Antibody responses

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Jaber Dehghany

Michael Meyer-Hermann

Alexey Uvarovskii

Scientific context:

Adaptive immune responses to pathogenic challenges can be subdivided into cellular and humoral immunity. The latter is associated with the production of specific antibodies that support and guide the immune response by opsonation of the antigen and by signalling to other immune effectors. High affinity antibodies are generated in lymphoid organs in a unique evolutionary process of B lymphocytes denoted as germinal centre reaction. B cells diversify and optimise their encoded antibody by division, mutation, competitive selection, and generation of high affinity antibodies for efficient elimination of a particular pathogen. However, the induction of humoral immune responses is not only beneficial but is also associated with autoimmunity (rheumatoid arthritis, multiple sclerosis, etc.) and graft rejection after transplantation. We want to understand the mechanisms of germinal centre induction, B cell selection and differentiation, and germinal centre shutdown.


Selected germinal centre B cells recycle to a re-dividing phenotype

During a germinal centre reaction B cells divide and mutate their encoded B cell receptor. Subsequently, B cells are selected based on the affinity of the receptor to the antigen that initiated the response. It was hypothesised by theoretical predictions from the Perelson group (Los Alamos, USA) in 1993 that B cells have to undergo several rounds of mutation and selection in order to identify high-affinity clones, which was further on associated with the term “recycling of B cells”. In cooperation with Andreas Deutsch (Dresden, Germany), we have predicted with a mathematical model that recycling is the dominant fate of selected B cells. Only in 2010 a direct proof of the recycling of B cells was provided by photoactivation experiments of Gabrial Victora (Cambridge, USA). This result is an example of how theoretical concepts can shape experimental research and is critical for understanding the evolutionary process of generation of high-affinity antibodies.

Photoactivation of B cells in the germinal centre light zone in silico (upper) and in vivo (lower). Within 6 hours a proportion of cells transmigrate to the dark zone located at the lower half of the…

  • Victora GD, Schwickert TA, Fooksman DR, Meyer-Hermann M, Dustin ML, Nussenzweig MC. Germinal center selection mechanism revealed by multiphoton microscopy using a photoactivatable fluorescent reporter. Cell 143 (2010) 592-605.
  • Meyer-Hermann M. Does Recycling in Germinal Centers exist? Immunol Cell Biol 80 (2002) 30-35.
  • Meyer-Hermann M, Deutsch A, Or-Guil M. Recycling probability and dynamical properties of germinal center reactions. J Theor Biol 210 (2001) 265-285.
  • Meyer-Hermann M, Mohr E, Pelletier N, Zhang Y, Victora GD, Toellner KM. A theory of germinal center B cell selection, division, and exit. Cell Rep 2 (2012) 162-174 .


Transient chemotaxis sensitivity model of germinal centre B cells

Germinal centres exhibit two characteristic zones, the dark zone associated with cell division and mutation and the light zone associated with cell selection and differentiation. The predominant model was that cells alternate between both zones by chemotaxis. However, intravital microscopy data did not show any sign of chemotaxis in germinal centre B cells. In cooperation with Marc-Thilo Figge (Jena, Germany) and the groups of Marie Kosco-Vilbois (Geneva, Switzerland), Matthias Gunzer (Essen, Germany) and Kai Toellner (Birmingham, UK) we showed with spatial mathematical models of cell motility, that B cells only transiently acquire sensitivity for chemokines and do random walk most of the time. This transient chemotaxis model solved the contradiction between the observed trans-zone migration of B cells and the measured random walk.

