caa a22 4500 445391510 CHVBK 20180317143048.0 cr unu---uuuuu 170323e20110701xx s 000 0 eng 10.1007/s10955-011-0241-8 doi (NATIONALLICENCE)springer-10.1007/s10955-011-0241-8 Diversity Against Adversity: How Adaptive Immune System Evolves Potent Antibodies [Elektronische Daten] [Muyoung Heo, Konstantin Zeldovich, Eugene Shakhnovich] Adaptive immunity is an amazing mechanism, whereby new protein functions—affinity of antibodies (Immunoglobulins) to new antigens—evolve through mutation and selection in a matter of a few days. Despite numerous experimental studies, the fundamental physical principles underlying immune response are still poorly understood. In considerable departure from past approaches, here, we propose a microscopic multiscale model of adaptive immune response, which consists of three essential players: The host cells, viruses, and B-cells in Germinal Centers (GC). Each moiety carries a genome, which encodes proteins whose stability and interactions are determined from their sequences using laws of Statistical Mechanics, providing an exact relationship between genomic sequences and strength of interactions between pathogens and antibodies and antibodies and host proteins (autoimmunity). We find that evolution of potent antibodies (the process known as Affinity Maturation (AM)) is a delicate balancing act, which has to reconcile the conflicting requirements of protein stability, lack of autoimmunity, and high affinity of antibodies to incoming antigens. This becomes possible only when antibody producing B cells elevate their mutation rates (process known as Somatic Hypermutation (SHM)) to fall into a certain range—not too low to find potency increasing mutations but not too high to destroy stable Immunoglobulins and/or already achieved affinity. Potent antibodies develop through clonal expansion of initial B cells expressing marginally potent antibodies followed by their subsequent affinity maturation through mutation and selection. As a result, in each GC the population of mature potent Immunoglobulins is monoclonal being ancestors of a single cell from initial (germline) pool. We developed a simple analytical theory, which provides further rationale to our findings. The model and theory reveal the molecular factors that determine the efficiency of affinity maturation, thereby providing insight into the variability of the immune response to cytopathic viruses (the direct response by germline antibodies) and poorly cytopathic viruses (a crucial role of SHM in the response). Springer Science+Business Media, LLC, 2011 Immune response nationallicence Adaptive immunity nationallicence Germinal centers nationallicence Darwinian evolution nationallicence Somatic hypermutation nationallicence Sequence diversity nationallicence B cells nationallicence Heo Muyoung Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, 02138, Cambridge, MA, USA aut Zeldovich Konstantin Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, 02138, Cambridge, MA, USA aut Shakhnovich Eugene Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, 02138, Cambridge, MA, USA aut Journal of Statistical Physics Springer US; http://www.springer-ny.com 144/2(2011-07-01), 241-267 0022-4715 144:2<241 2011 144 10955 https://doi.org/10.1007/s10955-011-0241-8 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10955-011-0241-8 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Heo Muyoung Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, 02138, Cambridge, MA, USA aut NATIONALLICENCE 700 1- Zeldovich Konstantin Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, 02138, Cambridge, MA, USA aut NATIONALLICENCE 700 1- Shakhnovich Eugene Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, 02138, Cambridge, MA, USA aut NATIONALLICENCE 773 0- Journal of Statistical Physics Springer US; http://www.springer-ny.com 144/2(2011-07-01), 241-267 0022-4715 144:2<241 2011 144 10955 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer