Follicular dendritic cells

Last updated
Histologic comparison of cell types in a germinal center, H&E stain: - Centrocytes are small to medium size with angulated, elongated, cleaved, or twisted nuclei. - Centroblasts are larger cells containing vesicular nuclei with one to three basophilic nucleoli apposing the nuclear membrane. - Follicular dendritic cells have round nuclei, centrally located nucleoli, bland and dispersed chromatin, and flattening of adjacent nuclear membrane. Centrocyte, centroblast and follicular dendritic cell in a follicular lymphoma.jpg
Histologic comparison of cell types in a germinal center, H&E stain:
- Centrocytes are small to medium size with angulated, elongated, cleaved, or twisted nuclei.
- Centroblasts are larger cells containing vesicular nuclei with one to three basophilic nucleoli apposing the nuclear membrane.
- Follicular dendritic cells have round nuclei, centrally located nucleoli, bland and dispersed chromatin, and flattening of adjacent nuclear membrane.

Follicular dendritic cells (FDC) are cells of the immune system found in primary and secondary lymph follicles (lymph nodes) of the B cell areas of the lymphoid tissue. [1] [2] [3] Unlike dendritic cells (DC), FDCs are not derived from the bone-marrow hematopoietic stem cell, but are of mesenchymal origin. [4] Possible functions of FDC include: organizing lymphoid tissue's cells and microarchitecture, capturing antigen to support B cell, promoting debris removal from germinal centers, and protecting against autoimmunity. Disease processes that FDC may contribute include primary FDC-tumor, chronic inflammatory conditions, HIV-1 infection development, and neuroinvasive scrapie.

Contents

Location and molecular markers

Follicular DCs are a non-migratory population found in primary and secondary follicles of the B cell areas of lymph nodes, spleen, and mucosa-associated lymphoid tissue (MALT). They form a stable network due to intercellular connections between FDCs processes and intimate interaction with follicular B cells. [5] [6] Follicular DCs network typically forms the center of the follicle and does not extend from the follicle to the interfollicular regions or T-cell zone. Supposedly, this separation from the sites of earliest antigen processing and capture provide a protected environment in which opsonized antigens can be displayed for a long time without being proteolyzed or removed by phagocytic cells. Follicular DCs have high expression of complement receptors CR1 and CR2 (CD 35 and CD 21 respectively) and Fc-receptor FcγRIIb (CD32). Further FDCs specific molecular markers are FDC-M1, FDC-M2 and C4. [7] Unlike other DCs and macrophages, FDCs lack MHC class II antigen molecules and express few pattern-recognition receptors, so they have little ability to capture non-opsonized antigens. [5]

Development

Follicular DCs develop from putative mesenchymal precursors. [7] Severe combined immunodeficiency (SCID) mice models demonstrate that these precursors may be transmitted to recipients with bone marrow allotransplants, in which case both donors' and recipients' FDCs networks may later be found in recipients' lymphoid compartments. [8] Interaction between FDCs precursors and lymphoid cells mediated by TNF-a and lymphotoxin (LT) is crucial for normal FDC development and maintenance. TNF-a binds on the TNFRI receptor, while LT interacts with LTβ-receptor expressed on FDC precursors. In mice lacking B cells, or with blocked TNF-a and lymphotoxin (LT) production, cells with FDC phenotype are missing. [9] [10]

Functions

Organizing lymphoid microarchitecture

In normal lymphoid tissue, recirculating resting B cells migrate through the FDC networks, whereas antigen-activated B cells are intercepted and undergo clonal expansion within the FDC networks, generating germinal centers (GC). FDCs are among main producers of the chemokine CXCL13 which attracts and organises lymphoid cells. [11]

Antigen capturing, memory B-cell support

Follicular DCs receptors CR1, CR2 and FcγRIIb trap antigen opsonized by complement or antibodies. These antigens are then taken up in a non-degradative cycling endosomal compartment for later presentation to B cells. [12] To become selected as a future memory cell, GC B cells must bind the antigen presented on FDCs, otherwise they enter apoptosis.

