and Immunology, where he studies the structure of lymphoid organs in relation to their function, in various immunological processes. He has developed several antibodies that are specific for pattern-recognition receptors expressed by myeloid cell types, and these antibodies have helped to identify these cells and their function in the spleen and the lymph nodes. At present, his research focuses on mucosal immunology and the role of lymph-node structure in immunological tolerance.
The structure of the spleen is such that two compartments can be distinguished: the blood-containing red pulp; and the white pulp, which is full of lymphoid cells.
In the red pulp, pathogens and cellular debris, as well as ageing erythrocytes, are efficiently removed from the blood by macrophages, which are abundant in this compartment. These macrophages are then well equipped to recycle iron from the erythrocytes.
The white pulp is a highly organized lymphoid region where adaptive immune responses can be initiated. It is composed of separate areas for B cells and T cells, which are surrounded by the marginal zone — a region that contains discrete subsets of macrophages and B cells. Whereas blood flows freely through the marginal zone, the white pulp is excluded from the bloodstream, and specific signals are required for entry.
Entry of leukocytes to the white pulp requires activation of G-protein-coupled receptors, a process which is reminiscent of the multistep extravasation process that has been described for leukocytes leaving the bloodstream and entering the lymph nodes or sites of inflammation.
The marginal zone forms a bridge between the innate and adaptive immune response, because the macrophages in this region, which express specific pattern-recognition receptors, can efficiently take up blood-borne pathogens. The specific subset of B cells in this region, the marginal-zone B cells, can be activated by these macrophages or can directly respond to blood-borne pathogens, after which they become antigen-presenting cells or IgM-producing plasma cells.
Entry of activated dendritic cells or marginal-zone B cells to the white pulp can initiate an adaptive immune response through activation of T cells, which then migrate to the edge of the B-cell follicles and provide help to B cells.
The organization of the white pulp into distinct areas, which promotes efficient interaction of cells of the immune system, is coordinated by the expression of chemokines, which attract the specific lymphoid subsets to the appropriate microdomains.
In addition, the organization of both the white pulp and the marginal zone is under strict control of lipid mediators and adhesion molecules, as well as chemokines, all of which help the specific cellular subsets to be retained within their compartments. Expression of these factors is, in turn, controlled by activation of the lymphotoxin-β receptor and tumour-necrosis-factor receptor 1, but it might also involve additional signalling receptors.
Through this unique organization of its compartments, the spleen can mount complex adaptive immune responses, as well as effectively clear pathogens from the blood.
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We thank all of our collaborators, particularly B. Steiniger, for helpful discussions.
Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center, v.d. Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
Correspondence to Reina E. Mebius.
Blood sinuses in which the blood is collected from the cords in the splenic red pulp and transported to the efferent vein of the spleen (the vena lienalis). The structure of the wall of the sinuses allows the removal of ageing erythrocytes from the circulation.
A bar of connective tissue that protrudes from the capsule into the splenic tissue. Together, the capsule and the trabeculae form a supporting, three-dimensional framework that provides some rigidity to the spleen.
A receptor that recognizes unique structures that are present at the surface of microorganisms. Signalling through these receptors leads to the production of pro-inflammatory cytokines and chemokines and to the expression of co-stimulatory molecules by antigen-presenting cells. The expression of co-stimulatory molecules, together with the presentation of antigenic peptides, by antigen-presenting cells couples innate immune recognition of pathogens with the activation of adaptive immune responses.
The efferent vein of the spleen.
An intracellular vesicle that results from the fusion of phagosomes, which enclose extracellular material that has been ingested, and lysosomes, which contain lytic enzymes.
A plasma protein that can bind free haemoglobin in the bloodstream.
A compound that is secreted by microorganisms that efficiently bind iron.
A type of pattern-recognition receptor that is expressed by macrophages and dendritic cells. These receptors recognize unique structures that are present at the surface of microorganisms.
An activated B cell at an intermediate stage of differentiation. Plasmablasts leave germinal centres and migrate through the lymph and the blood to distant sites, such as the skin and the lamina propria of the intestines, to become antibody-producing plasma cells.
A terminally differentiated cell of the B-cell lineage that secretes large amounts of antibodies.
An animal that contains cell populations of different genotypes as a result of the transfer of haematopoietic stem cells from fetal liver or bone marrow to a recipient in which haematopoietic-cell populations (and other actively dividing cell populations) have been fully or partially destroyed by lethal or sub-lethal ionizing radiation.
A stromal cell that is crucial for the development of germinal centres in B-cell follicles. The interaction between FDCs and B cells is thought to be essential for isotype switching and somatic hypermutation.
A large macrophage in the splenic marginal zone that is characterized by the expression of a unique set of pattern-recognition receptors.
A macrophage that is located at the border of the white pulp and the marginal zone of the spleen. The precise function of these cells at this site is not known.
A cell that is present in developing lymph nodes, Peyer's patches and nasopharynx-associated lymphoid tissue (NALT). Lymphoid-tissue inducer cells are required for the development of these lymphoid organs. The inductive capacity of these cells for the generation of Peyer's patches and NALT has been shown by adoptive transfer, and it is generally assumed that they have a similar function in the formation of lymph nodes.
A specialized venule that occurs in secondary lymphoid organs, except the spleen. HEVs allow continuous transmigration of lymphocytes as a consequence of the constitutive expression of adhesion molecules and chemokines at their luminal surface.

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 V. 
 V. 
 V. 
 V. 
 V. 
 V. 
 V.