B cells as therapeutic targets in SLE

Sanz, Iñaki; Lee, F. Eun-Hyung

doi:10.1038/nrrheum.2010.68

Cited by 231 publications

(190 citation statements)

References 96 publications

(96 reference statements)

Supporting

Mentioning

175

Contrasting

Unclassified

Order By: Relevance

“…59 The alterations in T-and B-cell subtypes has led to the investigation of many T and B cell-targeted therapies for the treatment of lupus, as recently reviewed. 60,61 We tested the effect of HSP90 on T and B cells by quantifying populations of splenocytes expressing markers for specific subtypes of T and B cells shown to be altered in MRL/lpr mice. Splenocytes were collected from 18-week-old mice treated with 17-DMAG for six weeks or treated with DMSO for six weeks (control), stained for appropriate markers and analyzed by flow cytometry.…”

Section: -Dmag Altered Splenocyte Profiles In Mrl/lpr Lupus Micementioning

confidence: 99%

“…[97][98][99] According to a recent review article, B cells act in lupus to present auto-antigens, induce T helper cells, CD8 1 effector cells, and to inhibit T REG cells. 61 Some B-cell therapy approaches being investigated include the therapeutic targeting of HSP90 client proteins such as TLR and phosphoinositide 3-kinase. When inhibited, these signal pathway proteins reduce B-cell activation and survival.…”

Section: Mature B Cells Were Decreased In Mice Treated With 17-dmagmentioning

confidence: 99%

“…It should also be noted that targeting IL-6 (an HSP90-dependent cytokine) reduces memory-cell differentiation. 61 The inhibitor for gp96 was shown to reduce populations of mature B cells, B2201 and MHC class II1 cells. 11 However, it has also been shown that splenic plasma cells and germinal center B cells are unaffected by 17-DMAG treatment.…”

Section: Mature B Cells Were Decreased In Mice Treated With 17-dmagmentioning

confidence: 99%

See 2 more Smart Citations

Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus

et al. 2012

View full text Add to dashboard Cite

Elevated expression of heat shock protein 90 (HSP90) has been found in kidneys and serum of systemic lupus erythematosus (SLE) patients and MRL/Mp-Fas lpr /Fas lpr (MRL/lpr) autoimmune mice. We investigated if inhibition of HSP90 would reduce disease in MRL/ lpr mice. In vitro, pretreatment of mesangial cells with HSP90 inhibitor Geldanamycin prior to immune-stimulation showed reduced expression of IL-6, IL-12 and NO. In vivo, we found HSP90 expression was elevated in MRL/lpr kidneys when compared to C57BL/6 mice and MRL/lpr mice treated with HSP90 inhibitor 17-DMAG. MRL/lpr mice treated with 17-DMAG showed decreased proteinuria and reduced serum anti-dsDNA antibody production. Glomerulonephritis and glomerular IgG and C3 were not significantly affected by administration of 17-DMAG in MRL/lpr. 17-DMAG increased CD8 1 T cells, reduced double-negative T cells, decreased the CD4/CD8 ratio and reduced follicular B cells. These studies suggest that HSP90 may play a role in regulating T-cell differentiation and activation and that HSP90 inhibition may reduce inflammation in lupus.

show abstract

Section: -Dmag Altered Splenocyte Profiles In Mrl/lpr Lupus Micementioning

confidence: 99%

Section: Mature B Cells Were Decreased In Mice Treated With 17-dmagmentioning

confidence: 99%

Section: Mature B Cells Were Decreased In Mice Treated With 17-dmagmentioning

confidence: 99%

See 1 more Smart Citation

Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Of note, autoantibody directed against dsDNA, which can be present prior to clinical symptoms of SLE, is implicated in the pathogenesis of lupus nephritis and is a major cause of morbidity and mortality in SLE (1)(2)(3)(4). In fact, anti-dsDNA Ab was reported as the central pathogenic autoantibody involved in SLE pathogenesis (5)(6)(7)(8)(9). However, the underlying mechanisms involved in the induction of anti-dsDNA Ab in patients with SLE remain unknown.…”

mentioning

confidence: 99%

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

View full text Add to dashboard Cite

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.