Debris removal

By secreting the bridging factor MFGE8, which crosslinks apoptotic cells and phagocytes, FDCs promote selective debris removal from the GC. [13] [14]

Preventing autoimmunity

Factor Mfge produced in lymphoid tissues mainly by FDCs is known to enhance engulfment of apoptotic cells. Deficit of this factor in mice leads to a state resembling systemic lupus erythematosus (SLE). Furthermore, mice lacking LT or LT receptors, which are devoid of FDC, develop generalized lymphocytic infiltrates, which are suggestive of autoimmunity. These findings suggest that FDC possibly protect organism against autoimmunity by the removal of potentially self-reactive debris from germinal centres. [13]

Interaction with B-cells

Noncognate (not antigen specific) B cells play a significant role in the transport of antigens to FDCs. They capture immune complexes in CR1/2-dependent way either directly from the lymph or from macrophages, and move to the lymphoid tissue, where they transfer complement opsonized antigen to the FDCs. [15] [16]

FDCs, in turn, attract B cells with chemoattractant CXCL13. B cells lacking CXCR5, the receptor for CXCL13, still enter the white pulp, but are mislocalized and disorganized. To generate follicular structures, FDCs need to be stimulated by lymphotoxin (LT), a mediator produced by B cells. The stimulation of CXCR5 on B cells upregulates LT production, which leads to FDCs activation and stimulates further CXCL13 secretion, thus generating a positive feed-forward loop. This results in the formation of germinal centers (GCs), where antigen-activated B cells are trapped to undergo somatic mutation, positive and negative selection, isotype switching, and differentiation into high-affinity plasma cells and memory B cells. Adhesion between FDCs and B cells is mediated by ICAM-1 (CD54)–LFA-1 (CD11a) and VCAM–VLA-4 molecules. [7] Activated B-cells with low affinity to antigen captured on FDCs surface as well as autoreactive B-cells undergo apoptosis, [17] whereas B cells bound to FDCs through the antigen complex, survive due to apoptosis blockage caused by interaction with FDCs.

Diseases

Rare primary FDC-tumors have been described. These sarcomas often involve lymphoid tissues, but in a number of cases the tumor has been found in the liver, bile duct, pancreas, thyroid, nasopharynx, palatum, submucosa of the stomach or the duodenum. In a number of chronic inflammatory conditions, cells producing CXCL13 chemokine and carrying such FDCs markers as VCAM-1 and CD21, have been observed at quite unexpected sites, including synovial tissue of patients with rheumatoid arthritis (RA), salivary glands of patients with Sjögren’s syndrome, and the skin of patients with pseudo B cells lymphoma. [7] Follicular dendritic cells participate in HIV-1 infection development both, by providing a haven for HIV-1 [18] [19] [20] and by stimulating HIV-1 replication in adjacent infected monocytic cells via a juxtacrine signaling mechanism. [21] There is also some evidence, that FDCs may promote prion replication and neuroinvasion in neuroinvasive scrapie. [22]

See also

Related Research Articles

<span class="mw-page-title-main">Lymphatic system</span> Organ system in vertebrates complementary to the circulatory system

The lymphatic system, or lymphoid system, is an organ system in vertebrates that is part of the immune system, and complementary to the circulatory system. It consists of a large network of lymphatic vessels, lymph nodes, lymphoid organs, lymphoid tissues and lymph. Lymph is a clear fluid carried by the lymphatic vessels back to the heart for re-circulation. The Latin word for lymph, lympha, refers to the deity of fresh water, "Lympha".

<span class="mw-page-title-main">Lymph node</span> Organ of the lymphatic system

A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that include B and T cells. Lymph nodes are important for the proper functioning of the immune system, acting as filters for foreign particles including cancer cells, but have no detoxification function.

<span class="mw-page-title-main">Dendritic cell</span> Accessory cell of the mammalian immune system

A dendritic cell (DC) is an antigen-presenting cell of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system. They act as messengers between the innate and adaptive immune systems.

