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Editor-in-ChiefEnzyme antibody is an important part of humoral immunity
.
For some pathogens and antigens, the neutralizing and non-neutralizing antibodies that can be directly produced by naive B cells can already play a sufficiently strong protective effect
.
However, for most pathogens, complex glycosylation and high mutation rates on the pathogen surface lead to high frequency of antibody escape
.
There is no initial antibody library that can efficiently cover specific antibodies against all pathogens, so B cells are required to improve protective efficacy through antibody affinity maturation
.
B cells complete the process of antibody affinity maturation through continuous somatic hypermutation (SHM) and clonal screening in the germinal centre of the secondary lymphatic system
.
One of the recent research hotspots is the forward screening mechanism of affinity in germinal centers
.
A more popular model over the past 25 years is that germinal center B cells require affinity-based competition for cyclic reentry each time they enter the bright zone
.
Cyclic reentry is defined as cells in the bright zone restarting the cell cycle (entering S phase from G1) and then migrating to the dark zone
.
70%-90% of cells in the bright zone fail this screening node and subsequently undergo apoptosis
.
The forward screening process of cells in the bright zone may occur during their interaction with TFH cells, because the current forward screening model assumes that TFH will give the highest affinity cells enough help/stimulation to encourage these cells to enter the bright zone every time.
Cyclic cell cycle restart is performed after the zone
.
However, this model cannot perfectly explain all phenomena: sometimes a screening mechanism that is too focused on antibody affinity may risk biasing the antibody response to certain high expression sites, which are not necessarily pathogenic sites weakest spot
.
A typical example is that antibody repertoires targeting HIV's conserved neutralizing sites often have very low affinity, and large-scale SHMs are required to accumulate all affinity-improving mutations
.
At the same time, it was found in recent new coronavirus research that if not targeting several sites on the virus at the same time, the virus is likely to develop mutations that can escape neutralizing antibodies
.
So expansion of high-affinity cells should not come at the expense of loss of antibody epitope diversity
.
At the same time, the comparative study of germinal center single-cell antibody affinity demonstrated that GC tolerated cells with a certain low affinity
.
These phenomena are difficult to explain with a screening mechanism that only targets antibody affinity
.
Recently, Oliver Bannard's laboratory of MRC Human Immunology at Oxford University published a paper in Science Immunology entitled: Competition for refueling rather than cyclic reentry initiation evident in germinal centers, which explored the screening mechanism of B cells in germinal centers.
The metabolic restart and cell cycle restart experienced by B cells are independent regulatory processes that work together to promote their positive screening process
.
Starting from several assumptions of the cycle reentry model, the authors applied a cell cycle fluorescent reporter gene mouse line (R26p-Fucci2) to track the first step of cell cycle restart (from G1 to S phase) in real-time cells in the bright zone
.
First of all, the experiment proved that TFH cells do not need immediate assistance in the process of reentry initiation
.
Using the SWHEL model, it was demonstrated that whether germinal center B cells acquire TFH cell-stimulated activation depends on the affinity of the antibodies they express
.
Indiscriminately knocking out a large number of germinal center B cells or increasing the number of antigens in them will lead to an increase in the proportion of TFH activation in the remaining bright zone cells (there will be high expression of BATF), proving that this process is also subject to competition between B cells.
and limit the number of antigens
.
The study demonstrated that the two processes of cell cycle restart initiation and TFH-dependent restart of B cell metabolism are independent of each other
.
Metabolic restart may involve various biochemical pathways that maintain the dark-zone phenotype
.
The level of stimulation is based on the affinity of the antibody expressed by the B cells and the amount of antigen in the germinal center environment
.
This not-so-black-and-white selection mechanism allows antibodies with different affinities to evolve together without overly suppressing the development potential of each other
.
Link to the original text: Publisher: 11th reprint notice [Non-original article] The copyright of this article belongs to the author of the article, and personal sharing is welcome.
Reprinting is prohibited without permission.
