A generalized quantitative antibody homeostasis model: antigen saturation, natural antibodies and a quantitative antibody network

Abstract

In a pair of articles, we present a generalized quantitative model for the homeostatic function of clonal humoral immune system. In this second paper, we describe how antibody production controls the saturation of antigens and the network of antibody interactions that emerges in the epitome space with the establishment of the immune system. Efficient control of antigens, be it self or foreign, requires the maintenance of antibody concentrations that saturate antigen to relevant levels. Simple calculations suggest that the observed diverse recognition of antigens by natural antibodies is only possible by cross-reactivity whereby particular clones of antibodies bind to diverse targets and shared recognition of particular antigens by multiple antibody clones contribute to the maintenance of antigen control. We also argue that natural antibodies are none else than the result of thymus-independent responses against immunological self. We interpret and explain antibody production and function in a virtual molecular interaction space and as a network of interactions. Indeed, the general quantitative (GQM) model we propose is in agreement with earlier models, confirms some assumptions and presumably provides the theoretical basis for the construction of a real antibody network using the sequence and interaction database data. The strength of the interaction between the antigenbinding site (paratope) of an antibody and the antibody-binding site (epitope) of the antigen is characterized by affinity, kinetics of association and dissociation, and binding energy. Antibodies often recognize more than one target. Immunological assays usually require the titration of the antibody, which is the identification of lowest concentration that binds to the nominal target but does not bind to others. This is quite logical for antibodies intentionally produced in animals, but how we define the target of an antibody in vivo? By changing the concentration of antigen and antibody, saturation of any can be achieved even when affinity of the interaction is low. The absolute and relative concentration of antigens and antibodies does matter and our GQM attempts to reveal antibody function by addressing these factors.The general equation defining equilibrium dissociation constant K D : Assuming that antibodies are produced with the intent of regulating antigen availability, best control over antigen concentration is achieved when the concentration of antibody is close to the K D (Figure 1). In our map, this zone for a range of [Ab] and K D values is defined by a line, where [Ab] = K D , which is the line representing 50% saturation of the antigen (Figure 1). By lowering or increasing antibody production, the host can release or capture antigens, and likewise by changing the efficiency of Ab binding, the host can modulate antigen saturation (Figure 1). Various immunological mechanisms are responsible for removing antibody-antigen complexes, called immune complexes, from the circulation.The range of [Ab] values we will be using in our model refl...

A generalized quantitative antibody homeostasis model: maintenance of global antibody equilibrium by effector functions

“…Since we previously separately addressed thymus‐independent (TI) and thymus‐dependent (TD) antibody production, 2 here we will also discuss effector functions using this categorization. We need to keep in mind, however, that these events actually show an overlap and continuity when represented in our molecular interaction space (Figures 3a and b).…”

“…1 Quantitative signals drive B-cell proliferation and antibody production to adjust free antibody concentration [Ab] = K D to achieve relevant antigen saturation. 2 Therefore, the system tends to reach K D = [Ag] = [Ab] at which point [AbAg] will also be equal to K D (Figure 1) based on the general equation:…”

“…In our model we assumed that the essence of antibody homeostasis is the maintenance of a regulated balance between the saturation of B-cell receptors (BCR) by antigen 1 and the saturation of antigen by antibodies, thereby controlling B-cell development and antigen fate in the body. 2 Regulated antibody production drives the system of molecules towards a binding equilibrium, which characterizes the nature and outcome of immunological recognition. The formation of antibody-antigen immune complexes (AbAg) is followed by their removal from the body.…”

Network organization of antibody interactions in sequence and structure space: the RADARS model

“…In this paper, following a brief introduction to the sequence space of antibodies, a model for the molecular organization of antibody structure space or interaction space is proposed. The model builds on the generalized quantitative model of antibody homeostasis (6,26,27), thus approaches antibody function from the physico-chemical perspective: antibodies are organized into a network based on their binding affinity to cognate target. The model also considers the architecture of B-cell development and hierarchy and provides a power law-based quantitative network description of the humoral immune system at rest.…”

A generalized quantitative antibody homeostasis model: regulation of B‐cell development by BCR saturation and novel insights into bone marrow function

“…Indeed, B1 cells spontaneously produce antibodies, which are presumably the source of natural antibodies, 22 as discussed in our accompanying paper. 24 Taking into account that the pre-BCR is selected for glycan reactivity, it may not be surprising that antibodies secreted by B1 cells show preference for binding glycans. 25 In fact, autoreactivity of natural antibodies can be at least partially attributed to their glycan binding properties.…”