Early Emergence of Adaptive Mechanisms Sustaining Ig Production: Application to Antibody Therapy

Abstract

Antibody therapy, where artificially-produced immunoglobulins (Ig) are used to treat pathological conditions such as auto-immune diseases and cancers, is a very innovative and competitive field. Although substantial efforts have been made in recent years to obtain specific and efficient antibodies, there is still room for improvement especially when considering a precise tissular targeting or increasing antigen affinity. A better understanding of the cellular and molecular steps of terminal B cell differentiation, in which an antigen-activated B cell becomes an antibody secreting cell, may improve antibody therapy. In this review, we use our recently published data about human B cell differentiation, to show that the mechanisms necessary to adapt a metamorphosing B cell to its new secretory function appear quite early in the differentiation process i.e., at the pre-plasmablast stage. After characterizing the molecular pathways appearing at this stage, we will focus on recent findings about two main processes involved in antibody production: unfolded protein response (UPR) and endoplasmic reticulum (ER) stress. We’ll show that many genes coding for factors involved in UPR and ER stress are induced at the pre-plasmablast stage, sustaining our hypothesis. Finally, we propose to use this recently acquired knowledge to improve productivity of industrialized therapeutic antibodies.

Integrative single-cell chromatin and transcriptome analysis of human plasma cell differentiation

“…The first wave of the UPR activation is associated with the mTORC1 pathway 31,32 . This mTORC1 mediated UPR activation was recently reported in murine activated B cells driving PC priming 26,33 before XBP1 gene expression. Among the UPR genes commonly identified in murine activated B cells and human PrePB of our model, XPOT, ASNS asparagine synthetase, SLC7A5 amino acid transporter and PSAT1 metabolic enzyme were identified.…”

Supervised discovery of interpretable gene programs from single-cell data

“…7a ). ER stress regulates the capacity of plasma cells to produce immunoglobulins 48 , likely because large quantities of misfolded antibodies 49 must be degraded, generating significant lysine 50 .…”