<span class="mw-page-title-main">Memory B cell</span> Cell of the adaptive immune system

In immunology, a memory B cell (MBC) is a type of B lymphocyte that forms part of the adaptive immune system. These cells develop within germinal centers of the secondary lymphoid organs. Memory B cells circulate in the blood stream in a quiescent state, sometimes for decades. Their function is to memorize the characteristics of the antigen that activated their parent B cell during initial infection such that if the memory B cell later encounters the same antigen, it triggers an accelerated and robust secondary immune response. Memory B cells have B cell receptors (BCRs) on their cell membrane, identical to the one on their parent cell, that allow them to recognize antigen and mount a specific antibody response.

Gut-associated lymphoid tissue (GALT) is a component of the mucosa-associated lymphoid tissue (MALT) which works in the immune system to protect the body from invasion in the gut.

<span class="mw-page-title-main">Germinal center</span> Lymphatic tissue structure

Germinal centers or germinal centres (GCs) are transiently formed structures within B cell zone (follicles) in secondary lymphoid organs – lymph nodes, ileal Peyer's patches, and the spleen – where mature B cells are activated, proliferate, differentiate, and mutate their antibody genes during a normal immune response; most of the germinal center B cells (BGC) are removed by tingible body macrophages. There are several key differences between naive B cells and GC B cells, including level of proliferative activity, size, metabolic activity and energy production. The B cells develop dynamically after the activation of follicular B cells by T-dependent antigen. The initiation of germinal center formation involves the interaction between B and T cells in the interfollicular area of the lymph node, CD40-CD40L ligation, NF-kB signaling and expression of IRF4 and BCL6.

<span class="mw-page-title-main">White pulp</span> Type of tissue in the spleen

White pulp is a histological designation for regions of the spleen, that encompasses approximately 25% of splenic tissue. White pulp consists entirely of lymphoid tissue.

<span class="mw-page-title-main">Complement receptor 2</span> Protein found in humans

Complement receptor type 2 (CR2), also known as complement C3d receptor, Epstein-Barr virus receptor, and CD21, is a protein that in humans is encoded by the CR2 gene.

Lymphotoxin is a member of the tumor necrosis factor (TNF) superfamily of cytokines, whose members are responsible for regulating the growth and function of lymphocytes and are expressed by a wide variety of cells in the body.

<span class="mw-page-title-main">CXCL13</span> Mammalian protein found in Homo sapiens

Chemokineligand 13 (CXCL13), also known as B lymphocyte chemoattractant (BLC) or B cell-attracting chemokine 1 (BCA-1), is a protein ligand that in humans is encoded by the CXCL13 gene.

<span class="mw-page-title-main">CXCR5</span> Mammalian protein found in Homo sapiens

C-X-C chemokine receptor type 5 (CXC-R5) also known as CD185 or Burkitt lymphoma receptor 1 (BLR1) is a G protein-coupled seven transmembrane receptor for chemokine CXCL13 and belongs to the CXC chemokine receptor family. It enables T cells to migrate to lymph node and the B cell zones. In humans, the CXC-R5 protein is encoded by the CXCR5 gene.

<span class="mw-page-title-main">Lymphotoxin alpha</span> Protein found in humans

Lymphotoxin-alpha (LT-α) formerly known as tumor necrosis factor-beta (TNF-β) is a protein that in humans is encoded by the LTA gene. Belonging to the hematopoietic cell line, LT-α exhibits anti-proliferative activity and causes the cellular destruction of tumor cell lines. As a cytotoxic protein, LT-α performs a variety of important roles in immune regulation depending on the form that it is secreted as. Unlike other members of the TNF superfamily, LT-α is only found as a soluble homotrimer, when found at the cell surface it is found only as a heterotrimer with LTβ.

