Germinal Centres

Caroline Thielen, University of Liège, Liège, Belgium
Ernst Heinen, University of Liège, Liège, Belgium

Published online: June 2010

DOI: 10.1002/9780470015902.a0000517.pub3

Germinal centres are transient lymphoid structures appearing inside lymph follicles after an antigenic stimulation. They are closely associated with T-dependent zones and oriented in the peripheral lymph organs in accordance with the entry of antigens. During this germinal centre reaction, B cells undergo not only clonal amplification but also affinity maturation and class switching of their immunoglobulins. These events, occurring under the control of T cells and in the peculiar environments created by the follicular dendritic cells, lead B cells to mature into B memory cells or into precursors of plasma cells. Most cells generated inside the germinal centres die by apoptosis and are eliminated by the tingible body macrophages. Peculiar genetic, infectious or proliferative pathological conditions can touch the germinal centres.

Key Concepts:

  • Germinal centres are polarised structures annexed to T-dependent zones.
  • Different cell populations exhibiting peculiar phenotypes compose the germinal centres.
  • Chemotactism, proliferation, survival and maturation of B cells are guided by follicular dendritic cells and follicular T cells.
  • Ig affinity maturation requires somatic hypermutations and stringent cell selection.
  • The germinal centre reaction, induced by antigenic stimulation, involves sequential steps and is time-limited.
  • Particular genetic, proliferative or infectious diseases can alter the germinal cell functions.

Keywords: humoral immune response; lymphoid structures; B cells; T cells; germinal centre reaction; follicular dendritic cells

