Polyreactive antibodies in adaptive immune responses to viruses

Abstract

B cells express immunoglobulins on their surface where they serve as antigen receptors. When secreted as antibodies, the same molecules are key elements of the humoral immune response against pathogens such as viruses. Although most antibodies are restricted to binding a specific antigen, some are polyreactive and have the ability to bind to several different ligands, usually with low affinity. Highly polyreactive antibodies are removed from the repertoire during B-cell development by physiologic tolerance mechanisms including deletion and receptor editing. However, a low level of antibody polyreactivity is tolerated and can confer additional binding properties to pathogen-specific antibodies. For example, high-affinity human antibodies to HIV are frequently polyreactive. Here we review the evidence suggesting that in the case of some pathogens like HIV, polyreactivity may confer a selective advantage to pathogen-specific antibodies.

Fig. 1

Tolerance checkpoints in human B-cell development. Tolerance checkpoints between developmental stages of B-cell lymphopoiesis; a central tolerance checkpoint in the bone marrow (1) followed by three tolerance checkpoints in periphery (2–4) ensure the removal of most autoreactive and polyreactive B cells [23, 39, 63, 154]. Bar graph shows the frequency of autoreactive (red bar) and polyreactive (orange bar) clones determined by testing monoclonal antibodies from single B cells at the different B-cell stages [23, 39, 63, 154]. The frequency of polyreactivity in the early immature, mature naïve and IgG memory B cells is indicated above the bars. mIg, membrane immunoglobulin

Fig. 2

Polyreactivity of anti-HIV gp160 antibodies. a Frequency of polyreactive anti-gp160 IgG memory B-cell antibodies isolated from HIV patients (HIV⁺ gp160⁺) infected with clade B (open green circles) or clade A (filled green circles) viruses compared to non gp160-binding B-cell antibodies from 2 of the clade B patients (red circles, HIV⁺ gp160⁻) [105, 106, 110], and historical control IgG memory B-cell antibodies isolated from healthy donors (HIV⁻ gp160⁻) [63]. Each symbol represents a donor. b Evolution of antibody polyreactivity throughout affinity maturation (transition from mature naïve/germline precursor B cells to IgG memory B cells) for B cells in healthy donors (HIV⁻) and gp160-specific B cells in HIV patients (HIV⁺). Pie charts summarize the frequency of polyreactive (orange) and non-polyreactive (white) antibodies isolated from the B-cell compartments in HIV-infected and healthy donors indicated by the schematic diagram. The number of antibodies tested is indicated in the center of the pie chart [39, 63, 106]

Fig. 3

Heteroligation of polyreactive HIV gp160-specific antibodies. gp160 glycoprotein is expressed at a very low density on the HIV surface (10–15 spikes) [127], indicating that the viral spikes are spaced too far apart for a bivalent antibody to bridge [128, 129] (1). Therefore, non-polyreactive anti-gp160 antibodies likely bind to their target with only one of their two high-affinity binding sites (monovalent binding) (2). In contrast, polyreactive anti-HIV gp160 antibodies are able to bind bivalently to the virus by heteroligation between one high-affinity anti-HIV-gp160 combining site and a second low-affinity site on another molecular structure on the HIV virion (3)