The germinal center reaction
2010; Elsevier BV; Volume: 126; Issue: 5 Linguagem: Inglês
10.1016/j.jaci.2010.09.007
ISSN1097-6825
AutoresDominique Gatto, Robert Brink,
Tópico(s)Immunotherapy and Immune Responses
ResumoThe germinal center (GC) reaction is the basis of T-dependent humoral immunity against foreign pathogens and the ultimate expression of the adaptive immune response. GCs represent a unique collaboration between proliferating antigen-specific B cells, T follicular helper cells, and the specialized follicular dendritic cells that constitutively occupy the central follicular zones of secondary lymphoid organs. The primary function of GCs is to produce the high-affinity antibody-secreting plasma cells and memory B cells that ensure sustained immune protection and rapid recall responses against previously encountered foreign antigens. However, the process of somatic mutation of antibody variable region genes that underpins GC function also carries significant risks in the form of unintended oncogenic mutations and generation of potentially pathogenic autoantibody specificities. Here we review the current knowledge on the recruitment, selection, and differentiation of B cells during GC responses and the implication of defects in GC physiology for autoimmune, inflammatory, and malignant diseases. Recent advances in documenting cellular movement within GCs and some of the key migratory signals responsible for GC formation are also discussed. The germinal center (GC) reaction is the basis of T-dependent humoral immunity against foreign pathogens and the ultimate expression of the adaptive immune response. GCs represent a unique collaboration between proliferating antigen-specific B cells, T follicular helper cells, and the specialized follicular dendritic cells that constitutively occupy the central follicular zones of secondary lymphoid organs. The primary function of GCs is to produce the high-affinity antibody-secreting plasma cells and memory B cells that ensure sustained immune protection and rapid recall responses against previously encountered foreign antigens. However, the process of somatic mutation of antibody variable region genes that underpins GC function also carries significant risks in the form of unintended oncogenic mutations and generation of potentially pathogenic autoantibody specificities. Here we review the current knowledge on the recruitment, selection, and differentiation of B cells during GC responses and the implication of defects in GC physiology for autoimmune, inflammatory, and malignant diseases. Recent advances in documenting cellular movement within GCs and some of the key migratory signals responsible for GC formation are also discussed. GlossaryAUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROMEAutoimmune lymphoproliferative syndrome is a disorder of lymphocyte apoptosis characterized by an increased incidence of autoimmunity, nonmalignant lymphoproliferation, and susceptibility to malignancy. Patients might have increased numbers CD3+αβ+CD4−CD8− (double-negative) T cells. Most cases are due to mutations in Fas.CHEMOKINEChemokines are the largest family of cytokines. They act by binding to G protein–coupled receptors. Their function in the immune system is to coordinate leukocyte trafficking and activation.DENDRITIC CELLSDendritic cells are hematopoietic cells that function as antigen-presenting cells for naive lymphocytes. Their name is derived from their multiple, thin membranous projections.GERMINAL CENTERThe germinal center is a specialized structure within secondary lymphoid organs in which responding B cells undergo somatic hypermutation and selection for increased antigen affinity (affinity maturation).GERMLINEThe germline is the cellular lineage from which eggs and sperm are derived. Germline mutations can be passed to the next generation.INDUCIBLE COSTIMULATOR (ICOS)ICOS is a member of the CD28 family of costimulatory receptors on T cells. ICOS binds to ICOS ligand on antigen-presenting cells. Function-loss mutations in the ICOS gene have been reported in patients with