The 16th International Conference on Lymphatic Tissues and Germinal Centers in Immune Responsesстатья из журнала
Аннотация: A biologist, a physicist and a mathematician stand in front of an empty room. They observe that two persons enter the room and after a while three persons leave the room. The biologist states: "This is an obvious case of replication." The physicist responds: "No, this is a clear case of a measurement error." The mathematician ignores this dispute and states: "If one person enters the room, the room would be empty." The latest International Conference on Lymphatic Tissues and Germinal Centers in Immune Responses, held this year in Frankfurt, Germany from July 5th through 9th, was designed to produce such a community-bridging event. For several days, scientists from these three disciplines sat together and shared visions in the hope of provoking synergism beyond the comfort zone of any one individual discipline. In total, researchers from 17 countries attended the 16th occasion of what has come to be known as the Germinal Center Conference (GCC). Since its inception in the mid-1960s, the conference remains loyal to holding a small, innovative forum in Europe in which students and young scientists intermingle with more established scientists who are publishing cutting edge research. The aim of the 16th GCC was to confront the thinking and data of classical immunologists, as well as neuroimmunologists, with those of computational biologists and intravital imaging researchers. In contrast to most conferences, experimental and mathematical contributions to research were not presented in separate symposia but in intermixed sessions. The intention was thus to induce intense interactions, facilitating dialog between the communities. Although the topics covered at earlier meetings were much broader, the more recent GCC have narrowed the focus to the cellular and molecular mechanisms unfolding in anatomical structures that give rise to humoral immunity. As such, the GCC's keynote speaker, Michel Nussenzweig, reviewed concepts related to this: the determination that the highest affinity B-cell receptor will outcompete lower affinity BCR in a GC reaction 1; that using the Ars/HEL transgenic system, two antigenic responses can be shown to co-exist in a single GC but the kinetics of each response will depend on the timing of T-cell help; and that GC are open structures, i.e. that naïve B cells can and will traverse the space of a GC reaction 2. Nussenzweig also reminded participants of the role of activation-induced cytidine deaminase (AID) in both class switching and directed mutation of immunoglobulin (Ig) genes and proposed that activation-induced cytidine deaminase (AID) may function as an oncogene for many of the B-cell-associated cancers 3. John Tew, examining the role of the follicular dendritic cell (FDC) in the GC response, demonstrated a link between immune complex periodicity as "presented" by FDC to GC B cells and induction of Ig somatic hypermutation 4. Tri Giang Phan 5 and Yolanda Carrasco 6 reported on the use of sophisticated imaging to show the shuttling of complexed antigen via a subcapsular poorly phagocytic leukocyte to B cells in follicles, capturing early in vivo stages of humoral responses. Incorporating these seemingly divergent concepts, i.e. proper exploitation of activation-induced cytidine deaminase (AID) function, immune complex targeting to subcapsular leukocytes and FDC, should provide the vaccine community with ideas of how to promote stronger and more long-lasting antibody titers especially for the developing world, where multiple injections are often a luxury not easily realized. As mathematical modeling is maturing to a point where this tool provides significant assistance for the design and interpretation of complex immunological experiments, the blending of mathematical thinking with wet lab immunology proved successful. Arup Chakraborty took participants on the long journey of how elegant modeling efforts aided Roose and colleagues to illustrate that intracellular signaling pathways have a "memory", that is, sustained low-level activation remains despite withdrawal of relevant stimuli 7. Alan Perelson explained how modeling of B-cell responses to variant strains of flu is helping the WHO and others to predict the potential of a vaccine. Furthermore, Perelson demonstrated, through modeling, the difficulty of removing infectious human immunodeficiency virions from the FDC and the challenges faced by attempts to annihilate this source of virus with current therapies 8. Michael Meyer-Hermann demonstrated with mathematical modeling that chemotaxis of B-cell migration in the GC is consistent with the measured random walk migration data 2, 9, 10 and that re-analyses of the data infer a novel GC migration model 11. In addition, experimental support for the recently proposed selection mechanism involving affinity-dependent T-cell help for GC B cells was discussed 12, 13. Uri Hershberg presented a novel statistical test to detect whether mutated Ig found in normal or pathological immune responses are driven by antigen-dependent selection 14. Users can analyze sequences at http://clip.med.yale.edu/selection/. Intense discussions showed the necessity of developing new concepts for the mathematical representation of antibodies and somatic hypermutation. As the emergence of intravital microscopy has provided the experimentalist with an unprecedented three dimensional view into intact living compartments, the GCC's opening workshop set the