Recent Advances in Lupus B Cell Biology: PI3K, IFNγ, and Chromatin

Abstract

In the autoimmune disease Systemic Lupus Erythematosus (SLE), autoantibodies are formed that promote inflammation and tissue damage. There has been significant interest in understanding the B cell derangements involved in SLE pathogenesis. The past few years have been particularly fruitful in three domains: the role of PI3K signaling in loss of B cell tolerance, the role of IFNγ signaling in the development of autoimmunity, and the characterization of changes in chromatin accessibility in SLE B cells. The PI3K pathway coordinates various downstream signaling molecules involved in B cell development and activation. It is governed by the phosphatases PTEN and SHIP-1. Murine models lacking either of these phosphatases in B cells develop autoimmune disease and exhibit defects in B cell tolerance. Limited studies of human SLE B cells demonstrate reduced expression of PTEN or increased signaling events downstream of PI3K in some patients. IFNγ has long been known to be elevated in both SLE patients and mouse models of lupus. New data suggests that IFNγR expression on B cells is required to develop autoreactive germinal centers (GC) and autoantibodies in murine lupus. Furthermore, IFNγ promotes increased transcription of BCL6, IL-6 and T-bet in B cells, which also promote GC and autoantibody formation. IFNγ also induces epigenetic changes in human B cells. SLE B cells demonstrate significant epigenetic reprogramming, including enhanced chromatin accessibility at transcription factor motifs involved in B cell activation and plasma cell (PC) differentiation as well as alterations in DNA methylation and histone modifications. Histone deacetylase inhibitors limit disease development in murine lupus models, at least in part via their ability to prevent B cell class switching and differentiation into plasma cells. This review will discuss relevant discoveries of the past several years pertaining to these areas of SLE B cell biology.

B‐cell intrinsic and extrinsic signals that regulate central tolerance of mouse and human B cells*

“…The activity of PI3K enzymes is mainly regulated by two lipid phosphatases, Phosphatase and Tensin Homolog deleted on Chromosome 10 (PTEN) and SH2‐containing inositol polyphosphate 5‐phosphatase (SHIP), which dephosphorylate PI(3,4,5)P 3 into PI(4,5)P 2 or PI(3,4)P 2 , respectively. Indeed, deletion of either PTEN or SHIP‐1 in B cells leads to activation of PI3K and dysregulated B cell development, maturation, and peripheral tolerance (reviewed in 70).…”

The Mango’s Mistletoe Leaves Extract Ameliorates Lupus by Inhibiting the Anti-dsDNA Antibody Production, the Percentages of CD8+CD28− and CD4+CD28− T Cells

“…In our study, we presume that the mechanisms are related to the active compounds found in the mango's mistletoe leaf having anti-inflammatory, antiproliferative, and antioxidant properties [17]. The most of the flavonoid compounds found in the mango's mistletoe leaf interfere with metabolism, proliferation, survival, growth of B cells through the Akt/mTOR and Ras/ERK signaling pathways [22], [23], inhibit BAFF receptors on B cells [8] and obstruct the production of IFN-α, and BAFF by inhibition of pDCs [22], [24], [25]. In addition, a flavonoid also interferes with mDCs to activate T cells and IFN-ϒ, IL-17, and IL-21 production by T cells [22], [26].…”

Systemic lupus erythematosus variants modulate the function of an enhancer upstream of TNFAIP3

“…IFNGR1 encodes the IFNγ receptor subunit 1, expressed on the surface of B cells. Elevated expression of IFNGR1 and subsequent IFNγ signaling activation promotes the loss of self-tolerance and production of autoantibodies in murine lupus models ( Bacalao and Satterthwaite, 2021 ). Our study suggests that the TNFAIP3 risk haplotype associated with SLE and other autoimmune diseases (e.g.…”