Lack of class switching in Germinal Centers
Class switch recombination describes the switching of one isotype of B cell to another one by replacement of the immunoglobulin heavy chain, resulting in production of antibody particularly suited for specific tasks. This process, driven by various enzymes that induce recombination within the heavy-chain gene locus, was generally considered to be a central property of Germinal Center (GC) B cells. However, multiple lines of evidence generated by experimental collaborators across several continents independently challenge that view by analyzing switch transcripts and phylogenetic trees of B cells within GCs, indicating that the isotype switching is unlikely to be a relevant and continued process during affinity maturation. Computer simulations based on an agent-based model developed in our department support this view. To that end, a large number of GC simulations was generated and each of these in silico GCs was characterized in terms of the fractions of different B cell isotypes at a late time point in the GC reaction. Several hypotheses including ongoing isotype switching, time-restricted switching in short time intervals, and dynamic downregulation of the switching probability were tested. Statistical analyses revealed that an ongoing, constant switching process throughout the GC reaction is incompatible with the experimentally observed distribution of B cell isotypes and that switching within the GC is unlikely to occur after the very onset of a GC.
Philippe Robert (former member), Michael Meyer-Hermann
Carola Vinuesa (Australian National University), Michael Dustin (Oxford University), Gabriel Victora (Rockefeller University), Kai Toellner (University of Birmingham)
Roco JA, Mesin L, Binder SC, Nefzger C, Gonzalez-Figueroa P, Canete PF, Ellyard J, Shen Q, Robert PA, Cappello J, Vohra H, Zhang Y, Schiepers A, Toellner K-M, Polo J, Meyer-Herman M, Victora G, Vinuesa CG. Determining the timing and location of class switch recombination during T-dependent immune responses. Immunity 2019 Aug 20; 51: 337-350.
He J-S, Meyer-Hermann M, Xiangying D, Zuan LY, Jones LA, Ramakrishna L, de Vries VC, Dolpady J, Aina H, Joseph S, Narayanan S, Subramaniam S, Puthia M, Wong G, Xiong H, Poidinger M, Urban JF, Lafaille JJ, Curotto de Lafaille MA. The distinctive germinal center phase of IgE+ B lymphocytes limits their contribution to the classical memory response. J Exp Med 210 (2013) 2755-2771.
Human Frontier Science Program
- System-Immunologie- Prof. Dr. Michael Meyer-Hermann