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Germinal center

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Germinal center
Germinal center of a lymph node showing proliferation and development stages of a B cell.
Identifiers
MeSHD018858
Anatomical terminology

Germinal centersorgerminal centres(GCs) are transiently formed structures within B cell zone (follicles) insecondary lymphoid organs–lymph nodes,ilealPeyer's patches,and thespleen[1]– where matureB cellsare activated, proliferate, differentiate, and mutate theirantibodygenes (throughsomatic hypermutationaimed at achieving higher affinity) during a normal immune response; most of the germinal center B cells (BGC) are removed bytingible body macrophages.[2]There are several key differences between naive B cells and GC B cells, including level of proliferative activity, size, metabolic activity and energy production.[3]The B cells develop dynamically after the activation offollicular B cellsby T-dependentantigen.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 signalingand expression ofIRF4andBCL6.[4]

GC B cells cycle through the two distinct zones of the germinal center: the light zone and the dark zone.[3][4][5][6]As they undergo rapid and mutative cellular division, B cells of the germinal center's dark zone are known ascentroblasts.Once these B cells have stopped proliferating in the dark zone and moved to the light zone, they are known ascentrocytes,and are subjected to selection byfollicular helper T (TFH) cellsin the presence offollicular dendritic cells(FDCs).[3][4][5][6]There are three possible fates for GC B cells that have been positively selected in the light zone: plasma cell, memory B cell or B cell licensed to return to the dark zone for proliferation and mutation.[4][6]These three fates are achieved via the distinct mechanisms described below. Germinal centers are an important part of the B cellhumoral immune response,acting as central factories for the generation ofaffinity maturedB cells specialized in producing improved antibodies that effectively recognize antigen (e.g. infectious agents), and for the production oflong-lived plasma cellsand durablememory B cells.

Naive B cells vs. germinal center B cells

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There are several key differences between naive B cells and GC B cells. Naive B cells do not undergo lots of cell division. On the other hand, B cells in GC tend to divide rapidly and frequently, and they can have cell cycles as short as only five hours. As a result of their highly proliferative quality, GC B cells are larger in size and are more metabolically active, as compared to naive B cells. Although GC B cells have a greater energy demand than naive B cells, they mainly produce energy by the process offatty acid oxidation,while naive B cells depend onglycolysis.[3]

Germinal center initiation

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Germinal centers are initiated in the B cell follicle of thelymph node.Following activation of naive B cells in the lymph node follicles, the B cells migrate to the interfollicular areas so that they can interact with T cells. When the B and T cells interact, the antigen-specific T cell receptors bind the antigen + MHC presented by the B cells. Additionally, the T cells are able to help the B cells by the interaction of the T cellCD40 ligandwith theB cell CD40 molecule,which causes asignaling cascadethat is beneficial for the survival and proliferation of B cells. B cell receptor activation results in the activation of theNF-kBsignaling pathway, which is essential for the initiation of the germinal center reaction. Specifically, the expression of IRF4 and BCL6 transcription factors are both required for germinal center development and regulated by NF-kB signaling. For example, BCL6 controls the location of B cells in the lymph node and allows them to have a higher tolerance to DNA damage, thus promoting the proliferation of GC B cells. All B cells begin by co-expressing antibodies that haveIgMandIgDconstant regions, but they are later able to exchange these constant regions forIgA,IgGorIgEconstant regions and express antibodies of a different class type via class switch recombination.Class switch recombinationoccurs during the germinal center initiation phase. The precursors of germinal center B cells start to expand four days following immunization and polarize into dark zones and light zones a week after immunization.[4]

Two distinct germinal center zones: dark zone and light zone

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There are two distinct regions of the germinal center: the light zone (LZ) and the dark zone (DZ).[3][4][5][6]These two zones are formed from pre-GC B cells that proliferate and polarize seven days following immunization.[3][4]GC B cells alternate between the dark zone and the light zone and undergo several rounds of mutation and selection, respectively.[5][6]