<span class="mw-page-title-main">GPR183</span> Protein-coding gene in the species Homo sapiens

G-protein coupled receptor 183 also known as Epstein-Barr virus-induced G-protein coupled receptor 2 (EBI2) is a protein (GPCR) expressed on the surface of some immune cells, namely B cells and T cells; in humans it is encoded by the GPR183 gene. Expression of EBI2 is one critical mediator of immune cell localization within lymph nodes, responsible in part for the coordination of B cell, T cell, and dendritic cell movement and interaction following antigen exposure. EBI2 is a receptor for oxysterols. The most potent activator is 7α,25-dihydroxycholesterol (7α,25-OHC), with other oxysterols exhibiting varying affinities for the receptor. Oxysterol gradients drive chemotaxis, attracting the EBI2-expressing cells to locations of high ligand concentration. The GPR183 gene was identified due to its upregulation during Epstein-Barr virus infection of the Burkitt's lymphoma cell line BL41, hence its name: EBI2.

<span class="mw-page-title-main">Marginal-zone B cell</span>

Marginal-zone B cells are noncirculating mature B cells that in humans segregate anatomically into the marginal zone (MZ) of the spleen and certain other types of lymphoid tissue. The MZ B cells within this region typically express low-affinity polyreactive B-cell receptors (BCR), high levels of IgM, Toll-like receptors (TLRs), CD21, CD1, CD9, CD27 with low to negligible levels of secreted-IgD, CD23, CD5, and CD11b that help to distinguish them phenotypically from follicular (FO) B cells and B1 B cells.

Within the immune system, Follicular B cells are a type of B cell that reside in primary and secondary lymphoid follicles of secondary and tertiary lymphoid organs, including spleen and lymph nodes. Antibody responses against proteins are believed to involve follicular B cell pathways in secondary lymphoid organs.

FDC-SP or follicular dendritic cell-secreted protein, is a small, secreted protein, located on chromosome 4 in humans. It is thought to play an immune role in the junctional epithelium at the gingival crevice in the human mouth. It is very similar in structure to statherin, a protein contained in saliva.

<span class="mw-page-title-main">Centrocyte</span>

A centrocyte generally refers to a B cell with a cleaved nucleus, as may appear in e.g. follicular lymphoma. Centrocytes are B cells that are found in the light zones of germinal centers. Centrocytes are the non-dividing progeny of Centroblasts, and although they are relatively similar in size, centrocytes lack distinct nucleoli and are more irregularly shaped than centroblasts Centrocytes also express the cell-surface hypermutated B-cell receptor following AID activation. This hypermutated B-cell receptor allows centrocytes to compete for binding of the antigen, internalize it, and then express the processed peptides through their MHC class II receptor. Centrocyte can also refer to a cell with a protoplasm that contains single and double granules of varying size stainable with hematoxylin, as seen in lesions of lichen planus, or a nondividing, activated B cell that expresses membrane immunoglobulin.

Lymph node stromal cells are essential to the structure and function of the lymph node whose functions include: creating an internal tissue scaffold for the support of hematopoietic cells; the release of small molecule chemical messengers that facilitate interactions between hematopoietic cells; the facilitation of the migration of hematopoietic cells; the presentation of antigens to immune cells at the initiation of the adaptive immune system; and the homeostasis of lymphocyte numbers. Stromal cells originate from multipotent mesenchymal stem cells.

<span class="mw-page-title-main">Centroblast</span>

A centroblast generally refers to an activated B cell that is enlarged and is rapidly proliferating in the germinal center of a lymphoid follicle. They are specifically located in the dark zone of the germinal center. Centroblasts form from naive B cells being exposed to follicular dendritic cell cytokines, such as IL-6, IL-15, 8D6, and BAFF. Stimulation from helper T cells is also required for centroblast development. Interaction between CD40 ligand on an activated T helper cell and the B cell CD40 receptor induces centroblasts to express activation-induced cytidine deaminase, leading to somatic hypermutation, allowing the B cell receptor to potentially gain stronger affinity for an antigen. In the absence of FDC and helper T cell stimulation, centroblasts are unable to differentiate and will undergo CD95-mediated apoptosis.

<span class="mw-page-title-main">Bronchus-associated lymphoid tissue</span>

Bronchus-associated lymphoid tissue (BALT) is a tertiary lymphoid structure. It is a part of mucosa-associated lymphoid tissue (MALT), and it consists of lymphoid follicles in the lungs and bronchus. BALT is an effective priming site of the mucosal and systemic immune responses.