theme by discussing powerful images generated through two-photon microscopy, as well as the challenges faced by those using and optimizing this tool to conduct meaningful and robust experiments. Joost Beltman and Michael Meyer-Hermann demonstrated to the attendees the limits of interpretation of intravital cell-tracking data and the necessity to combine space-resolved mathematical models with two-photon-imaging experiments in order to set the data into a functional context 14-16. In addition to reinforcing the often neglected role of "roadways" provided by lymphoid stromal elements (i.e. the dark holes in many imaging experiments) during immune responses, Ron Germain demonstrated that a key component of stable adhesion between antigen-specific T cells and antigen-bearing B cells is the small adapter SAP in the T cells 17. These data support evidence that adhesive interactions regulate the duration of cell–cell associations, which in turn, are required for high-affinity humoral products. Contributing to this theme was the presentation by Marc Thilo Figge who demonstrated that an interactive cycle between in silico and in vivo experiments facilitated the identification of the impact points for TLR4 signaling through FDC in GC. As opposed to an impact on B-cell proliferation, differentiation, migration or many other possibilities, mathematical modeling predicted that suppression of TLR4 signaling impacts on adequate ICAM-dependent cellular interactions and on the capacity to invoke Ig mutation. Matthias Gunzer, chair and coordinator of the workshop, demonstrated that the bone marrow in long bones can now be successfully captured with two-photon microscopy explaining to the audience the details of the protocol that allowed the visualization of neutrophil extravasation, following injection of granulocyte colony-stimulating factor. Another feature of the 16th GCC was to discuss how B-cell biology and microenvironments may be altered, giving rise to autoimmunity. The discovery by Francesco Aloisi and colleagues concerning ectopic lymphoid tissue in the meninges of patients with MS has sparked a debate concerning the role of EBV during disease 18. In total, 23 out of 24 patient samples coming from a repository of MS tissue showed B-cell infiltrates and 100% were EBV positive. Claudia Berek continued on this theme of ectopic lymphoid tissue, reporting on differences in chemokine receptor usage by B cells from patients with RA versus SLE pointing toward a disease-specific regulation of B-cell motility 19. This subject was further explored by Rainer Straub and Georg Pongratz, who connected the immunology of rheumatoid arthritis with control by the sympathetic and sensory nervous system 20. Hedda Wardemann demonstrated an altered repertoire of splenic B cells in FcγRIIB-deficient mice, which develop a spontaneous lupus-like disease 21. Interestingly, Yang Liu elegantly demonstrated that PAMP (pathogen-associated molecular pathogen, e.g. LPS) and DAMP (damage-associated molecular pathogen, e.g. HMGB1) may trigger opposite effects in NF-κB signaling, turning an acute regulator into a chronic signaling response 22. Thus, responses to infection may not be equivalent to tissue injury, but be separate processes, with infection-triggered events having the potential to become chronic, and thus underlie many forms of autoimmunity, e.g. MS, rheumatoid arthritis and systemic lupus erythematosus. Concerning intravital imaging, a strong sentiment was that rare cell interaction events, e.g. initiating adaptive immunity or during B-cell selection, are easily hidden behind a majority of tracked but inactive cells. Mathematical modeling of these rare events can help to identify conclusive observables. In addition, it was acknowledged that the window of tracking live cells is constrained to a few hours, a day at the most, which bears the risk of hiding slow processes in GC reactions 16. However, as the optimization and invention of protocols, reagents and technologies progresses, enabling the GC reaction to be explored throughout its 21 day time course, further treasures will be uncovered and more clues provided as to how immunity functions in health and disease. For the mathematical modeling, it was agreed that collaborations between mathematicians and biologists are beginning to foster innovative experimental designs through reduction of potential outcomes. The above examples are a small but representative cross-sampling of the presentations given during the 16th GCC. By the time the 17th GCC gets underway in Birmingham, UK, in the autumn of 2011, the organizer, Kai-Michael Toellner will certainly have lots of ripened fruits from the seeds planted at this year's meeting. Furthermore, perhaps, by then the immunologist will be convinced and provide further evidence that research in immunology can take advantage of well conceived and simplifying mathematical models that bring out the essence of complex biological systems. The Potts Memorial Foundation, The Trudeau Institute and an Anonymous Donor provided generous support for the meeting.
Год издания: 2009
Авторы: Marie Kosco‐Vilbois, Michael Meyer‐Hermann
Издательство: Wiley
Источник: European Journal of Immunology
Ключевые слова: Immunotherapy and Immune Responses, Immune Response and Inflammation, Immune Cell Function and Interaction
Другие ссылки: European Journal of Immunology (PDF)
European Journal of Immunology (HTML)
PubMed (HTML)
European Journal of Immunology (HTML)
PubMed (HTML)
Открытый доступ: bronze
Том: 39
Выпуск: 9
Страницы: 2310–2312