The author owns all legal rights, and violators will be prosecuted
.
.
For some pathogens and antigens, the neutralizing and non-neutralizing antibodies that can be directly produced by naive B cells can already play a sufficiently strong protective effect
.
However, for most pathogens, complex glycosylation and high mutation rates on the pathogen surface lead to high frequency of antibody escape
.
There is no initial antibody library that can efficiently cover specific antibodies against all pathogens, so B cells are required to improve protective efficacy through antibody affinity maturation
.
B cells complete the process of antibody affinity maturation through continuous somatic hypermutation (SHM) and clonal screening in the germinal centre of the secondary lymphatic system
.
One of the recent research hotspots is the forward screening mechanism of affinity in germinal centers
.
A more popular model over the past 25 years is that germinal center B cells require affinity-based competition for cyclic reentry each time they enter the bright zone
.
Cyclic reentry is defined as cells in the bright zone restarting the cell cycle (entering S phase from G1) and then migrating to the dark zone
.
70%-90% of cells in the bright zone fail this screening node and subsequently undergo apoptosis
.
The forward screening process of cells in the bright zone may occur during their interaction with TFH cells, because the current forward screening model assumes that TFH will give the highest affinity cells enough help/stimulation to encourage these cells to enter the bright zone every time.
Cyclic cell cycle restart is performed after the zone
.
However, this model cannot perfectly explain all phenomena: sometimes a screening mechanism that is too focused on antibody affinity may risk biasing the antibody response to certain high expression sites, which are not necessarily pathogenic sites weakest spot
.
A typical example is that antibody repertoires targeting HIV's conserved neutralizing sites often have very low affinity, and large-scale SHMs are required to accumulate all affinity-improving mutations
.
At the same time, it was found in recent new coronavirus research that if not targeting several sites on the virus at the same time, the virus is likely to develop mutations that can escape neutralizing antibodies
.
So expansion of high-affinity cells should not come at the expense of loss of antibody epitope diversity
.
At the same time, the comparative study of germinal center single-cell antibody affinity demonstrated that GC tolerated cells with a certain low affinity
.
These phenomena are difficult to explain with a screening mechanism that only targets antibody affinity
.
Recently, Oliver Bannard's laboratory of MRC Human Immunology at Oxford University published a paper in Science Immunology entitled: Competition for refueling rather than cyclic reentry initiation evident in germinal centers, which explored the screening mechanism of B cells in germinal centers.
The metabolic restart and cell cycle restart experienced by B cells are independent regulatory processes that work together to promote their positive screening process
.
Starting from several assumptions of the cycle reentry model, the authors applied a cell cycle fluorescent reporter gene mouse line (R26p-Fucci2) to track the first step of cell cycle restart (from G1 to S phase) in real-time cells in the bright zone
.
First of all, the experiment proved that TFH cells do not need immediate assistance in the process of reentry initiation
.
Using the SWHEL model, it was demonstrated that whether germinal center B cells acquire TFH cell-stimulated activation depends on the affinity of the antibodies they express
.
Indiscriminately knocking out a large number of germinal center B cells or increasing the number of antigens in them will lead to an increase in the proportion of TFH activation in the remaining bright zone cells (there will be high expression of BATF), proving that this process is also subject to competition between B cells.
and limit the number of antigens
.
The study demonstrated that the two processes of cell cycle restart initiation and TFH-dependent restart of B cell metabolism are independent of each other
.
Metabolic restart may involve various biochemical pathways that maintain the dark-zone phenotype
.
The level of stimulation is based on the affinity of the antibody expressed by the B cells and the amount of antigen in the germinal center environment
.
This not-so-black-and-white selection mechanism allows antibodies with different affinities to evolve together without overly suppressing the development potential of each other
.
Link to the original text: Publisher: 11th reprint notice [Non-original article] The copyright of this article belongs to the author of the article, and personal sharing is welcome.
Reprinting is prohibited without permission.
The author owns all legal rights, and violators will be prosecuted
.
