B Cell Activation and Plasma Cell Differentiation Are Promoted by IFN-λ in Systemic Lupus Erythematosus

Background: Neuromyelitis optica (NMO)–systemic lupus erythematosus (SLE) association is a rare condition characterized by multiple autoantibodies. Objective: To examine if, during the evolution of NMO, anti-AQP4 responses are part of polyclonal B cell activation, and if T cell responses contribute. Methods: In 19 samples of six patients who developed NMO during SLE, we examined the correlation of AQP4-IgG1 and IgM with (i) anti-MOG IgG and IgM, (ii) anti-nuclear, anti-nucleosome and anti-dsDNA IgG antibodies, (iii) cytokines and chemokines in the serum and (iv) longitudinal relation to NMO relapses/remission. Results: AQP4-IgG1 was present 1–2–5 years before the first NMO relapse. During relapse, AQP4-IgG1, ANA, anti-dsDNA and anti-nucleosome antibodies were elevated. Anti-MOG IgG/IgM and AQP4-IgM antibodies were not detected. AQP4-IgG1 antibodies correlated with concentration of anti-nucleosome, IFN-γ,interferon-gamma-induced CCL10/IP-10 and CCL17/TARC ( p<0.05, respectively). CCL17/TARC correlated with levels of anti-nucleosome and anti-dsDNA ( p<0.05, respectively). Compared to healthy subjects, concentration of IFN-γ and CCL17/TARC was higher in NMO/SLE ( p<0.05). Conclusions: AQP4-IgG1 antibodies are present in the sera years before the first NMO attack in patients with SLE; elevation of anti-AQP4 is part of a polyclonal B cell response during NMO relapses; in spite of multiple autoantibodies in the serum, MOG antibodies were not present; Th1 responses accompany autoantibody responses in NMO/SLE.

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Polyclonal B Cell Activation in the Acute Phase of Systemic Lupus Erythematosus—Aspects of Pathogenic Significance

Journal of Investigative Dermatology ◽

10.1111/1523-1747.ep12505687 ◽

1982 ◽

Vol 78 (2) ◽

pp. 87-90 ◽

Cited By ~ 4

Author(s):

Wolfgang Diezel ◽

Wolfgang Günther ◽

Hans Meffert ◽

Niels Sönnichsen

Keyword(s):

Systemic Lupus Erythematosus ◽

B Cell ◽

Acute Phase ◽

Lupus Erythematosus ◽

Cell Activation ◽

B Cell Activation ◽

Systemic Lupus

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The suppression of Brd4 inhibits peripheral plasma cell differentiation and exhibits therapeutic potential for systemic lupus erythematosus

10.22541/au.161841605.50547094/v1 ◽

2021 ◽

Author(s):

Shan Zeng ◽

Qian Qiu ◽

Yi Zhou ◽

Youjun Xiao ◽

Jingnan Wang ◽

...

Keyword(s):

Cell Differentiation ◽

B Cells ◽

B Cell ◽

Plasma Cell ◽

Lupus Erythematosus ◽

Plasma Cells ◽

Therapeutic Potential ◽

Systemic Lupus ◽

Plasma Cell Differentiation ◽

Brd4 Inhibition

Background and purpose: To investigate the role of bromodomain-containing protein 4 (Brd4) in regulating B cell differentiation and its therapeutic potential for B cell-mediated autoimmune diseases such as systemic lupus erythematosus (SLE). Experimental Approach: Human and murine B cells were purified and cultured with different stimuli. B cell surface markers, proliferation and apoptosis were estimated by flow cytometry. Gene expression was measured by quantitative real-time PCR. Brd4 binding sites were analysed by the luciferase reporter assay and the chromatin immunoprecipitation (ChIP) assay. PFI-1 or JQ1 was used to inhibit Brd4. Mice with B cell-specific deletion of the Brd4 gene (Brd4flox/floxCD19-Cre+/-) and MRL/lpr mice were used to perform the in vivo experiments. Key Results: Brd4 inhibition suppressed plasmablast-mediated plasma cell differentiation but did not influence proliferation or apoptosis in healthy human and murine CD19+ B cells. PFI-1 treatment reduced the secretion of IgG and IgM in the supernatants of costimulation-induced B cells. Mechanistically, Brd4 regulates the terminal differentiation of B cells into plasma cells by targeting BLIMP1 by directly binding and activating the endogenous BLIMP1 promoter. Interestingly, PFI-1 treatment decreased the percentages of plasmablasts and plasma cells from patients with SLE. PFI-1 administration reduced the percentages of plasma cells, hypergammaglobulinemia and attenuated nephritis in MRL/lpr mice. Pristane-injected Brd4flox/floxCD19-Cre+/- mice exhibited improved nephritis and reduced percentages of plasma cells. Conclusions and Implications: Brd4 is an essential factor in regulating plasma cell differentiation. Brd4 inhibition may be a potential new strategy for the treatment of B cell-associated autoimmune disorders, including SLE.

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