Partial Protection From Lupus-Like Disease by B-Cell Specific Type I Interferon Receptor Deficiency

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease that can present with many different permutations of symptom presentation. A large subset of SLE patients have been shown to present with elevated interferon stimulated gene (ISG) expression, and Type I IFNs (IFNαβ) have been shown to drive disease in murine models through global IFNα Receptor (IFNAR) knockouts. However, the disease contribution of distinct immune cell subsets in response to constitutively increased levels of IFNαβ is not fully understood. We utilized a B-cell specific IFNAR knockout (BΔIFNAR) on the B6.Nba2 spontaneous-lupus background to determine the contribution of IFNαβ stimulated B cells in disease. We found that IFNαβ signaling in B cells is driving increased splenomegaly, increased populations of activated B cells, and increased populations of germinal center (GC) B cells, memory B cells, and plasma blasts/cells, but did not affect the development of glomerulonephritis and immune-complex deposition. IFNAR expression by B cells also drove production of anti-chromatin IgG, and anti-dsDNA and -nRNP IgG and IgG2C auto-antibody levels, as well as increased Bcl2 expression, affecting GC B cell survival in B6.Nba2 mice.

B Cell Signatures Distinguish Cutaneous Lupus Erythematosus Subtypes and the Presence of Systemic Disease Activity

“…However, we subsequently identified a B cell gene signature in CLE skin that did indeed distinguish DLE from ACLE and SCLE, and this CLE-associated gene signature was highest in DLE lesions without associated systemic disease. These data indicate that while type I IFNs are known to contribute to the recruitment and activation of B cells in autoimmune disease (25)(26)(27), they may not be critical drivers in the differential recruitment of B cells observed in DLE skin.…”

Regulation of B Cell Responses in SLE by Three Classes of Interferons

“…Previous studies have highlighted the role of MZB cells and their regulation by T1IFNs in SLE mouse models. Elevated levels of circulating T1IFNs have also been shown to promote the activation and accumulation of plasmacytoid dendritic cells (pDCs) in several mouse models of SLE, including the Wiskott–Aldrich syndrome (WAS) chimera model of B cell-driven autoimmunity [ 49 ], B6.Nba2 [ 50 ], B6.Sle1.Sle2.Sle3 [ 51 ], and MRL/lpr models [ 52 ]. Subsequently, T1IFN production by activated pDCs in the MZ compartment of BXD2 lupus-prone mice was shown to deplete MARCO + MZ macrophages and allow for the migration of MZB cells into the B cell follicle [ 53 ].…”

“…Enhanced BCR signaling was also observed in CD27+CD43+ plasmablasts from SLE patients after pre-treatment with T1IFN in vitro [ 64 ]. Furthermore, T1IFN signaling in B cells increased BCL-2 expression [ 50 ], proliferation, antigen presentation, and CD40 expression [ 61 ]. Collectively, these data suggest the involvement of T1IFN signaling in B cells in regulating B cell selection and survival within the AFC and GC pathways in SLE ( Figure 1 ).…”

“…B cell responses, including GC and plasma cell responses and autoantibody production, were moderately reduced in the B6.Nba2 model after conditional deletion of IFNαR in total B cells using the Mb1-Cre mice. However, the deletion of IFNαR on B cells in B6.Nba2 mice did not affect immune complex deposition in the kidney or the development of glomerulornephritis [ 50 ]. Using the Wiskott–Aldrich syndrome (WAS) chimera model of B cell-driven SLE autoimmunity, Jackson et al found a minor role of T1IFN signaling in B cells in autoimmune B cell responses, autoantibody production, and nephritis [ 49 ].…”

“…Although the detailed mechanisms involved in the development of spontaneous GCs and AFCs in SLE are yet to be fully defined, several studies have highlighted the B cell-intrinsic requirement of T1IFN signaling in the regulation of spontaneous GC and AFC responses and increased titers of anti-nuclear antibodies in autoimmune-prone B6.Nba2, B6.Sle1b, BXD2, and bm12 cGVHD mice [53,61,62]. However, unlike in BXD2 mice, the marginal zone compartment, including MZB cells and MZ macrophages, remained intact in B6.Nba2 and B6.Sle1b mice [50,53,61,62]. Interestingly, B6.Sle1b mice overexpressing TLR7 had a reduced number of MZB cells but heightened autoimmune AFC, GC, and autoantibody responses similar to those observed in BXD2 mice [63], and these heightened responses were strongly correlated with increased T1IFN responses (63).…”