Dark zone

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The dark zone of the germinal center is proximal to the T cell zone in the lymph node, and it consists of GC B cells andreticular cellsthat resemblefollicular dendritic cells.[3]The B cells within the dark zone of the germinal center are calledcentroblasts.[3]They are larger than the cells in the light zone of the germinal center and are more proliferative (i.e. undergo more cell division).[3][5]Somatic hypermutation,a process in which theactivation-induced cytidine deaminase(AID) enzyme randomly mutates the variable regions of the antibody and alters their affinity for the antigen, occurs in the dark zone.[3][4][5][6]Additionally, B cells that were positively selected in the light zone because they express B cell receptors with high affinity for the antigen proliferate extensively in the dark zone, which is a process called clonal expansion.[3][6]Aftersomatic hypermutationand before entering the light zone, the old B cell receptors on the surfaces of the B cells are replaced with the new, mutated B cell receptors.[4]B cells expressing antibodies that have decreased affinity for the antigen following somatic hypermutation undergoapoptosis,while B cells expressing antibodies that have increased affinity for the antigen after somatic hypermutation migrate to the light zone for further selection.[4]

Light zone

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The light zone consists of GC B cells andT follicular helper cells.[3]It is proximal to the lymph node and near the network offollicular dendritic cells.[3]The GC B cells in the light zone, known ascentrocytes,are smaller, less abundant and divide less as compared to the GC B cells in the dark zone.[3][4][5]The nearby follicular dendritic cells present the antigen to the light zone GC B cells that were mutated in the dark zone previously, and those with the highest affinity for the antigen are able to bind and receive help from T follicular helper cells that have T cell receptors specific for the same antigen.[3][4][5][6]Therefore, the GC B cells in the light zone compete for antigen and stimulation by T follicular helper cells.[3][4][5][6]The mechanism by which this occurs is that, when the B cell receptor binds the antigen presented by the follicular dendritic cells, the antigen is internalized. Then the antigen is bound byclass II MHCand presented on the surface of the T cell, which allows the B cell to be helped by the T follicular helper cell.[6]GC B cells that are best able to present antigen to T follicular helper cells and produce the strongest B cell receptor signal are positively selected in the light zone of the germinal center.[4]Therefore, positive selection of GC B cells in the light zone results in B cells that express antibodies with high affinity for the antigen.[3]The B cells that are positively selected in the light zone begin to expresscMyc,which regulates the germinal center and the proliferation of the B cells in the germinal center.[3]Finally, the positively-selected GC B cells (cMyc+) are "licensed," which means they are ready to be sent back to the dark zone of the germinal center where they will further proliferate and be mutated bysomatic hypermutation.[6]

Process

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Histology of a normal secondarylymphoid follicle,showing dark, light, mantle and marginal zones
Histologic comparison of cell types in a germinal center, H&E stain:
-Centrocytesare small to medium size with angulated, elongated, cleaved, or twisted nuclei.
-Centroblastsare larger cells containing vesicular nuclei with one to three basophilic nucleoli apposing the nuclear membrane.
-Follicular dendritic cellshave round nuclei, centrally located nucleoli, bland and dispersed chromatin, and flattening of adjacent nuclear membrane.
  1. Within lymph nodes, mature peripheral B cells known asfollicular (Fo) B cellsacquire antigen fromFDCsand in turn present it to cognateCD4+TFHcellsat the border that demarcates the interfollicular T cell area and B cell zone (also known as lymphoid follicles).
  2. After several rounds of cellular division, the B cells go throughsomatic hypermutation,a process by which they mutate theirantibody-encodingDNAand thus generate a diversity ofclonesin the germinal center. This involves pseudo-random substitutions biased towards regions encoding the antigen recognition surface of the antibodies the B cells produce. This phenomenon underscores the process ofaffinity maturation,whereby greater affinity antibodies are produced and selected for after antigen recognition.
  3. Upon receiving an unidentified stimulus, the maturing B cells (centroblasts) migrate from the dark zone to the light zone and start to express their edited BCRs on the cell surface and at this stage are referred to ascentrocytes.The centrocytes are in a state ofactivatedapoptosisand compete for survival signals derived from FDCs andTFHcells.This rescue process, known as germinal center selection, is believed to be dependent on theaffinityof their surface antibody to the antigen. Such that, a B cell that has successfully gained mutations that confer a higher affinity surface antibody towards antigen gains a survival advantage over lower affinity B cell clones and those that have gained deleterious mutations. Cyclic re-entry into the dark zone once again ascentroblastsallows a chance for otherwise non-selected B cell mutants to gain more mutations in order to improve affinity towards antigen. Interactions with T cells are also believed to prevent the generation of autoreactive germinal center B cells.[7]
  4. At some unclear stage of their centroblast-centrocyte cycling, maturing B cells receive a final differentiation signal to exit the germinal center as an antibody producingplasma cellwhich are cells that secrete large quantities of antibody or amemory B cellthat can be reactivated in subsequent contacts with the same antigen. Selected B cells may also restart the whole cycle of mutative centroblast division and centrocyte selection. In this way the adaptive immune system, in part through these germinal center reactions, can gradually better recognize antigens over time.

