Promiscuity and Polyreactivity of Antibodies and their Binding Modes during B-Cell Differentiation

Abstract

Many diversification mechanisms occurr during central tolerance leading to a wide array of antibodies (Abs) with a range of binding specificities, some of which lead to polyreactivity. The repertoire of preB cells (before central tolerance), immature B cells (during central tolerance) and naive B cells in the peripheral blood (after central tolerance) has been interrogated by high throughput sequencing of heavy and light chain Ig genes. It has been shown that older people display a less diverse repertoire of antibody-producing cells, and that this loss of diversity is associated with poor health. Within a population of responding cells there are favoured characteristics of a the Ab gene CDRH3 loop that is crucial in binding the foreign antigen. We hypothesise that favoured physico-chemical CDRH3 characteristics make a structure capable of binding to multiple foreign antigens (polyspecific).The ability to predict this promiscuous behaviour with respect to binding specificity would greatly improve the efficiency of the therapeutic antibody discovery process. From these data we want to extract the molecular determinants playing a role in polyreactivity by exploiting structural and dynamical information. We use statistical analyses to classify CDRH3 physico-chemical properties and Molecular Dynamics (MD) simulations at the atomistic and/or coarse grained levels to characterise flexibility requirements for binding multiplicity.Martin V, Wu YC, Kipling D, Dunn-Walters DK. Ann N Y Acad Sci. 2015 http://dx.doi.org/10.1111/nyas.12823.Fornili A, Pandini A, Lu HC, Fraternali F. J Chem Theory Comput. 2013 9:5127-5147.Marcatili P, et al. J Immunol. 2013 190:5771-8.