B cell expression of the SH2-containing inositol 5-phosphatase (SHIP-1) is required to establish anergy to high affinity, proteinacious autoantigens. (August 2015)

• Record Type: Journal Article
• Authors: Akerlund, Janie; Getahun, Andrew; Cambier, John C.
• Is Part Of: Journal of autoimmunity. Volume 62(2015)
• Page Start: 45
• Page End: 54
• Publication Date: 2015-08
• Subjects: B cells -- Tolerance -- SHIP-1 -- MD4.ML-5 -- Autoimmunity; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2015.06.007
• Languages: English
• ISSNs: 0896-8411

Abstract

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. Highlights: SHIP-1 is required for B cell anergy to hen egg lysozyme in the high affinity MD4.ML-5 immunoglobulin transgenic model. Low dose antigen exposure primes B cells for subsequent responses to antigen. SHIP-1 regulates responses of both naïve and antigen experienced B cells to antigen. SHIP-1 deficiency licenses naive MD4 B cells to both proliferate and differentiate upon transfer to antigen sufficient ML5.