title: A one-shot germinal center model under protein structural stability constraints.
abstract: The germinal center reaction is the process by which low-affinity B cells evolve into potent, immunoglobulin-secreting plasma and memory B cells. Since the recycling hypothesis was created, experimental studies have both tracked movement of a small population of B cells from the light zone into the dark zone, supporting the recycling model, and parallel to the light zone-dark zone interface, indicating a one-way trajectory. We present a novel, sequence-based ab initio model of protein stability and protein interactions. Our model contains a dark zone region of clonal expansion and somatic hypermutation and a light zone site of antigenic selection. We show not only that a one-shot model is sufficient to achieve biologically-realistic rates of affinity growth, population dynamics, and silent:non-silent mutation ratios in the complementary determining region and framework region of antibodies, but also that a stochastic recycling program with or without realistic constraints on the structural stabilities of GC antibodies cannot produce biologically-observed affinity growth, population dynamics or silent:non-silent mutation profiles. The effect of recycling erases affinity gains made by potent antibodies cycling back from the light zone and causes B cells to pool in the dark zone under high replication rates.
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Sana
authors.initials: S
authors.lastname: Raoof
authors.forename: Muyoung
authors.initials: M
authors.lastname: Heo
authors.forename: Eugene I
authors.initials: EI
authors.lastname: Shakhnovich
mesh_terms: D000906:Antibodies / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D000915:Antibody Affinity; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000737:chemistry / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D003198:Computer Simulation; D018858:Germinal Center / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D018448:Models, Immunological; D009154:Mutation; D059645:Mutation Rate; D011487:Protein Conformation; D055550:Protein Stability
chemical_list: D000906:Antibodies