Affinity Inequality among Serum Antibodies That Originate in Lymphoid Germinal Centers

Abstract

Upon natural infection with pathogens or vaccination, antibodies are produced by a process called affinity maturation. As affinity maturation ensues, average affinity values between an antibody and ligand increase with time. Purified antibodies isolated from serum are invariably heterogeneous with respect to their affinity for the ligands they bind, whether macromolecular antigens or haptens (low molecular weight approximations of epitopes on antigens). However, less is known about how the extent of this heterogeneity evolves with time during affinity maturation. To shed light on this issue, we have taken advantage of previously published data from Eisen and Siskind (1964). Using the ratio of the strongest to the weakest binding subsets as a metric of heterogeneity (or affinity inequality), we analyzed antibodies isolated from individual serum samples. The ratios were initially as high as 50-fold, and decreased over a few weeks after a single injection of small antigen doses to around unity. This decrease in the effective heterogeneity of antibody affinities with time is consistent with Darwinian evolution in the strong selection limit. By contrast, neither the average affinity nor the heterogeneity evolves much with time for high doses of antigen, as competition between clones of the same affinity is minimal.

Optimal immunization cocktails can promote induction of broadly neutralizing Abs against highly mutable pathogens

“…We also describe the biological reasons for the existence of this optimum and how it is influenced by the variables that we study. Our simulations exhibit some of the qualitative behavior observed during the course of natural infection (23)(24)(25)(26)(27) and in laboratory studies of AM (41,42). Finally, we discuss how our results may provide conceptual guidelines for the design of optimal immunization protocols to elicit bnAbs to HIV and other highly mutable pathogens.…”

Plasma cell output from germinal centers is regulated by signals from Tfh and stromal cells

“…Before the initiation of GCs, some B cells rapidly mature into extrafollicular plasma cells (PCs) that generate an early low-affinity germline-derived antibody ( MacLennan et al, 2003 ). Increases in antibody affinity are easily detectable after secondary immunization ( Eisen and Siskind, 1964 ), but also noticeable during the primary response ( Takahashi et al, 1998 ; Kang et al, 2015 ). Mutated PCs were found as early as 10 d after primary immunization ( Jacob and Kelsoe, 1992 ; Smith et al, 1997 ), which is only a few days after the onset of mutational activity in primary GCs ( Weiss et al, 1992 ; Jacob et al, 1993 ; McHeyzer-Williams et al, 1993 ).…”

A Population Dynamics Model for Clonal Diversity in a Germinal Center

“…Initially, as the affinity distribution spreads from a delta function and before the GC reaches its capacity, the ratio decays, but following the initial relaxation phase, the mean affinity increases faster than the spread of the distribution (Figure 3D ). Thus, our system operates in the strong selection limit as in the experimental system studied in Kang et al ( 2015 ).…”

“…We can consider the width of the affinity distribution of a GC population to be a proxy for its clonal diversity. It was shown that the ratio of the mean affinity to its standard deviation (STD) grows during AM when the amount of antigen used in the immunization was relatively low (Kang et al, 2015 ). Indeed, the STD of a stochastic variable grows with time (Schuss, 2009 ), while the growth of the average affinity is evidence of selection (Desai and Fisher, 2007 ).…”