GWAS and candidate studies have identified risk-conferring allelic variants that impair the ability to maintain immune tolerance. Several of these risk alleles are thought to function in B cell signaling, including negative regulators of the PI3K pathway. Following BCR stimulation, activation of the PI3K pathway leads to production of PI(3,4,5)P3 in the plasma membrane. The accumulation of this lipid second messenger is crucial for B cell activation, cytokine secretion, proliferation, antigen

more »

... esentation and differentiation into antibody secreting cells. However, in situations where the responding B cell is recognizing self-antigen, tight regulation of this pathway is crucial for the maintenance of peripheral tolerance. The inositol lipid phosphatases, PTEN and SHIP-1 play an essential role in maintaining B cell anergy through hydrolysis of PI(3,4,5)P3 to PI(4,5)P2 and PI(3,4)P2, respectively, resulting in the dampening of BCR induced signaling. We and others have demonstrated these regulatory phosphatases are indispensable for preservation of B cell tolerance with rapid proliferation and autoantibody production occurring upon removal of either PTEN or SHIP-1 from anergic cells. Importantly, reduced expression in PTEN and SHIP-1 are observed in B cells from T1D and SLE patients, consequent to aberrant regulation by miRNA-7 and miRNA-155, respectively. It therefore appears this pathway in anergic B cells may be an attractive target for therapeutic intervention in autoimmunity.