Figure 1. Schematic representation of a germinal centre within a secondary lymph follicle located in the cortex of a lymph node. It is polarised: the dark zone close to the T-dependent zone (paracortex) and the light zone on the subcapsular side. The light zone can further be subdivided into a lower and an upper part. The so-called outer zone separates the germinal centre from the corona or mantle zone.
Figure 2. Possible migration pathways of B cells in a human tonsil. B cells, after passing through high endothelial venules (HEVs), come into contact with T cells and antigen-presenting cells (1). When activated, they migrate to the dark zone (2) and become centroblasts, in the vicinity of tingible body macrophages (TBM) and FDC. Centroblasts mature to memory cells in the light zone (3). Centrocytes (3) can transform into centroblasts or, more probably, into small memory lymphocytes that leave the follicles through the corona (4). On encountering IL-6 in the subcapsular area (5), these lymphocytes can become plasma cells (AFC) beneath the epithelium. Memory B cells migrate to the efferent lymphatics (6) and recirculate. Solid arrows, probable route; dotted arrows, hypothetical route. ? denotes hypothetical route to lymphatic vessels or the subepithelial area. Adapted from Heinen E, Kinet–Denoël C, Bosseloir A, Cormann N and Simar L (1990) B cell microenvironments during antigen stimulation In: Sorg C (ed.) Molecular Biology of B cells Developments pp. 24–60. Basel: Karger.
Figure 3. Schematic representation of an activated FDC surrounded by numerous cytoplasmic extensions of lymphoid B- and T cells. The window summarises FDC main surface molecules, their connections and some of the factors released.
close
 References
    Ansel KM, McHeyzer-Williams LJ, Ngo VN et al. (1999) In vivo-activated CD4 T cells upregulate CXC chemokine receptor 5 and reprogram their response to lymphoid chemokines. Journal of Experimental Medicine 190: 1123–1134.
    Aydar Y, Balogh P, Tew JG and Szakal AK (2004) Follicular dendritic cells in aging, a “bottle-neck” in the humoral immune response. Aging Research Reviews 3: 15–29.
    Aydar Y, Sukumar S, Szakal AK and Tew JG (2005) The influence of immune complex-bearing follicular dendritic cells on the IgM response, Ig class switching, and production of high affinity IgG. Journal of Immunology 174: 5358–5366.
    Balogh P, Aydar Y, Tew JG and Szakal AK (2002) Appearance and phenotype of murine follicular dendritic cells expressing VCAM-1. Anatomical Record 268: 160–168.
    Bofill M, Akbar AN and Amlot PL (2000) Follicular dendritic cells share a membrane-bound protein with fibroblasts. Journal of Pathology 191: 217–226.
    Bowen MB, Butch AW, Parvin CA, Levine A and Nahm MH (1991) Germinal center T cells are distinct helper-inducer T cells. Human Immunology 31: 67–75.
    Burton GF, Keele BF, Estes JD, Thacker TC and Gartner S (2002) Follicular dendritic cell contributions to HIV pathogenesis. Seminars in Immunology 14: 275–284.
    Caron G, Le Gallou S, Lamy T, Tarte K and Fest T (2009) CXCR4 expression functionally discriminates centroblast versus centrocytes within human germinal center B cells. Journal of Immunology 182: 7595–7602.
    Chalouni C, Banchereau J, Vogt AB et al. (2003) Human germinal centre B cells differ from naive and memory B cells by their aggregated MHC class II-rich compartments lacking HLA-DO. International Immunology 15: 457–466.
    Chtanova T, Tangye SG, Newton R et al. (2004) T follicular helper cells express a distinctive transcriptional profile, reflecting their role as non-Th1/Th2 effector cells that provides help for B cells. Journal of Immunology 173: 68–78.
    Cyster JG, Ansel KM, Reif K et al. (2000) Follicular stromal cells and lymphocytes homing to follicles. Immunological Reviews 176: 181–193.
    Dubois B, Barthelemy C, Durand I et al. (1999) Toward a role of dendritic cells in the germinal centre reaction: triggering of B-cell proliferation and isotype switching. Journal of Immunology 162: 3428–3436.
    Ebert LM, Horn MP, Lang AB and Moser B (2004) B cells alter the phenotype and function of follicular-homing CXCR5+ T cells. European Journal of Immunology 34: 3562–3571.
    van Eijk M, Defrance T, Hennino A and de Groot C (2001) Death-receptor contribution to the germinal-centre reaction. Trends in Immunology 22: 677–682.
    Goval JJ, Greimers R, Boniver J and de Leval L (2006) Germinal center dendritic cells express more ICAM-1 than extrafollicular dendritic cells and ICAM-1/LFA-1 interactions are involved in the capacity of dendritic cells to induce PBMCs proliferation. Journal of Histochemistry and Cytochemistry 54: 75–84.
    Grouard G, Durand I, Filgueira L, Banchereau J and Liu YJ (1996) Dendritic cells capable of stimulating T cells in germinal centres. Nature 384: 364–367.
    Hardie D, Johnson G, Khan M and MacLennan I (1993) Quantitative analysis of molecules which distinguish functional compartments within germinal centres. European Journal of Immunology 23: 997–1004.
    Hauser AE, Shlomchik MJ and Haberman AM (2007) In vivo imaging studies shed light on germinal-centre development. Nature Reviews. Immunology 7: 499–504.
    Haynes NM, Allen CD, Lesley R et al. (2007) Role of CXCR5 and CCR7 in follicular Th cell positioning and appearance of a programmed cell death gene-1high germinal center-associated subpopulation. Journal of Immunology 179: 5099–5108.