References

  1. ↑ Liu Y, Grouard G, de Bouteiller O, Banchereau J (1996). Follicular dendritic cells and germinal centers. International Review of Cytology. Vol. 166. pp. 139–79. doi:10.1016/S0074-7696(08)62508-5. ISBN   978-0-12-364570-8. PMID   8881775.{{cite book}}: |journal= ignored (help)
  2. ↑ Heesters, Balthasar A.; Myers, Riley C.; Carroll, Michael C. (2014-06-20). "Follicular dendritic cells: dynamic antigen libraries". Nature Reviews Immunology. 14 (7): 495–504. doi:10.1038/nri3689. ISSN   1474-1733. PMID   24948364. S2CID   7082877.
  3. ↑ Aguzzi, Adriano; Kranich, Jan; Krautler, Nike Julia (March 2014). "Follicular dendritic cells: origin, phenotype, and function in health and disease". Trends in Immunology. 35 (3): 105–113. doi:10.1016/j.it.2013.11.001. ISSN   1471-4906. PMID   24315719.
  4. ↑ Banchereau J, Steinman RM (1998). "Dendritic cells and the control of immunity". Nature. 392 (6673): 245–52. Bibcode:1998Natur.392..245B. doi:10.1038/32588. PMID   9521319. S2CID   4388748.van Nierop K, de Groot C (2002). "Human follicular dendritic cells: function, origin and development". Semin Immunol. 14 (4): 251–7. doi:10.1016/S1044-5323(02)00057-X. PMID   12163300.
  5. 1 2 Male D, Brostoff J, Roth D, Roitt I (2007). Immunology (7th ed.). Elsevier Health Sciences. ISBN   978-0-323-03399-2.
  6. ↑ Banchereau J, Steinman RM (1998). "Dendritic cells and the control of immunity". Nature. 392 (6673): 245–52. Bibcode:1998Natur.392..245B. doi:10.1038/32588. PMID   9521319. S2CID   4388748.
  7. 1 2 3 4 van Nierop K, de Groot C (2002). "Human follicular dendritic cells: function, origin and development". Semin Immunol. 14 (4): 251–7. doi:10.1016/S1044-5323(02)00057-X. PMID   12163300.
  8. ↑ Kapasi ZF, Qin D, Kerr WG, Kosco-Vilbois MH, Shultz LD, Tew JG, Szakal AK (1998). "Follicular dendritic cell (FDC) precursors in primary lymphoid tissues". The Journal of Immunology. 160 (3): 1078–84. doi: 10.4049/jimmunol.160.3.1078 . PMID   9570519. S2CID   1838950.
  9. ↑ Wang Y, Wang J, Sun Y, Wu Q, Fu YX (2001). "Complementary effects of TNF and lymphotoxin on the formation of germinal center and follicular dendritic cells". Journal of Immunology. 166 (1): 330–7. doi: 10.4049/jimmunol.166.1.330 . PMID   11123309.
  10. ↑ Ettinger R, Mebius R, Browning JL, Michie SA, van Tuijl S, Kraal G, van Ewijk W, McDevitt HO (1998). "Effects of tumor necrosis factor and lymphotoxin on peripheral lymphoid tissue development". Int Immunol. 10 (6): 727–41. doi: 10.1093/intimm/10.6.727 . PMID   9678753.
  11. ↑ Cyster JG (2010). "B cell follicles and antigen encounters of the third kind". Nat Immunol. 11 (11): 989–96. doi:10.1038/ni.1946. PMID   20959804. S2CID   26439962.
  12. ↑ Balthasar, Heesters; Priyadarshini, Chatterjee; Young-A, Kim; Santiago, Gonzalez; Michael, Kuligowski; Tomas, Kirchhausen; Michael, Carroll (2013). "Endocytosis and recycling of immune complexes by follicular dendritic cells enhances B cell binding and activation". Frontiers in Immunology. 4. doi: 10.3389/conf.fimmu.2013.02.00438 . ISSN   1664-3224.