common variable immunodeficiency.INTEGRINIntegrins are cell-surface proteins that mediate adhesion. Leukocyte adhesion deficiency I is caused by mutations in a subfamily of integrins containing the conserved β2 chain (CD18).ISOTYPE SWITCHINGIsotype switching is the process of changing the class (isotype) of antibody production. There are 5 different antibody isotypes (IgM, IgD, IgG, IgA, and IgE), which are determined by the type of heavy chain present. Isotype switching allows an antibody-producing cell to alter the biological effects of its secreted product without affecting its specificity.OPSONINSOpsonins are various proteins (eg, complement or antibodies) that bind to foreign particles and microorganisms, making them more susceptible to the action of phagocytes. Mannose-binding lectin is an example of an opsonin that initiates complement activation.PLASMABLASTA plasmablast is an immature plasma cell still capable of proliferating and presenting antigens to T cells. A plasmablast can differentiate into a plasma cell, which is a terminally differentiated antibody-secreting B lymphocyte. Development of plasma cells is dependent on the induction of the transcription factor BLIMP-1.SILENT MUTATIONA silent mutation is a mutation having no detectable effect, such as DNA base changes that do not alter the amino acid sequence of the encoded protein.SOMATIC MUTATIONA somatic mutation is a mutation relating to nonreproductive parts of the body that is therefore not inherited. In the immune response antibody variable regions undergo intense somatic mutation (hypermutation) within germinal centers.SPLENIC MARGINAL ZONEThe splenic marginal zone is the interface between the red pulp and the white pulp in the spleen. Antigen from blood first encounters B cells in the marginal zone.SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 (STAT3)STAT3 is necessary for the development of TH17 cells, and mutations in the STAT3 gene are associated with hyper-IgE syndrome.TINGIBLE BODY MACROPHAGESTingible body macrophages take on a distinct “starry-sky” appearance after phagocytosing cellular debris.TWO-PHOTON MICROSCOPYTwo-photon microscopy is a form of laser scanning fluorescence microscopy that allows images of living cells and other microscopic objects.ZINC FINGERZing fingers are small protein domains that use zinc ion binding to help stabilize the protein’s folds. Zinc fingers are present in a variety of proteins, including those that participate in replication, repair, transcription, signaling, proliferation, and apoptosis.The Editors wish to thank Daniel A. Searing, MD, for preparing this glossary.Information for Category 1 CME CreditCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.Date of Original Release: November 2010. Credit may be obtained for these courses until October 31, 2012.Copyright Statement: Copyright © 2010-2012. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.List of Design Committee Members: Dominique Gatto, PhD, and Robert Brink, PhDActivity Objectives1.To understand the formation and structure of the germinal center (GC) reaction.2.To identify the role of GC regulation in pathological disease states.Recognition of Commercial Support: This CME activity has not received external commercial support.Disclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: D. Gatto has received research support from the Alliance for Lupus Research and the National Health and Medical Research Council of Australia. R. Brink has received research support from the National Health and Medical Research Council of Australia.The presence of areas with high mitotic activity in lymph nodes and other lymphoid tissues was first described in 1884 by Walther Flemming.1Flemming W. Studien über Regeneration der Gewebe.Arch Mikrosk Anat. 1885; 24: 50-91Crossref Scopus (40) Google Scholar, 2Flemming W. Schlussbemerkungen über die Zellvermehrung in den lymphoiden Drüsen.Arch Mikrosk Anat. 1885; 24: 355-361Google Scholar, 3Nieuwenhuis P. Opstelten D. Functional anatomy of germinal centers.Am J Anat. 1984; 170: 421-435Crossref PubMed Scopus (177) Google Scholar He named these structures with strong cell division germinal centers (GCs) under the assumption that they were the main origin of lymphocytes. Although this notion was subsequently disproved, GCs remain a key source of effector B-cell populations and are crucial for the generation of humoral immunity. In particular, GCs function to generate the high-affinity antibodies that form a key defense against infectious pathogens and are crucial to the efficacy of virtually all vaccines. However, although GC reactions provide a cellular milieu for the affinity maturation of antibody responses, they also bear the risk of generating autoreactive B-cell clones and B-cell lymphomas. This article presents an overview of the current understanding of the GC reaction based on the study of human tonsils and murine lymphoid tissues and discusses the association of GCs with disease.Initial stages of B-cell activation and differentiationGCs develop in B-cell follicles of secondary lymphoid organs in response to antigen challenge. Mature B cells continuously recirculate through secondary lymphoid organs in search of signs of infection and, on reaching the follicles, move rapidly within them to survey these areas for antigen. On antigen encounter, B cells initially congregate at the boundary between B-cell follicles and T-cell areas in search of T-cell help.4Garside P. Ingulli E. Merica R.R. Johnson J.G. Noelle R.J. Jenkins M.K. Visualization of specific B and T lymphocyte interactions in the lymph node.Science. 1998; 281: 96-99Crossref PubMed Scopus (621) Google Scholar This movement is directed by the rapid upregulation of the chemokine receptor CCR7 consequent on antigen activation.5Reif K. Ekland E.H. Ohl L. Nakano H. Lipp M. Forster R. et al.Balanced responsiveness to chemoattractants from adjacent zones determines B-cell position.Nature. 2002; 416: 94-99Crossref PubMed Scopus (431) Google Scholar Cognate encounters with T cells at the T zone–B zone (T-B) boundary drive initial B-cell proliferation and are required for the induction of GC responses. Notably, the interaction of the TNF receptor family member CD40, which is constitutively expressed by B cells, and its ligand, CD40L (CD154), which is expressed by activated TH cells, is crucial for formation of GCs.6Foy T.M. Laman J.D. Ledbetter J.A. Aruffo A. Claassen E. Noelle R.J. gp39-CD40 interactions are essential for germinal center formation and the development of B cell memory.J Exp Med. 1994; 180: 157-163Crossref PubMed Scopus (375) Google Scholar, 7Han S. Hathcock K. Zheng B. Kepler T.B. Hodes R. Kelsoe G. Cellular interaction in germinal centers. Roles of CD40 ligand and B7-2 in established germinal centers.J Immunol. 1995; 155: 556-567PubMed Google Scholar Thus GCs are believed to be heavily dependent on TH cells, although transient GC formation has been observed in the absence of T-cell help under some experimental conditions.8de Vinuesa C.G. Cook M.C. Ball J. Drew M. Sunners Y. Cascalho M. et al.Germinal centers without T cells.J Exp Med. 2000; 191: 485-494Crossref PubMed Scopus (228) Google ScholarIn addition to expressing CD40L, activated TH cells also secrete cytokines that deliver signals through specific cell-surface receptors that serve to drive B-cell proliferation and differentiation. Cytokine signals play a central role in triggering the molecular events that lead to the onset of immunoglobulin class-switch recombination (CSR) and thus the production of IgG-, IgE- and IgA-expressing B cells. Typically, signals delivered through cytokine receptors lead to the preferential targeting of the intracellular enzyme activation-induced cytidine deaminase (AID) to one of the switch recombination sequences located at the 5′ end of each of the γ, ε, and α immunoglobulin heavy chain constant region genes. Demethylation by AID of deoxycytidine residues in the targeted switch recombination sequences and the proximal μ heavy chain switch recombination sequence is followed by excision of the resulting deoxyuracil bases by uracil DNA glycosylase (UNG). This ultimately triggers recombination between the switch recombination sequences such that the downstream heavy chain gene assumes the original location of the μ heavy chain gene immediately 3′ of the rearranged immunoglobulin heavy chain variable region gene and is expressed as IgG, IgE, or IgA.9Stavnezer J. Guikema J.E. Schrader C.E. Mechanism and regulation of class switch recombination.Annu Rev Immunol. 