  • Meyer-Hermann M, Figge MT, Toellner KM. Germinal centres seen through the mathematical eye: B cell models on the catwalk. Trends Immunol 30 (2009) 157-164.
  • Figge MT, Garin A, Gunzer M, Kosco-Vilbois M, Toellner K-M, Meyer-Hermann M. Deriving a germinal center lymphocyte migration model from two-photon data. J Exp Med 205 (2008) 3019-3029.
  • Meyer-Hermann M, Maini PK. Cutting edge: Back to “one-way” germinal centers.  J Immunol 174 (2005) 2489-2493.
  • Meyer-Hermann M, Maini PK. Interpreting two-photon imaging data of lymphocyte motility. Phys Rev E 71 (2005) 061912-1-12.
  • Beyer T, Meyer-Hermann M, Soff G. A possible role of chemotaxis in germinal center formation. Int Immunol 14 (2002) 1369-1381.
  • Meyer-Hermann M. A mathematical model for the germinal center morphology and affinity maturation. J Theor Biol 216 (2002) 273-300.


T cell help is the limiting factor of germinal centre B cell selection

Antigen are fragments of a pathogenic molecule, which initiate the germinal centre B cell response and are presented on follicular dendritic cells. B cells need to bind antigen for survival and the predominant model was that the amount of antigen is the limiting factor of B cell selection. In a cooperation with Philip K Maini (Oxford, UK) and Dagmar Iber (Basel, Switzerland), using agent-based spatio-temporal mathematical models, we have predicted that among many possible selection mechanisms, limiting antigen is the least efficient. Instead we proposed a new mechanism according to which high-affinity B cells collect antigen more efficiently than low-affinity ones. This leads to more processed antigen and a higher density of peptide-MHC presented on the B cells. The subsequent interaction with follicular helper T cells would be the limiting factor of B cell selection, in which the B cells with highest density of peptide-MHC are more likely to get survival and division signals. This prediction got strong support in the subsequent years with the help of photoactivation experiments and changed the paradigm of how B cells are selected in germinal centres.

  • Victora GD, Schwickert TA, Fooksman DR, Meyer-Hermann M, Dustin ML, Nussenzweig MC. Germinal center selection mechanism revealed by multiphoton microscopy using a photoactivatable fluorescent reporter. Cell 143 (2010) 592-605.
  • Meyer-Hermann M. B cell selection mechanisms revisited: A concerted action. Adv Compl Sys 10 (2007) 557-580.
  • Meyer-Hermann M, Maini PK, Iber D. An analysis of B cell selection mechanisms in germinal centers. Math Med Biol 23 (2006) 255-277.


Ways to optimise quality and quantity of antibodies

The goal of a germinal centre reaction is the formation of plasma cells, which generate large amounts of high affinity antibodies. At each selection step the fate of the selected B cell is either recycling or differentiation to an output cell. Our mathematical models show that increasing the recycling probability, in contrast to intuition, increases the number of generated output cells. In cooperation with Gabriel Victora (Cambridge, USA) and Kai Toellner (Birmingham, UK), we have proposed a new theory of the germinal centre reaction – the LEDA model – according to which all selected B cells are recycled and leave the germinal centre only after further rounds of division. As mechanism for fate decision, we proposed the amount of intracellular antigen in the course of asymmetric B cell division (shown by Facundo Batista, London, UK). B cells with high amount of antigen would preferably leave the germinal centre as output cells while B cells with low antigen would stay in the germinal centre for another round of selection. In cooperation with Michael Dustin (Oxford, UK), we found that in a model with limiting T cell help this leads to a 10-fold higher overall production of output cells, thus, providing a strong evolutionary advantage. There is no experimental support for this theory yet. However, if true, it opens a new line of treatment targets with the aim of controlling the strength of humoral immune responses. Building on these results we have searched for a possibility to increase both the quantity and the quality (in terms of B cell receptor affinity to the antigen) of germinal centre derived plasma cells. We have identified only one mechanisms: Dynamic and affinity-dependent number of divisions induced in positively selected B cells.