    Hjelmstrom P (2001) Lymphoid neogenesis: de novo formation of lymphoid tissue in chronic inflammation through expression of homing chemokines. Journal of Leukocyte Biology 69: 331–339.
    Ho J, Moir S, Kulik L et al. (2007) Role for CD21 in the establishment of an extracellular HIV reservoir in lymphoid tissues. Journal of Immunology 178: 6968–6974.
    Kim CH, Lim HW, Kim JR et al. (2004) Unique gene expression program of human germinal center T helper cells. Blood 104: 1952–1960.
    King C, Tangye SG and Mackay CR (2008) T follicular helper (TFH) cells in normal and dysregulated immune responses. Annual Review Immunology 26: 741–766.
    Kosco-Vilbois MH (2003) Are follicular dendritic cells really good for nothing? Nature Reviews. Immunology 3: 764–769.
    Kranich J, Krautler NJ, Heinen E et al. (2008) Follicular dendritic cells control engulfment of apoptotic bodies by secreting Mfge8. Journal of Experimental Medicine 205: 1293–1302.
    Lee IY and Choe J (2003) Human follicular dendritic cells and fibroblasts share the 3C8 antigen. Biochemical and Biophysical Research Communications 304: 701–707.
    Lee IY, Cho W, Kim J, Park CS and Choe J (2008) Human follicular dendritic cells interact with T cells via expression and regulation of cyclooxygenases and prostaglandin E and I synthases. Journal of Immunology 180: 1390–1397.
    Li L and Choi YS (2002) Follicular dendritic cell-signaling molecules required for proliferation and differentiation of GC-B cells. Seminars in Immunology 14: 259–266.
    Lindhout E, Vissers JL, Hartgers FC et al. (2001) The dendritic cell-specific CC-chemokine DC-CK1 is expressed by germinal center dendritic cells and attracts CD38-negative mantle zone B lymphocytes. Journal of Immunology 166: 3284–3289.
    Lindstedt M, Johansson-Lindbom B and Borrebaeck CA (2003) Expression of CD137 (4-1BB) on human follicular dendritic cells. Scandinavian Journal of Immunology 57: 305–310.
    Mabbott NA and Bruce ME (2002) Follicular dendritic cells as targets for intervention in transmissible spongiform encephalopathies. Seminars in Immunology 14: 285–293.
    Marinova E, Hans S and Zheng B (2007) Germinal center helper T cells are dual functional regulatory cells with suppressive activity to conventional CD4+ T cells. Journal of Immunology 178: 5010–5017.
    Marshall AJ, Du Q, Draves KE et al. (2002) FDC-SP, a novel secreted protein expressed by follicular dendritic cells. Journal of Immunology 169: 2381–2389.
    McHeyzer-Williams LJ, Pelletier N, Mark L, Fazilleau N and McHeyzer-Williams MG (2009) Follicular helper T cells as cognate regulators of B cell immunity. Current Opinion in Immunology 21: 266–273.
    Nurieva RI, Chung Y, Hwang D et al. (2008) Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2 or 17 cell lineages. Immunity 29: 139–149.
    Pauly S, Broll K, Wittmann M, Giegerich G and Schwarz H (2002) CD137 is expressed by follicular dendritic cells and costimulates B lymphocyte activation in germinal centers. Journal of Leukocyte Biology 72: 35–42.
    Rasheed AU, Rahn HP, Sallusto F, Lipp M and Muller G (2006) Follicular B helper T cell activity is confined to CXCR5(hi)ICOS(hi) CD4 T cells and is independent of CD57 expression. European Journal of Immunology 36: 1892–1903.
    Sasaki K, Doh-ura K, Ironside J, Mabbott N and Iwaki T (2006) Clusterin expression in follicular dendritic cells associated with prion protein accumulation. Journal of Pathology 209: 484–491.
    Schaerli P, Willimann K, Lang AB et al. (2000) CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. Journal of Experimental Medicine 192: 1553–1562.
    Schwartzberg PL, Mueller KL, Qi H and Cannons JL (2009) SLAM receptors and SAP influence lymphocyte interactions, development and function. Nature Reviews. Immunology 9: 39–46.
    Szakal AK, Aydar Y, Balogh P and Tew JG (2002) Molecular interactions of FDCs with B cells in aging. Seminars in Immunology 14: 267–274.
    Vinuesa CG, Cook MC, Angelucci C et al. (2005b) A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature 435: 452–458.
    Vinuesa CG, Tangye SG, Moser B and Mackay CR (2005a) Follicular B helper T cells in antibody responses and autoimmunity. Nature Reviews. Immunology 5: 853–865.
    Vogelzang A, McGuire HM, Yu D et al. (2008) A fundamental role of interleukin-21 in the generation of T follicular helper T cells. Immnuity 29: 127–137.
    Wu Y, El Shikh ME, El Sayed RM et al. (2009) Il-6 produced by immune complex-activated follicular dendritic cells promotes germinal center reactions, IgG responses and somatic hypermutation. International Immunology 21: 745–756.
    Yoon SO, Zhang X, Berner P, Blom B and Choi YS (2009) Notch ligands expressed by follicular dendritic cells protect germinal center B cells from apoptosis. Journal of Immunology 183: 352–358.
 Further Reading
    Cassemajor-Palleja M, Gubranson-Judge A and MacLennan IC (1997) T cells in the selection of germinal centre B cells. Chemical Immunology 67: 27–44.
    book Heinen E (1995) Follicular Dendritic Cells in Normal and Pathological Conditions. New York: Springer.
    Zheng B, Han S, Takahashi Y and Kelsoe G (1997) Immunosenescence and germinal center reaction. Immunological Reviews 160: 63–67.

Related Sub-Topics:

Cells of the Immune System | Tissues of the Immune System
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Germinal Centres
 
How to Cite close
Thielen, Caroline, and Heinen, Ernst(Jun 2010) Germinal Centres. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000517.pub3]