2008; 26: 261-292Crossref PubMed Scopus (715) Google Scholar The process of immunoglobulin isotype switching can be initiated within days of initial B-cell activation.10Chan T.D. Gatto D. Wood K. Camidge T. Basten A. Brink R. Antigen affinity controls rapid T-dependent antibody production by driving the expansion rather than the differentiation or extrafollicular migration of early plasmablasts.J Immunol. 2009; 183: 3139-3149Crossref PubMed Scopus (170) Google Scholar, 11Pape K.A. Kouskoff V. Nemazee D. Tang H.L. Cyster J.G. Tze L.E. et al.Visualization of the genesis and fate of isotype-switched B cells during a primary immune response.J Exp Med. 2003; 197: 1677-1687Crossref PubMed Scopus (121) Google Scholar Thus although CSR can occur in the GC, it is not limited to this phase of the B-cell response.After initial activation, proliferating B-cell blasts proceed down one of 2 independent pathways of migration and differentiation.12Liu Y.J. Zhang J. Lane P.J. Chan E.Y. MacLennan I.C. Sites of specific B cell activation in primary and secondary responses to T cell-dependent and T cell-independent antigens.Eur J Immunol. 1991; 21: 2951-2962Crossref PubMed Scopus (604) Google Scholar, 13Jacob J. Kassir R. Kelsoe G. In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. I. The architecture and dynamics of responding cell populations.J Exp Med. 1991; 173: 1165-1175Crossref PubMed Scopus (591) Google Scholar On the one hand, responding B cells migrate from the T-B boundary to extrafollicular areas, where they are induced to rapidly expand and differentiate into plasmablasts and plasma cells.14MacLennan I.C. Toellner K.M. Cunningham A.F. Serre K. Sze D.M. Zuniga E. et al.Extrafollicular antibody responses.Immunol Rev. 2003; 194: 8-18Crossref PubMed Scopus (440) Google Scholar These transient antibody-secreting cells provide the most immediate source of antigen-specific antibodies and provide rapid protection before the slower GC response is established.14MacLennan I.C. Toellner K.M. Cunningham A.F. Serre K. Sze D.M. Zuniga E. et al.Extrafollicular antibody responses.Immunol Rev. 2003; 194: 8-18Crossref PubMed Scopus (440) Google Scholar Alternatively, antigen-engaged B cells remain localized in B-cell follicles, where they seed GCs. Typically only 1 to 6 clones were found to colonize B-cell follicles, and thus GCs are believed to be of oligoclonal nature in both mice and human subjects.15Jacob J. Kelsoe G. In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. II. A common clonal origin for periarteriolar lymphoid sheath-associated foci and germinal centers.J Exp Med. 1992; 176: 679-687Crossref PubMed Scopus (399) Google Scholar, 16Kuppers R. Zhao M. Hansmann M.L. Rajewsky K. Tracing B cell development in human germinal centres by molecular analysis of single cells picked from histological sections.EMBO J. 1993; 12: 4955-4967PubMed Google ScholarRecruitment of B cells into the plasmablast versus GC pathwayMigration of activated B cells to the distinct microenvironments that support their differentiation into plasma cells or GC B cells is mediated by their differential expression of chemotactic receptors. Pivotal roles in the control of B-cell migration are played by the chemokine receptors CXCR5, CCR7, and CXCR4 and their respective ligands CXCL13, CCL19/21, and CXCL12, which are selectively produced in distinct anatomic regions of secondary lymphoid organs, such as the spleen and lymph nodes (Table I and Fig 1). Naive recirculating B cells express high levels of the chemokine receptor CXCR5 and therefore predominantly respond to its ligand, CXCL13, which is produced by stromal cells in B-cell follicles.17Cyster J.G. Ansel K.M. Reif K. Ekland