Abstract
BackgroundA hallmark of systemic lupus erythematosus is high titers of circulating autoantibodies. Recently, a novel CD11c+ B-cell subset has been identified that is critical for the development of autoimmunity. However, the role of CD11c+ B cells in the development of lupus is unclear. Chronic graft-versus-host disease (cGVHD) is a lupus-like syndrome with high autoantibody production. The purpose of this study was to explore the role of CD11c+ B cells in the pathogenesis of lupus in cGVHD mice.MethodscGVHD was induced by an intraperitoneal injection of 5 × 107 Bm12 splenocytes into B6 mice. Flow cytometry was used to analyze mice splenocytes and human samples. Magnetic beads were used to isolate mice B cells. Gene expression was determined by real-time quantitative polymerase chain reaction (RT-qPCR). Enzyme-linked immunosorbent assay (ELISA) was used to detect antibodies in serum and supernatants.ResultsThe percentage and absolute number of CD11c+ B cells was increased in cGVHD-induced lupus, with elevated levels of antichromatin immunoglobulin (Ig)G and IgG2a in sera. CD11c+ plasma cells from cGVHD mice produced large amounts of antichromatin IgG2a upon stimulation. Depletion of CD11c+ B cells reduced antichromatin IgG and IgG2a production. T-bet was upregulated in CD11c+ B cells. Knockout of T-bet in B cells alleviated cGVHD-induced lupus. Importantly, the percentage of T-bet+CD11c+ B cells increased in lupus patients and positively correlated with serum antichromatin levels.ConclusionT-bet+CD11c+ B cells promoted high antichromatin IgG production in the lupus-like disease model cGVHD. In lupus patients, the percentage of T-bet+CD11c+ B cells was elevated and positively correlated with antichromatin antibodies. The findings provide potential therapeutic insight into lupus disease treatment.
Highlights
A hallmark of systemic lupus erythematosus is high titers of circulating autoantibodies
Antiphospholipid antibodies are critically linked to the development of thrombotic events and obstetric morbidity [6], antiribonucleoprotein (RNP) antibodies are associated with myositis and Raynaud’s phenomenon [7], and antidouble-stranded DNA antibodies are associated with lupus nephritis [8]
CD11c+ B cells were increased in Chronic graft-versus-host disease (cGVHD) autoimmune mice Consistent with the results of the earlier study [20], we found that B6 mice that received splenocytes from Bm12 mice developed a lupus-like syndrome after 14 days of injection
Summary
A hallmark of systemic lupus erythematosus is high titers of circulating autoantibodies. Data accumulated over recent years have indicated that antichromatin autoantibody is involved in the pathogenesis of SLE and is associated with disease activity and lupus nephritis [10,11,12]. Immunization with active chromatin induces lupus-like syndrome in BALB/c mice [14]. Certain knockout mice, such as C1q, serum amyloid protein (SAP) and Dnase Ideficient mice, have high titers of antichromatin antibodies [15, 16]. It is not quite clear how B cells lose tolerance to chromatin in the development of lupus
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