 | This articleneeds additional citations forverification. Please helpimprove this article byadding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Germinal center" – news ·newspapers ·books ·scholar ·JSTOR(May 2016) (Learn how and when to remove this message) |
| Germinal center | |
|---|---|
 Germinal center of a lymph node showing proliferation and development stages of a B cell. | |
| Identifiers | |
| MeSH | D018858 |
| 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 cells are activated, proliferate, differentiate, and mutate theirantibody genes (throughsomatic hypermutation aimed 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 cells by 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 signaling and expression ofIRF4 andBCL6.[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) cells in 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 matured B cells specialized in producing improved antibodies that effectively recognize antigen (e.g. infectious agents), and for the production oflong-lived plasma cells and durablememory B cells.
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 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 ligand with theB cell CD40 molecule, which causes asignaling cascade that is beneficial for the survival and proliferation of B cells. B cell receptor activation results in the activation of theNF-kB signaling 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 haveIgM andIgD constant regions, but they are later able to exchange these constant regions forIgA,IgG orIgE constant regions and express antibodies of a different class type via class switch recombination.Class switch recombination occurs 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]
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]
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 cells that 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 hypermutation and 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 B cell receptors that have decreased affinity for the antigen following somatic hypermutation undergoapoptosis, while B cells expressing B cell receptors that have increased affinity for the antigen after somatic hypermutation migrate to the light zone for further selection.[4]
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 MHC and 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]
There areT helper cells in 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 theCD40 molecule 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 cytokine which serves as a signal for GC B cells to proliferate and for the creation of plasma cells with long life spans.[3][5]
Following positive selection, there are three possible fates for B cells undergoing the germinal center reaction: become aplasma cell, become amemory B cell or enter into the dark zone of the germinal center.[4][6] The processes initiating each of these three fates are described below:
The GC B cells that differentiate intoplasma cells are 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]
The GC B cells that differentiate intomemory B cells are 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]
Any B cells that were positively selected in the light zone of the germinal center, but that did not differentiate intoplasma cells ormemory B cells are 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 byFoxO1 andcyclin 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]
Themorphology of GCs is very specific and shows properties which are characteristic for different stages of the reaction.
As germinal centers are important structures of theadaptive immune system, their deregulation is implied in many immune diseases, for examplerheumatoid arthritis,immunodeficiency and manylymphomas likeDLBCL andBurkitt's lymphoma.
Despite thatV(D)J recombination is 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-affinityAb and 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]
{{cite journal}}: CS1 maint: date and year (link)