The role of T follicular helper cells in the germinal center

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There areT helper cellsin the follicles of the lymph nodes called T follicular helper cells that promote germinal center formation and the differentiation of GC B cells into plasma cells and memory B cells.[5]T follicular helper cells mediate the germinal center reaction in two key ways. First, T follicular helper cells expressCD40L,which is atumor necrosis factor(TNF) cytokine that binds theCD40molecule expressed on GC B cells. This interaction upregulates the NF-kB signaling pathway, which stimulates the division of GC B cells. Second, T follicular helper cells secrete theIL-21 cytokinewhich serves as a signal for GC B cells to proliferate and for the creation of plasma cells with long life spans.[3][5]

The fates of positively-selected germinal center B cells

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Following positive selection, there are three possible fates for B cells undergoing the germinal center reaction: become aplasma cell,become amemory B cellor enter into the dark zone of the germinal center.[4][6]The processes initiating each of these three fates are described below:

Plasma cell differentiation

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The GC B cells that differentiate intoplasma cellsare B cells that show high affinity for the antigen.[3][6]When GC B cells receive help from T follicular helper cells, there is an interaction between CD40 (expressed on the B cell) and CD40L (expressed on the T follicular helper cell), which increases the activation of NF-kB in the B cell. The upregulation of the NF-kB signaling pathway results in greater expression of IRF4, a transcription factor that is essential for plasma cell differentiation.[6]The progression of the germinal center response results in plasma cells that secrete higher affinity antibodies having an increased lifespan and being sent to thebone marrow.[5]

Memory B cell differentiation

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The GC B cells that differentiate intomemory B cellsare distinct from plasma cell precursors, as they show lower affinity for the antigen[3][6]and do not need much help from T follicular helper cells. Because of this, many scientists believe that memory B cell precursors are B cells from the light zone that were "non-positively selected." Memory B cell precursors express a transcription factor calledhematopoietically-expressed homeobox protein (Hhex)that drives differentiation of memory B cells from GC B cells.[6]

Entering the dark zone of the germinal center

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Any B cells that were positively selected in the light zone of the germinal center, but that did not differentiate intoplasma cellsormemory B cellsare sent to the dark zone of the germinal center for further proliferation. These are the B cells that had intermediate affinity for the antigen.[3]The dark zone proliferation program is regulated byFoxO1andcyclin D3.These two genes are down-regulated by strong BCR signals. Therefore, when there are weak BCR signals and the GC B cell does not have high affinity for the antigen, it will be sent to the dark zone of the germinal center so that it can continue to divide rather than being secreted as a plasma cell or a memory B cell.[6]

Morphology at different stages

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Themorphologyof GCs is very specific and shows properties which are characteristic for different stages of the reaction.

  • In an early state of the reaction a network of FDCs is fully filled with proliferating B cells.
  • Later at day 4 of the reaction, GCs show a separation of two zones, the dark and the light zone.[8]The former still contains dominantly proliferating and mutating B cells while the latter one is the area of B cell selection.
  • These zones dissolve after 10 days of GC development which ends after about 3 weeks.

