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García-Valiente, R., Merino Tejero, E., Stratigopoulou, M. et al. Understanding repertoire sequencing data through a multiscale computational model of the germinal center. npj Syst Biol Appl 9, 8 (2023). https://doi.org/10.1038/s41540-023-00271-y
Introduction
B-Cells and T-Cells are two of the most important lymphocytes or white blood cells in the human body. B-Cells produce antibodies for our bodies to destroy toxins and diseases within our body, while T-Cells directly fight against any cancerous or compromised cells. Each of these types of cells has its own receptor attached to it to recognize and bind cells of antigens. Antigens are toxins or foreign substances that may pose threats to the human body; some examples include parasites, pollen, bacteria, or even viruses like the common flu or cold. Arranging for and analyzing all receptors of a population of B-Cells, referred to as a repertoire, allows for a better understanding of the immune response. B-Cell and T-Cell repertoire-sequencing experiments are incredibly important in areas such as vaccinology, infection, and auto-immune disorders, due to their responsibility in antigen detection and control in mammals. Prior to this research, the only understanding of these repertoires was based on their frequency in detecting antigens as threats to an organism’s body, whereas now, computing power and analysis has led to breakthroughs in repertoires’ understanding of antigen specificity and affinity. Antigen specificity refers to the accuracy of the human body in identifying foreign substances, whereas affinity measures the effectiveness of antibodies against an antigen. The key component of this analysis is the newly developed model of the Germinal Center. The Germinal Center is a type of microstructure, similar to a piece of tissue in the human body, and part of the lymphatic organ system that cleans and maintains the human body. It serves as a hub for antibody creation and maturation and also synthesizes and matures B-Cells. Understanding the Germinal Center and its properties gives insight into the abundance and affinity of B-Cells in an organic system, which can anticipate the body’s responses to certain antigens.
Prior Research
Due to the vastness of B-Cells in the human body, most analysis is done with a set of engineered clone cell clusters. Clone cells are synthetic cells made from the remains of B-Cells, which can be easily manipulated and created for mass analysis. Each of these clusters represents a fraction of the hundreds of millions of B-Cells. The clusters can also be engineered to have sub-clone clusters, which offer a smaller, but more accurate representation of a B-Cell cluster’s characteristics. The previous research of this group developed a model of the Germinal Center with clone cell clusters and ordinary differential equations (ODEs), a type of equations used for comparison of rates of B-Cell production. However, the ODE model could not individually analyze clone cells, only focusing on the large clusters, which meant it could only offer general approximations. The model was also limited to focus on results only obtained from the analysis of one type of lymphocyte even though there are several species within the Germinal Center.
The Model
To effectively analyze the clone cells and understand the affinity and antigen recognition of these B-Cell and T-Cell repertoires, the team of researchers developed an extended multiscale model (eMS) for the Germinal Center, a system that incorporates multiple separate simulations across various scales. The group’s research aims to form a generalization of the germinal center functions by running simulations with the eMS to confirm its accuracy and any relationship between the number of clone cells and their affinity. The new eMS was built from the foundation of the previous model and its Germinal Center design, while being simultaneously upgraded to include a larger breadth of B-Cells and improve the efficiency at which it analyzed the receptors’ interactions. The newly developed model tracks the frequencies and affinities of all clones and sub-clones of B-Cells, a major flaw in the previous differential equations model. After nine simulations on DNA and RNA-based repertoires, the derived theoretical data was matched with experimental data and confirmed the accuracy of the eMS model. A weakness that the research team hopes to improve on is that the model only provided a generalization for bodily immune response, meaning that it is currently unable to visualize the repertoire’s reaction to a specific antigen and its conditions.
Findings and Future Research
The model’s predictions on the number of clones match with previous studies, but it was the affinity of the simulated antibodies that proved so revolutionary with this research. Their simulations confirmed their idea that there was a relationship between the amount of B-Cells and their respective affinity, essentially demonstrating that repertoires are more effective with an abundance of antibodies. The group’s research also serves as a key step into the future of studying the germinal center. New efforts to validate the model include developing a single-cell approach to the generation of germinal centers, which would offer a broader understanding of B-Cells, and capture the true diversity of these lymphocytes. As technical and computing power grows, the understanding of biology and its millions of microscopic cells only gets larger.
Summarised by Romir Mohan
Works Cited:
Doria-Rose NA, Joyce MG. Strategies to guide the antibody affinity maturation process. Curr Opin Virol. 2015 Apr;11:137-47. doi: 10.1016/j.coviro.2015.04.002. Epub 2015 Apr 24. PMID: 25913818; PMCID: PMC4456294.
Stebegg, Marisa, et al. “Regulation of the Germinal Center Response.” Frontiers, Frontiers, 5 Oct. 2018, https://www.frontiersin.org/articles/10.3389/fimmu.2018.02469/full.
Shlesinger, Danielle, et al. “Single-Cell Immune Repertoire Sequencing of B and T Cells in Murine Models of Infection and Autoimmunity.” 2022, https://doi.org/10.1101/2022.02.07.479381.
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