Affinity war: forging immunoglobulin repertoires

Abstract

B cell immunoglobulin (Ig) repertoire composition shapes immune responses. The generation of Ig diversity begins with Ig variable region exon assembly from gene segments, random inter-segment junction sequence diversity, and combinations of Ig heavy and light chain. This generates vast preemptive sequence freedom in early developing B lineage cell Ig genes that can anticipate a great diversity of threats. This freedom is met with large restrictions that ultimately define the naïve (i.e. preimmune) Ig repertoire. Activation-induced somatic hypermutation (SHM), which further diversifies Ig V regions, is also met with strong selection that shapes Ig affinity maturation. While individual repertoire features, such as affinity for self and competition for foreign antigen, are known to drive selection, the selection filters themselves may be subject to regulation. Large sequence freedom coupled with strong selection for each diversification process provides flexibility for demand-driven regulation to dynamically balance antigen recognition capacities and associated autoimmune risks according to host needs.

Figure 1.. Polyreactivity in the B cell system.

Schematic of the B cell development and literature-based representations of general locations of tolerance checkpoints and polyreactivity of associated B cell subsets. Shown are two B cell tolerance checkpoints. Tolerance checkpoints in the bone marrow are designated central tolerance, and those in the periphery are designated as such. Immature (imm.), transitional (trans.), mature naïve (IgM IgD), and IgA B cells (green) are indicated.

Figure 2.. Physiologic control of B cell tolerance filter stringency may be a demand-driven process.

Schematic representation of our hypothesis that plasticity of B cell developmental checkpoint stringency is an adaptive feature, balancing risks of infection and autoimmunity to host needs.

Figure 3.. Acquisition of de novo recognition capacities from concealed Ig diversity.

Schematic representation of an implication the discovery that non-cognate B cells can be activated and undergo SHM. Shown is a hypothetical scenario where new antigen recognition capacities could be acquired from concealed Ig diversity (i.e. not initially recognized by immunizing antigen) through SHM. Colored boxes represent Ig variable (V) region specificities. Thin curved arrows represent affinity maturation pathways of some V region specificities (asterisked) in B cells that fail to initially recognize antigen, but gain de novo recognition capacity through non-specific B cell activation-induced SHM. Shaded areas represent B gene segments that do not bind a given antigen, but may have recognition potential.