E.H. Hyman P.L. Tang H.L. et al.Follicular stromal cells and lymphocyte homing to follicles.Immunol Rev. 2000; 176: 181-193Crossref PubMed Scopus (330) Google Scholar, 18Forster R. Mattis A.E. Kremmer E. Wolf E. Brem G. Lipp M. A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen.Cell. 1996; 87: 1037-1047Abstract Full Text Full Text PDF PubMed Scopus (951) Google Scholar As B cells differentiate into plasma cells, they downregulate the chemokine receptor CXCR5 and upregulate CXCR4,10Chan T.D. Gatto D. Wood K. Camidge T. Basten A. Brink R. Antigen affinity controls rapid T-dependent antibody production by driving the expansion rather than the differentiation or extrafollicular migration of early plasmablasts.J Immunol. 2009; 183: 3139-3149Crossref PubMed Scopus (170) Google Scholar events that are critical for their localization in the splenic red pulp and lymph node medullary cords.19Hargreaves D.C. Hyman P.L. Lu T.T. Ngo V.N. Bidgol A. Suzuki G. et al.A coordinated change in chemokine responsiveness guides plasma cell movements.J Exp Med. 2001; 194: 45-56Crossref PubMed Scopus (507) Google Scholar In addition, the expression of the orphan G protein–coupled receptor Epstein-Barr virus-induced gene 2 (EBI2), which is high on naive and recently activated B cells, plays an important role for their migration to the periphery of B-cell follicles, splenic marginal zone bridging channels, and interfollicular regions.20Gatto D. Paus D. Basten A. Mackay C.R. Brink R. Guidance of B cells by the orphan G protein-coupled receptor EBI2 shapes humoral immune responses.Immunity. 2009; 31: 259-269Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar, 21Pereira J.P. Kelly L.M. Xu Y. Cyster J.G. EBI2 mediates B cell segregation between the outer and centre follicle.Nature. 2009; 460: 1122-1126Crossref PubMed Scopus (252) Google Scholar The EBI2-mediated localization of activated B cells to these areas of secondary organs is essential for the generation of robust extrafollicular plasmablast responses.20Gatto D. Paus D. Basten A. Mackay C.R. Brink R. Guidance of B cells by the orphan G protein-coupled receptor EBI2 shapes humoral immune responses.Immunity. 2009; 31: 259-269Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar B cells seeding GCs, on the other hand, retain expression of CXCR5 and downregulate EBI2 expression.20Gatto D. Paus D. Basten A. Mackay C.R. Brink R. Guidance of B cells by the orphan G protein-coupled receptor EBI2 shapes humoral immune responses.Immunity. 2009; 31: 259-269Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar, 21Pereira J.P. Kelly L.M. Xu Y. Cyster J.G. EBI2 mediates B cell segregation between the outer and centre follicle.Nature. 2009; 460: 1122-1126Crossref PubMed Scopus (252) Google Scholar, 22Allen C.D. Ansel K.M. Low C. Lesley R. Tamamura H. Fujii N. et al.Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5.Nat Immunol. 2004; 5: 943-952Crossref PubMed Scopus (537) Google Scholar The low levels of EBI2 on GC B cells compared with the bulk of naive follicular B cells cause their accumulation in the center of B-cell follicles, where GCs originate.20Gatto D. Paus D. Basten A. Mackay C.R. Brink R. Guidance of B cells by the orphan G protein-coupled receptor EBI2 shapes humoral immune responses.Immunity. 2009; 31: 259-269Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar, 21Pereira J.P. Kelly L.M. Xu Y. Cyster J.G. EBI2 mediates B cell segregation between the outer and centre follicle.Nature. 2009; 460: 1122-1126Crossref PubMed Scopus (252) Google Scholar Downregulation of EBI2 on B cells committed to the GC pathway was shown to enable them to access the center of follicles and be required for efficient GC formation.20Gatto D. Paus D. Basten A. Mackay C.R. Brink R. Guidance of B cells by the orphan G protein-coupled receptor EBI2 shapes humoral immune responses.Immunity. 2009; 31: 259-269Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar, 21Pereira J.P. Kelly L.M. Xu Y. Cyster J.G. EBI2 mediates B cell segregation between the outer and centre follicle.Nature. 