show abstract

“…B cells play a central role in the pathogenesis of SLE [2], and patients with SLE exhibit abnormal B-cell activation and increased sensitivity and proliferation of B cells [3]. Moreover, the Correspondence: Dr. Yayi Hou e-mail: yayihou@nju.edu.cn clinical success of B-cell depletion therapy further proves the important role of B cells in SLE pathogenesis [4,5]. B cells not only produce antibodies and release cytokines and chemokines but also present both peptide and lipid antigens [6].…”

mentioning

confidence: 99%

TLR9‐induced miR‐155 and Ets‐1 decrease expression of CD1d on B cells in SLE

et al. 2015

View full text Add to dashboard Cite

B cells present lipid antigens to CD1d-restricted invariant natural killer T (iNKT) cells to maintain autoimmune tolerance, and this process is disrupted in systemic lupus erythematosus (SLE). Inflammation may inhibit CD1d expression to exacerbate the pathology of lupus. However, how inflammation regulates CD1d expression on B cells is unclear in SLE.In the present study, we showed that the surface expression of CD1d on B cells from SLE mice was decreased and that stimulation of inflammatory responses through TLR9 decreased the membrane and total CD1d levels of CD1d on B cells. Moreover, inflammation-related microRNA-155 (miR-155) negatively correlated with the expression of CD1d in B cells. miR-155 directly targeted the 3 -untranslated region (3 -UTR) of CD1d upon TLR9 activation in both humans and mice. The inhibitory effects of miR-155 on CD1d expression in B cells impaired their antigen-presenting capacity to iNKT cells. In addition, Ets-1, a susceptibility gene of SLE, also directly regulated the expression of the CD1d gene at the transcriptional level. These findings provide new insight into the mechanism underlying decreased CD1d expression on B cells in SLE, suggesting that inhibition of inflammation may increase CD1d expression in B cells to ameliorate SLE via modulating iNKT cells.Keywords: B cells r CD1d r Ets-1 r miR-155 r SLE Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionSystemic lupus erythematosus (SLE) is a complex and chronic autoimmune disease with an unclear etiology [1]. B cells play a central role in the pathogenesis of SLE [2], and patients with SLE exhibit abnormal B-cell activation and increased sensitivity and proliferation of B cells [3]. Moreover, the Correspondence: Dr. Yayi Hou e-mail: yayihou@nju.edu.cn clinical success of B-cell depletion therapy further proves the important role of B cells in SLE pathogenesis [4,5]. B cells not only produce antibodies and release cytokines and chemokines but also present both peptide and lipid antigens [6].CD1 family molecules are nonclassical MHC proteins related to the class I MHC proteins and are involved in the presentation of lipid antigens to T cells. Several studies have suggested that CD1d may play an immunoregulatory role in the development of lupus, and CD1d deficiency exacerbates lupus nephritis in the pristineinduced model [7] and inflammatory dermatitis in MRL-lpr/lpr C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 1934-1945 Cellular immune response 1935 mice [8]. Importantly, endogenous DNA stimulates inflammatory responses through TLR9 and exacerbates lupus disease pathology [9,10]. Viral infection could downregulate the expression of CD1d in APCs, such as B cells [11,12], DCs, and macrophages [13]. A number of exogenous viruses, especially Epstein-Barr virus (EBV) [14,15], also have been linked to the pathogenesis of SLE [16]. Our previous studies have indicated that ligands for both TLR9 and TLR7 lead to B...

show abstract

B cells as therapeutic targets in SLE

Cited by 231 publications

References 96 publications

Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus

Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus

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

TLR9‐induced miR‐155 and Ets‐1 decrease expression of CD1d on B cells in SLE

Contact Info

Product

Resources

About