Unfavourable H-CDR3 Loops in preB Cells Lead to Highly Expanded Plasma Cell Clones

The immune system is essential for protection against invading pathogens. However, if it fails to distinguish between non-self (pathogens) and self, autoimmunity can result. B cells recognise pathogens using their B-cell antigen receptor (BCR), a membrane-bound antibody. The variable region of the BCR contacts antigens via complementarity-determining regions (CDRs). This region is encoded by immunoglobulin (Ig) V(D)J gene segments, which are randomly recombined during B-cell development. Failure to counter-select unfavourable H-CDR3s is considered an underlying feature of autoimmunity. Here, we examined the effect of impaired pre-BCR selection on plasma cells (PCs) using a model of autoimmunity characterised by elevated serum autoantibody levels. Our results demonstrate that the absence of a pre-BCR leads to an increase in H-CDR3s that are translated into unfavourable reading frames, encoding highly hydrophobic and/or basic amino acid residues, including a subset with extremely short H-CDR3s. These features are not fully corrected by Ig light chains and persist in mature B cells. Ultimately resulting in the massive clonal expansion of PCs expressing a repertoire skewed towards extremely short H-CDR3s that contain highly hydrophobic and/or positively charged residues. Consequently, preB cells with unfavourable H-CDR3 features lead to the expansion of autoreactive PCs with the same features.