Serum from patients with SLE instructs monocytes to promote IgG and IgA plasmablast differentiation

Joo, Hye Mee; Coquery, Christine M.; Xue, Yaming; Gayet, Ingrid; Dillon, Stacey R.; Punaro, Marilynn; Zurawski, Gérard; Banchereau, Jacques; Pascual, Virginia; Oh, Sang Kon

doi:10.1084/jem.20111644

Cited by 99 publications

(92 citation statements)

References 70 publications

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“…In these pathologies, elevated type I IFN levels are thought to induce hyperactivation of the immune response based on increased antigen presentation by cDCs and IFN-DCs, increased activation of professional cytotoxic cells and stimulation of auto-antibodies production, which all play an important role in the loss of tolerance and persistent autoimmune reaction. This close relationship was demonstrated in a recent paper by showing that SLE patient serum could induce the differentiation of monocytes into DCs in an IFN-dependent manner, and that these DCs could stimulate naive and memory B cells to differentiate into IgG-and IgA-plasmablasts resembling those found in the blood of SLE patients [195]. Elevated levels of type I IFNs were also recognized as important pathogenic factors for the increased risk of atherosclerosis described in SLE patients because of the above described detrimental vascular effects [40].…”

Section: Pdc-derived Type I Ifns In Autoimmunitymentioning

confidence: 53%

Dendritic cell recruitment and activation in autoimmunity

Sozzani

Prete

Bosisio

2017

Journal of Autoimmunity

108

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Section: Pdc-derived Type I Ifns In Autoimmunitymentioning

confidence: 53%

Dendritic cell recruitment and activation in autoimmunity

Sozzani

Prete

Bosisio

2017

Journal of Autoimmunity

108

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“…These findings indicated a potential role for circulating DNA-containing ICs in autoantibody production in SLE patients. Consistently, studies of SLE patients revealed that exposure of healthy monocytes to SLE serum resulted in the generation of dendritic cells that were endowed with a unique ability to promote IgG and IgA plasmablast differentiation (17)(18)(19). Combining these findings prompted us to hypothesize that the SLE plasma, especially circulating DNA-containing ICs, might induce anti-dsDNA autoantibody and, thus, maintained production of anti-dsDNA autoantibody in SLE patients.…”

mentioning

confidence: 81%

Autoantibody Induction by DNA-Containing Immune Complexes Requires HMGB1 with the TLR2/MicroRNA-155 Pathway

Wen

Lin

Chen

et al. 2013

The Journal of Immunology

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Anti-dsDNA Ab is reported to be the central pathogenic autoantibody involved in systemic lupus erythematosus (SLE) pathogenesis. However, the mechanisms involved in anti-dsDNA Ab production remain unclear. Recent evidence indicated that DNA-containing immune complexes (ICs) in circulation (termed “circulating DNA-containing ICs”), which are one of the hallmarks of SLE, might be involved in autoantibody production. In this study, we explored their potential role in anti-dsDNA Ab production and the underlying mechanisms in patients with SLE. We demonstrated that circulating DNA-containing ICs were able to induce anti-dsDNA Ab. Of note, HMGB1 in circulating DNA-containing ICs was crucial for anti-dsDNA Ab induction. The HMGB1 content of circulating DNA-containing ICs also correlated positively with anti-dsDNA Ab production in patients with SLE. Further, we revealed that the TLR2/MyD88/microRNA-155 (miR-155) pathway was pivotal for HMGB1 to confer anti-dsDNA Ab induction, and Ets-1 was a functional target of miR-155 in the induction of anti-dsDNA Ab by circulating DNA-containing ICs. Finally, we validated the expression of miR-155 and Ets-1 and their correlation with anti-dsDNA Ab production in patients with SLE. To our knowledge, this is the first report of the crucial role of HMGB1 in autoantibody production mediated by the TLR2/MyD88/miR-155/Ets-1 pathway. These findings identify a novel mechanism to account for the persistent production of anti-dsDNA Ab in SLE and a clue for developing a novel therapeutic strategy against SLE.

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“…B cells were isolated from peripheral blood of healthy donors and cultured with CpG (a TLR9 agonist) and/or cytokine cocktails including IL-2, IL-6, and interferon-alpha (IFN-a), which are known to provide conditions for effective plasmablast differentiation (Jego et al, 2003;Joo et al, 2012). Indeed, we detected CD27 hi CD38 + putative plasmablasts after culture with CpG, while concomitant treatment with CpG and cytokine cocktails induced a greater frequency of an additional population of CD27 int CD38 + cells as well as CD27 hi CD38 + cells ( Figure 6A).…”

Section: Plasmablast-derived Il-10 Inhibits Dendritic Cell Function Tmentioning

confidence: 99%

Interleukin-10-Producing Plasmablasts Exert Regulatory Function in Autoimmune Inflammation

et al. 2014

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B cells can suppress autoimmunity by secreting interleukin-10 (IL-10). Although subpopulations of splenic B lineage cells are reported to express IL-10 in vitro, the identity of IL-10-producing B cells with regulatory function in vivo remains unknown. By using IL-10 reporter mice, we found that plasmablasts in the draining lymph nodes (dLNs), but not splenic B lineage cells, predominantly expressed IL-10 during experimental autoimmune encephalomyelitis (EAE). These plasmablasts were generated only during EAE inflammation. Mice lacking plasmablasts by genetic ablation of the transcription factors Blimp1 or IRF4 in B lineage cells developed an exacerbated EAE. Furthermore, IRF4 positively regulated IL-10 production that can inhibit dendritic cell functions to generate pathogenic T cells. Our data demonstrate that plasmablasts in the dLNs serve as IL-10 producers to limit autoimmune inflammation and emphasize the importance of plasmablasts as IL-10-producing regulatory B cells.

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Serum from patients with SLE instructs monocytes to promote IgG and IgA plasmablast differentiation

Abstract: Monocytes exposed to serum from SLE patients promote B cell differentiation to IgG and IgA plasmablasts dependent on BAFF and IL-10 or APRIL, respectively.

Cited by 99 publications

References 70 publications

Dendritic cell recruitment and activation in autoimmunity

Dendritic cell recruitment and activation in autoimmunity

Autoantibody Induction by DNA-Containing Immune Complexes Requires HMGB1 with the TLR2/MicroRNA-155 Pathway

Interleukin-10-Producing Plasmablasts Exert Regulatory Function in Autoimmune Inflammation

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