EndoU is a novel regulator of AICD during peripheral B cell selection

Poe, Jonathan C.; Kountikov, Evgueni I.; Lykken, Jacquelyn M.; Natarajan, Abirami; Marchuk, Douglas A.; Tedder, Thomas F.

The divergence of phenotypes between high-responder and augmented-responder mice has precedent based on previous studies. For example, Ig Tg sHEL mice deficient in the inositol phosphatase PTEN have reduced BCR occupancy by sHEL and produce anti-HEL auto-Abs at a higher level than Ig Tg sHEL mice. This results in a subsequent break in tolerance in some mice caused by depletion of available sHEL auto-Ag (Browne et al., 2009) . Likewise, Ig Tg sHEL mice transgenic for CD19 overexpression progressively break tolerance as they age and eventually produce high anti-HEL auto-Ab levels (Inaoki et al., 1997) . In fact, remarkably similar to EndoU / Ig Tg sHEL mice, CD19 Tg Ig Tg sHEL mice develop as both high-and augmented-responder mice by 2 mo of age. Thus, modest increases in B cell numbers or enhancement in auto-Ab production resulting from altered B cell signaling can lead to auto-Ag depletion. Once this initial reduction in sHEL levels occurs, the resulting lack of B cell anergy enables peripheral B cell numbers to be maintained at a level that exceeds sHEL production, resulting in sustained and high-level anti-HEL auto-Ab production. Thereby, the EndoU regulatory pathway is likely to be an important component of B cell tolerance regulation, which is consistent with the known polygenic origins of autoimmunity.