Germinal center

Source: Wikipedia, the free encyclopedia.
(Redirected from
Germinal centre
)

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

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[1] – where mature B cells are activated, proliferate, differentiate, and mutate their antibody genes (through somatic hypermutation aimed at achieving higher affinity) during a normal immune response; most of the germinal center B cells (BGC) are removed by tingible 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 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.[4]

GC B cells cycle through the two distinct zones of the germinal center: the light zone and the dark zone.

memory B cells
.

Naive B cells vs. germinal center 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 of

fatty acid oxidation, while naive B cells depend on glycolysis.[3]

Germinal center initiation

Germinal centers are initiated in the B cell follicle of the

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]

Two distinct germinal center zones: dark zone and light zone

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

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 and reticular cells that resemble follicular dendritic cells.[3] The B cells within the dark zone of the germinal center are called centroblasts.[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 the activation-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] After somatic 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 antibodies that have decreased affinity for the antigen following somatic hypermutation undergo apoptosis, 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

The light zone consists of GC B cells and

cMyc, 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 by somatic hypermutation.[6]
   

Process

lymphoid follicle
, showing dark, light, mantle and marginal zones
Follicular dendritic cells
have round nuclei, centrally located nucleoli, bland and dispersed chromatin, and flattening of adjacent nuclear membrane.
  1. Within lymph nodes, mature peripheral B cells known as follicular (Fo) B cells acquire antigen from FDCs and in turn present it to cognate CD4+ TFH cells at 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 through
    clones in 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 of affinity 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 as
    affinity of 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 as centroblasts allows 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 producing plasma cell which are cells that secrete large quantities of antibody or a memory B cell that 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

There are

CD40L, which is a tumor necrosis factor (TNF) cytokine that binds the CD40 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 the IL-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]
 

The fates of positively-selected germinal center B cells

Following positive selection, there are three possible fates for B cells undergoing the germinal center reaction: become a plasma cell, become a memory 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:

Plasma cell differentiation

The GC B cells that differentiate into plasma 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 the bone marrow.[5]

Memory B cell differentiation

The GC B cells that differentiate into memory 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 called hematopoietically-expressed homeobox protein (Hhex) that drives differentiation of memory B cells from GC B cells.[6]

Entering the dark zone of the germinal center

Any B cells that were positively selected in the light zone of the germinal center, but that did not differentiate into

FoxO1 and cyclin 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

The morphology of 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

As germinal centers are important structures of the

Burkitt's lymphoma
.

Germinal centers in evolution

Despite that

vertebrates, GC appeared in homeothermic 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-affinity Ab and maintaining long-lasting humoral immune memory.[10]

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

See also

References

  1. PMID 18024632
    .
  2. PMID 24315719
    .
  3. ^
    ISSN 0732-0582
    .
  4. ^
    PMID 33868306
    .
  5. ^
    PMID 32132626
    .
  6. ^
    ISSN 0952-7915
    .
  7. S2CID 83999556
    .
  8. S2CID 2141888
    .
  9. doi:10.4049/jimmunol.172.6.3369
    .
  10. doi:10.1146/annurev-immunol-051116-052510
    .
  11. PMID 36569890.{{cite journal}}: CS1 maint: date and year (link
    )

External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=Germinal_center&oldid=1211565672"