Flow cytometry showing antigen dilution by division. Starting point in experiment (left) and after 3 days (centre). Data from Thaunat et al. Science 2012, where asymmetric division of antigen was…

  • Meyer-Hermann M. Overcoming the dichotomy of quantity and quality of antibody responses. J Immunol 193 (2014) 5414-9.
  • Meyer-Hermann M, Mohr E, Pelletier N, Zhang Y, Victora GD, Toellner K-M. A theory of germinal center B cell selection, division and exit. Cell Reports 2 (2012) 162-174. 
  • Dustin ML, Meyer-Hermann M. Antigen feast or famine. Science 335 (2012) 408-409.


Do germinal centres interact via their produced antibodies?

Antibodies generated by the germinal centre output cells dilute over the whole organism. In particular, these antibodies may re-enter germinal centres and eventually influence the affinity maturation process. In cooperation with the group of Kai Toellner (Birmingham, UK), we investigated this question in a combined experimental and theoretical approach and found that antibodies re-enter germinal centres in an affinity-dependent manner and that produced antibodies compete with germinal centre B cells for binding antigen. Mathematical models showed that this competition accelerates affinity maturation by about 24 hours. The main impact seemed to be the initiation of the shutdown of the germinal centre reaction. A natural implication is that germinal centres may interact via their products. We want to understand whether this interaction leads to a synchronisation or an inhibition of germinal centres. This is of particular importance for the elderly population with frequent chronic inflammatory states.

Penetration of antibodies into murine splenic germinal centres. a) Endogenous IgMb (red) is displaced by exogenous low affinity IgMa (green), which is replaced by endogenous IgMb (red) again after…

  • Zhang* Y, Meyer-Hermann* M, George L, Khan M, Figge MT, Falciani F, Kosco-Vilbois M, Toellner K-M. Germinal centre B cells govern their own fate via antibody feedback. J Exp Med 210 (2013) 457-464. [*shared first author]


Innate immunity supports the initiation of germinal centre reactions

The initiation of germinal centre reactions relies on B cells, having seen the native pathogen, and on interaction of B and T cells at the follicular border. However, in cooperation with the groups of Marie Kosco-Vilbois (Geneva, Switzerland) and Kai Toellner (Birmingham, UK), we have shown that factors associated with innate immunity are also critical for germinal centre formation. Toll-like-receptor 4 was required for the proper formation of the follicular dendritic cell network in B cell follicles and, thus, instrumental for B cell mutation and maturation. This finding contributes to medical research on poor immune responses, e.g. after vaccination of the elderly population. 

  • Garin* A, Meyer-Hermann* M, Contie M, Figge MT, Buatois V, Gunzer M, Toellner, K-M, Elson G, Kosco-Vilbois MH. Toll-Like Receptor 4 signaling by Follicular Dendritic Cells is pivotal for germinal center onset and affinity maturation, Immunity 33 (2010) 84-95. [*shared first author]
  • Meyer-Hermann M, Beyer T. The type of seeder cells determines the efficiency of germinal center reactions. Bull Math Biol 66 (2004) 125-141.


What controls the initiation of tertiary lymphoid tissue?

Tertiary lymphoid tissue are lymphoid structures that emerge at ectopic places, which normally do not contain lymphoid structures like synovial tissue in rheumatoid arthritis or transplanted organs. Building on our model for the formation of secondary (i.e. normal) lymphoid tissue, we investigate in cooperation with the group of Friedrich Feuerhake (Hannover, Germany) conditions for the formation of tertiary lymphoid tissue in the context of renal transplantations. The goal is to determine early signatures of a rejection of the transplant for use in clinical practice.

  • Beyer T, Meyer-Hermann M. Cell transmembrane receptors determine tissue pattern stability. Phys Rev Lett 101 (2008) 148102.
  • Beyer T, Meyer-Hermann M. Mechanisms of organogenesis of primary lymphoid follicles. Int Immunol 20 (2008) 615-623.
  • Beyer T, Meyer-Hermann M. Modeling emergent tissue organization involving high-speed migrating cells in a flow equilibrium. Phys Rev E 76 (2007) 021929-1-13.





The Human Frontier Science Program Organization (HFSP)

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