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.