2009; 460: 1122-1126Crossref PubMed Scopus (252) Google Scholar Thus the regulated responsiveness of activated B cells to chemokines and EBI2 ligand, as mediated by changes in expression of CXCR5, CXCR4, and EBI2, directs the cells to the distinct microenvironments that sustain their differentiation into plasmablasts or GC B cells (Fig 1).Table IChemokine receptors and ligands controlling B-cell migration in secondary lymphoid organsReceptorReceptor expressionLigandSite of ligand productionCXCR5Naive B cells, activated B cells, GC B cellsCXCL13B-cell folliclesCCR7Activated B cellsCCL19, CCL21T-cell zoneCXCR4GC B cells (centroblasts mainly), plasmablasts, plasma cellsCXCL12GC dark zone, splenic red pulp, lymph node medullary cordsEBI2Naive B cells, activated B cells (but not GC B cells), plasmablasts, plasma cells?Perifollicular and interfollicular areas, marginal zone bridging channels Open table in a new tab B-cell differentiation decisions are linked to the migration of activated B cells to distinct regions of secondary lymphoid organs providing environmental clues that sustain their differentiation, but the signals controlling this early bifurcation of B-cell differentiation to plasma cells or GC B cells are not completely understood. Factors that influence the fate of responding B cells include transcriptional control, the availability and quality of T-cell help, and the strength of the B cell receptor-antigen interaction. Indeed, several studies with different experimental systems have indicated that the production of short-lived plasma cells increases with initial B-cell affinity for antigen, whereas B cells carrying a broad range of antigen affinities undergo GC B-cell differentiation.10Chan T.D. Gatto D. Wood K. Camidge T. Basten A. Brink R. Antigen affinity controls rapid T-dependent antibody production by driving the expansion rather than the differentiation or extrafollicular migration of early plasmablasts.J Immunol. 2009; 183: 3139-3149Crossref PubMed Scopus (170) Google Scholar, 23O’Connor B.P. Vogel L.A. Zhang W. Loo W. Shnider D. Lind E.F. et al.Imprinting the fate of antigen-reactive B cells through the affinity of the B cell receptor.J Immunol. 2006; 177: 7723-7732PubMed Google Scholar, 24Paus D. Phan T.G. Chan T.D. Gardam S. Basten A. Brink R. Antigen recognition strength regulates the choice between extrafollicular plasma cell and germinal center B cell differentiation.J Exp Med. 2006; 203: 1081-1091Crossref PubMed Scopus (355) Google ScholarStructure of GCsCentroblasts and centrocytesA classical view of GC organization has emerged from histologic analysis of human tonsils and murine lymphoid tissues (Fig 2). In mature GCs 2 compartments are established, termed the dark zone and light zone on the basis of their histologic appearance, which are surrounded by naive follicular mantle B cells. The dark zone is localized proximal to T-cell areas and contains a high density of large, proliferating B cells with downregulated surface immunoglobulin expression known as centroblasts.3Nieuwenhuis P. Opstelten D. Functional anatomy of germinal centers.Am J Anat. 1984; 170: 421-435Crossref PubMed Scopus (177) Google Scholar, 25MacLennan I.C. Germinal centers.Annu Rev Immunol. 1994; 12: 117-139Crossref PubMed Scopus (1693) Google Scholar At the distal pole lies the light zone, where the density of B cells is lower due to the presence of a follicular dendritic cell (FDC) network. Light-zone B cells, so called centrocytes, are small, nonmitotic B cells expressing surface immunoglobulins.3Nieuwenhuis P. Opstelten D. Functional anatomy of germinal centers.Am J Anat. 1984; 170: 421-435Crossref PubMed Scopus (177) Google Scholar, 25MacLennan I.C. Germinal centers.Annu Rev Immunol. 1994; 12: 117-139Crossref PubMed Scopus (1693) Google Scholar Compartmentalization of GC B cells into dark and light zones is dependent on the differential abundance of the chemokines CXCL12 and CXCL13 in these zones and the regulated expression of CXCR4 on centrocytes and centroblasts.22Allen C.D. Ansel K.M. Low C. Lesley R. Tamamura H. Fujii N. et al.Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5.Nat Immunol. 2004; 5: 943-952Crossref PubMed Scopus (537) Google Scholar Centroblasts express higher levels of CXCR4 than centrocytes, and the ligand of this chemokine receptor, CXCL12, is more abundant in GC dark zones than in light zones. Thus upregulation of CXCR4 on centroblasts drives their localization to GC dark zones. On the other hand, accumulation of CXCR4low centrocytes in GC light zones is mediated by CXCR5 and the high levels of its ligand, CXCL13, present in these areas of GCs.22Allen C.D. Ansel K.M. Low C. Lesley R. Tamamura H. Fujii N. et al.Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5.Nat Immunol. 2004; 5: 943-952Crossref PubMed Scopus (537) Google ScholarFig 2Organization of GCs. A, Histological staining of hen egg lysozyme (HEL)–specific B cells (green) organized into GCs in response to immunization with HEL coupled to sheep red blood cells. Naive follicular mantle B cells are stained with anti-IgD (red), and FDC networks in GC light zones are detected with anti-CD21/35 (blue). DZ, Dark zone; LZ, light zone; T, T-cell area. B, Schematic diagram of the structure of GCs. Centroblasts and centrocytes are organized in GC dark and light zones, and their positioning in the respective compartments is controlled by the chemokine-chemokine receptor pairs CXCL12-CXCR4 and CXCL13-CXCR5. CXCR4 is more abundant on centroblasts than centrocytes, whereas CXCR5 is expressed at similar levels on all GC B cells. FDCs, which display native antigen and express CXCL13, and TFH cells are localized in GC light zones. Interaction of GC B cells with FDCs and TFH cells drives affinity maturation and leads to differentiation of selected GC B cells to memory B cells and long-lived plasma cells.View Large Image Figure ViewerDownload Hi-res image Download (PPT)FDCsFDCs are radio-resistant stromal cells with long processes that form a network occupying much of the GC light zone.17Cyster J.G. Ansel K.M. Reif K. Ekland E.H. Hyman P.L. Tang H.L. et al.Follicular stromal cells and lymphocyte homing to follicles.Immunol Rev. 2000; 176: 181-193Crossref PubMed Scopus (330) Google Scholar Unlike the professional antigen-presenting dendritic cells, FDCs are not derived from hematopoietic precursors and do not express class II MHC molecules. FDCs do, however, trap and retain unprocessed antigen in the form of immune complexes through Fc receptors, such as FcγRIIb (CD32) and FcεRII (CD23), and complement receptors, such as CR1 (CD35), CR2 (CD21), and CR3 (CD11b/CD18).17Cyster J.G. Ansel K.M. Reif K. Ekland E.H. Hyman P.L. Tang H.L. et al.Follicular stromal cells and lymphocyte homing to follicles.Immunol Rev. 2000; 176: 181-193Crossref PubMed Scopus (330) Google Scholar, 26Reynes M. Aubert J.P. Cohen J.H. Audouin J. Tricottet V. Diebold J. et al.Human follicular dendritic cells express CR1, CR2, and CR3 complement receptor antigens.J Immunol. 1985; 135: 2687-2694PubMed Google Scholar Thus they serve as long-term antigen deposits and are generally believed to be important for selection of high-affinity GC B-cell clones, as well as the generation and maintenance of immunologic memory.27Mandel T.E. Phipps R.P. Abbot A. Tew J.G. The follicular dendritic cell: long term antigen retention during immunity.Immunol Rev. 1980; 53: 29-59Crossref PubMed Scopus (293) Google Scholar Interactions between FDCs and GC B cells are facilitated by the high expression of the integrin ligands vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 on FDCs.28Koopman G. Parmentier H.K. Schuurman H.J. Newman W. Meijer C.J. Pals S.T. Adhesion of human B cells to follicular dendritic cells involves both the lymphocyte function-associated antigen 1/intercellular adhesion molecule 1 and very late antigen 4/vascular cell adhesion molecule 1 pathways.J Exp Med. 1991; 173: 1297-1304Crossref PubMed Scopus (249) Google Scholar In addition, FDCs are a major source of CXCL13 in GC light zones, where it accumulates on their processes.17Cyster J.G. Ansel K.M. Reif K. Ekland E.H. Hyman P.L. Tang
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