Positive Selection of Natural Poly-Reactive B Cells in the Periphery Occurs Independent of Heavy Chain Allelic Inclusion

<div><p>Natural autoreactive B cells are important mediators of autoimmune diseases. Receptor editing is known to play an important role in both central and peripheral B cell tolerance. However, the role of allelic inclusion in the development of natural autoreactive B cells is not clear. Previously, we generated μ chain (TgV_H3B4I) and μ/κ chains (TgV_H/L3B4) transgenic mice using transgene derived from the 3B4 hybridoma, which produce poly-reactive natural autoantibodies. In this study, we demonstrate that a considerable population of B cells edited their B cells receptors (BCRs) via light chain or heavy chain allelic inclusion during their development in TgV_H3B4I mice. Additionally, allelic inclusion occurred more frequently in the periphery and promoted the differentiation of B cells into marginal zone or B-1a cells in TgV_H3B4I mice. B cells from TgV_H/L3B4 mice expressing the intact transgenic 3B4 BCR without receptor editing secreted poly-reactive 3B4 antibody. Interestingly, however, B cell that underwent allelic inclusion in TgV_H3B4I mice also produced poly-reactive autoantibodies in vivo and in vitro. Our findings suggest that receptor editing plays a minor role in the positive selection of B cells expressing natural poly-reactive BCRs, which can be positively selected through heavy chain allelic inclusion to retain their poly-reactivity in the periphery.</p>