Medical relevance

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As germinal centers are important structures of theadaptive immune system,their deregulation is implied in many immune diseases, for examplerheumatoid arthritis,immunodeficiencyand manylymphomaslikeDLBCLandBurkitt's lymphoma.

Germinal centers in evolution

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Despite thatV(D)J recombinationis observed in allvertebrates,GC appeared inhomeothermic animals.Under evolutionary new conditions, when elevated body temperature contributed to the increased rates of microorganism proliferation, dissemination in tissues, and their antigenic diversification[9] , these temporary but constantly observed histological structures turned to be beneficial as their unique microenvironment could provide the conditions favourable for the shift from the initial broad to subsequent specific immune response resulting in B lineage cells differentiated to those producing high-affinityAband maintaining long-lasting humoral immune memory.[10]

Among cold-blooded vertebrates, fish seem have functionally analogous structures represented by "clusters ofAicda+cells encircled by pigmented 'melano-macrophages' ".[11]

See also

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References

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  1. ^Natkunam Y(1 January 2007)."The biology of the germinal center".Hematology. American Society of Hematology. Education Program.2007:210–215.doi:10.1182/asheducation-2007.1.210.PMID18024632.
  2. ^Aguzzi A, Kranich J, Krautler NJ (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.PMID24315719.
  3. ^abcdefghijklmnopqrstuvVictora, Gabriel D.; Nussenzweig, Michel C. (26 April 2022)."Germinal Centers".Annual Review of Immunology.40(1): 413–442.doi:10.1146/annurev-immunol-120419-022408.ISSN0732-0582.
  4. ^abcdefghijklmnoKennedy, Domenick E.; Clark, Marcus R. (31 March 2021)."Compartments and Connections Within the Germinal Center".Frontiers in Immunology.12.doi:10.3389/fimmu.2021.659151.ISSN1664-3224.PMC8045557.PMID33868306.
  5. ^abcdefghijklChoi, Seung-Chul; Morel, Laurence (March 2020)."Immune metabolism regulation of the germinal center response".Experimental & Molecular Medicine.52(3): 348–355.doi:10.1038/s12276-020-0392-2.ISSN2092-6413.PMC7156389.PMID32132626.
  6. ^abcdefghijklmnopqLau, Angelica WY; Brink, Robert (1 April 2020)."Selection in the germinal center".Current Opinion in Immunology.Lymphocyte development and activation.63:29–34.doi:10.1016/j.coi.2019.11.001.ISSN0952-7915.
  7. ^Thorbecke GJ, Amin AR, Tsiagbe VK (August 1994)."Biology of germinal centers in lymphoid tissue".FASEB Journal.8(11): 832–840.doi:10.1096/fasebj.8.11.8070632.PMID8070632.S2CID83999556.
  8. ^Meyer-Hermann M (June 2002). "A mathematical model for the germinal center morphology and affinity maturation".Journal of Theoretical Biology.216(3): 273–300.arXiv:physics/0203021.Bibcode:2002JThBi.216..273M.doi:10.1006/jtbi.2002.2550.PMID12183119.S2CID2141888.
  9. ^Manser, Tim (15 March 2004)."Textbook Germinal Centers?".J Immunol.172(6): 3369–3375.doi:10.4049/jimmunol.172.6.3369.
  10. ^Brink, R.; Phan, T. G. (2018). "Self-Reactive B Cells in the Germinal Center Reaction".Annual Review of Immunology.36:339–357.doi:10.1146/annurev-immunol-051116-052510.
  11. ^Waly, D.; Muthupandian, A.; Fan, C. W.; Anzinger, H.; Magor, B. G. (8 December 2022)."Immunoglobulin VDJ repertoires reveal hallmarks of germinal centers in unique cell clusters isolated from zebrafish (Danio rerio) lymphoid tissues".Frontiers in Immunology.13:1058877.doi:10.3389/fimmu.2022.1058877.PMC9772432.PMID36569890.{{cite journal}}:CS1 maint: date and year (link)
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