  13. 1 2 Aguzzi A, Krautler NJ (2010). "Characterizing follicular dendritic cells: A progress report". European Journal of Immunology. 40 (8): 2134–8. doi: 10.1002/eji.201040765 . PMID   20853499.
  14. ↑ Kranich J, Krautler NJ, Heinen E, Polymenidou M, Bridel C, Schildknecht A, Huber C, Kosco-Vilbois MH, Zinkernagel R, Miele G, Aguzzi A (2008). "Follicular dendritic cells control engulfment of apoptotic bodies by secreting Mfge8". J Exp Med. 205 (6): 1293–302. doi:10.1084/jem.20071019. PMC   2413028 . PMID   18490487.
  15. ↑ Phan, Tri Giang; Grigorova, Irina; Okada, Takaharu; Cyster, Jason G (2007-07-29). "Subcapsular encounter and complement-dependent transport of immune complexes by lymph node B cells". Nature Immunology. 8 (9): 992–1000. doi: 10.1038/ni1494 . ISSN   1529-2908. PMID   17660822. S2CID   35256900.
  16. ↑ Carrasco, Yolanda R.; Batista, Facundo D. (July 2007). "B Cells Acquire Particulate Antigen in a Macrophage-Rich Area at the Boundary between the Follicle and the Subcapsular Sinus of the Lymph Node". Immunity. 27 (1): 160–171. doi: 10.1016/j.immuni.2007.06.007 . ISSN   1074-7613. PMID   17658276.
  17. ↑ Aguzzi A, Kranich J, Krautler NJ (2014). "Follicular dendritic cells: origin, phenotype, and function in health and disease". Trends in Immunology . 35 (3): 105–113. doi:10.1016/j.it.2013.11.001. PMID   24315719.
  18. ↑ Cavert W, Notermans DW, Staskus K, Wietgrefe SW, Zupancic M, Gebhard K, Henry K, Zhang ZQ, Mills R, McDade H, Schuwirth CM, Goudsmit J, Danner SA, Haase AT (1997). "Kinetics of response in lymphoid tissues to antiretroviral therapy of HIV-1 infection". Science. 276 (5314): 960–4. doi:10.1126/science.276.5314.960. PMID   9139661. S2CID   6800040.
  19. ↑ Pantaleo G, Graziosi C, Demarest JF, Butini L, Montroni M, Fox CH, Orenstein JM, Kotler DP, Fauci AS (1993). "HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease". Nature. 362 (6418): 355–8. Bibcode:1993Natur.362..355P. doi:10.1038/362355a0. PMID   8455722. S2CID   4326634.
  20. ↑ Heesters, Balthasar A.; Lindqvist, Madelene; Vagefi, Parsia A.; Scully, Eileen P.; Schildberg, Frank A.; Altfeld, Marcus; Walker, Bruce D.; Kaufmann, Daniel E.; Carroll, Michael C. (2015-12-01). "Follicular Dendritic Cells Retain Infectious HIV in Cycling Endosomes". PLOS Pathogens. 11 (12): e1005285. doi: 10.1371/journal.ppat.1005285 . ISSN   1553-7374. PMC   4666623 . PMID   26623655.
  21. ↑ Ohba K, Ryo A, Dewan MZ, Nishi M, Naito T, Qi X, Inagaki Y, Nagashima Y, Tanaka Y, Okamoto T, Terashima K, Yamamoto N (2009). "Follicular dendritic cells activate HIV-1 replication in monocytes/macrophages through a juxtacrine mechanism mediated by P-selectin glycoprotein ligand 1". Journal of Immunology. 183 (1): 524–32. doi:10.4049/jimmunol.0900371. PMID   19542463. S2CID   21434580.
  22. ↑ Montrasio F, Frigg R, Glatzel M, Klein MA, Mackay F, Aguzzi A, Weissmann C (2000). "Impaired prion replication in spleens of mice lacking functional follicular dendritic cells". Science. 288 (5469): 1257–9. Bibcode:2000Sci...288.1257M. doi:10.1126/science.288.5469.1257. PMID   10818004.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.