B cell expression of the SH2-containing inositol 5-phosphatase (SHIP-1) is required to establish anergy to high affinity, proteinacious autoantigens

Abstract

Many self-reactive B cells exist in the periphery in a rapidly reversible state of unresponsiveness referred to as anergy. Reversibility of anergy indicates that chronically occupied BCR must transduce non-durable regulatory signals that maintain unresponsiveness. Consistent with such a mechanism, studies of immunoglobulin transgenic, as well as naturally occurring polyclonal autoreactive B cells demonstrate activation of the inositol 5-phosphatase SHIP-1 in anergic cells, and low affinity chromatin autoantigen-reactive B cells have been shown to require expression of this phosphatase to maintain anergy. However, it has been reported that anergy of B cells recognizing high affinity soluble antigen may not require SHIP-1, and is instead mediated by upregulation of the inositol 3-phosphatase PTEN. To further explore this apparent difference in mechanism we analyzed the effect of B cell-targeted SHIP-1 deletion on immune tolerance of high affinity anti-HEL B cells in mice expressing soluble HEL (MD4.ML-5). We report that SHIP-1 functions to dampen responses of naïve and low-dose antigen-primed B cells in vitro, and is required for induction of B cell tolerance. Thus, while anergy of B cells reactive with low affinity and likely polyvalent chromatin antigens is maintained by activation of inhibitory signaling circuitry involving SHIP-1, anergy of B cells recognizing soluble self antigen with high affinity also requires increased activity of SHIP-1.

Activated PI3Kδ breaches multiple B cell tolerance checkpoints and causes autoantibody production

“…Indeed, expression and/or function of PTEN or SHIP1, phosphatases that antagonize the PI3K pathway, are increased in anergic B cells (Browne et al, 2009;O'Neill et al, 2011;Smith et al, 2019). Similarly, expression of constitutively active p110α, deletion of PTEN or SHIP1, or overexpression of CD19, one of the B cell coreceptors that recruits and activates PI3K, all disrupt B cell tolerance (Akerlund et al, 2015;Browne et al, 2009;Greaves et al, 2019;Inaoki et al, 1997;Leung et al, 2013). However, the break in tolerance we observed here differs in multiple ways from these previous findings.…”

Continuous inhibitory signaling by both SHP-1 and SHIP-1 pathways is required to maintain unresponsiveness of anergic B cells

“…Besides allowing more definitive analysis of the requirements for maintaining anergy, use of anergic B cells that were allowed to develop normally before acute induction of alterations in inhibitory signaling eliminated influences of confounding developmental effects. Although our findings regarding the role of SHIP-1 in anergy are consistent with previously published work using mb-1cre-driven deletion of SHIP-1 (O'Neill et al, 2011;Akerlund et al, 2015), they pinpoint the function of SHIP-1 to maintenance of anergy. Although SHP-1 was shown previously to be essential for maintenance of tolerance (Pao et al, 2007), its role in B cell anergy was unclear (Cyster and Goodnow, 1995).…”

“…6). This is consistent with a reported disability of anergic B cells to accumulate PI(3,4,5) P3 in their membrane upon BCR stimulation (Browne et al, 2009), the observed increase in SHIP-1 activity (O'Neill et al, 2011;Akerlund et al, 2015), and increased PTEN expression (Browne et al, 2009) in anergic B cells. The fact that the PI3K pathway promotes plasma cell differentiation (Omori et al, 2006) fits with the observed autoantibody response seen when inhibition of the PI3K pathway is relieved.…”

Regulation of immune cell signaling by SHIP1: A phosphatase, scaffold protein, and potential therapeutic target

“…While deletion of SHIP in B cells does not lead to lung and gut inflammation, it does lead to the development of a chronic autoantibody-mediated disease similar to Systemic Lupus Erythematosus (SLE) [89]. Deletion of SHIP in BCR-transgenic B cells specific for Ars or HEL antigens was found to reverse their anergic phenotype in two models of self-tolerance [89,90]. We found that B cells bearing mutations uncoupling the TAPP adaptors from PI(3,4)P 2 were hyper-active and drive an SLE-like phenotype [51], suggesting that proteins binding this SHIP enzymatic product may contribute important regulatory functions.…”