P100 Proportions of B cell subsets are altered in incomplete lupus erythematosus patients and correlate with interferon score and IgG levels

Background:Systemic lupus erythematosus (SLE) is characterized by two pathogenic key signatures, type I interferon (IFN) (1.) and B-cell abnormalities (2.). How these signatures are interrelated is not known. Type I-II IFN trigger activation of Janus kinase (JAK) – signal transducer and activator of transcription (STAT).Objectives:JAK-STAT inhibition is an attractive therapeutic possibility for SLE (3.). We assess STAT1 and STAT3 expression and phosphorylation at baseline and after IFN type I and II stimulation in B-cell subpopulations of SLE patients compared to other autoimmune diseases and healthy controls (HD) and related it to disease activity.Methods:Expression of STAT1, pSTAT1, STAT3 and pSTAT3 in B and T-cells of 21 HD, 10 rheumatoid arthritis (RA), 7 primary Sjögren’s (pSS) and 22 SLE patients was analyzed by flow cytometry. STAT1 and STAT3 expression and phosphorylation in PBMCs of SLE patients and HD after IFNα and IFNγ incubation were further investigated.Results:SLE patients showed substantially higher STAT1 but not pSTAT1 in B and T-cell subsets. Increased STAT1 expression in B cell subsets correlated significantly with SLEDAI and Siglec-1 on monocytes, a type I IFN marker (4.). STAT1 activation in plasmablasts was IFNα dependent while monocytes exhibited dependence on IFNγ.Figure 1.Significantly increased expression of STAT1 by SLE B cells(A) Representative histograms of baseline expression of STAT1, pSTAT1, STAT3 and pSTAT3 in CD19+ B cells of SLE patients (orange), HD (black) and isotype controls (grey). (B) Baseline expression of STAT1 and pSTAT1 or (C) STAT3 and pSTAT3 in CD20+CD27-, CD20+CD27+ and CD20lowCD27high B-lineage cells from SLE (orange) patients compared to those from HD (black). Mann Whitney test; ****p≤0.0001.Figure 2.Correlation of STAT1 expression by SLE B cells correlates with type I IFN signature (Siglec-1, CD169) and clinical activity (SLEDAI).Correlation of STAT1 expression in CD20+CD27- näive (p<0.0001, r=0.8766), CD20+CD27+ memory (p<0.0001, r=0.8556) and CD20lowCD27high (p<0.0001, r=0.9396) B cells from SLE patients with (A) Siglec-1 (CD169) expression on CD14+ cells as parameter of type I IFN signature and (B) lupus disease activity (SLEDAI score). Spearman rank coefficient (r) was calculated to identify correlations between these parameters. *p≤0.05, **p≤0.01. (C) STAT1 expression in B cell subsets of a previously undiagnosed, active SLE patient who was subsequently treated with two dosages of prednisolone and reanalyzed.Conclusion:Enhanced expression of STAT1 by B-cells candidates as key node of two immunopathogenic signatures (type I IFN and B-cells) related to important immunopathogenic pathways and lupus activity. We show that STAT1 is activated upon IFNα exposure in SLE plasmablasts. Thus, Jak inhibitors, targeting JAK-STAT pathways, hold promise to block STAT1 expression and control plasmablast induction in SLE.References:[1]Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A. 2003;100(5):2610-5.[2]Lino AC, Dorner T, Bar-Or A, Fillatreau S. Cytokine-producing B cells: a translational view on their roles in human and mouse autoimmune diseases. Immunol Rev. 2016;269(1):130-44.[3]Dorner T, Lipsky PE. Beyond pan-B-cell-directed therapy - new avenues and insights into the pathogenesis of SLE. Nat Rev Rheumatol. 2016;12(11):645-57.[4]Biesen R, Demir C, Barkhudarova F, Grun JR, Steinbrich-Zollner M, Backhaus M, et al. Sialic acid-binding Ig-like lectin 1 expression in inflammatory and resident monocytes is a potential biomarker for monitoring disease activity and success of therapy in systemic lupus erythematosus. Arthritis Rheum. 2008;58(4):1136-45.Disclosure of Interests:Arman Aue: None declared, Franziska Szelinski: None declared, Sarah Weißenberg: None declared, Annika Wiedemann: None declared, Thomas Rose: None declared, Andreia Lino: None declared, Thomas Dörner Grant/research support from: Janssen, Novartis, Roche, UCB, Consultant of: Abbvie, Celgene, Eli Lilly, Roche, Janssen, EMD, Speakers bureau: Eli Lilly, Roche, Samsung, Janssen

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The expansion of activated naive DNA autoreactive B cells and its association with disease activity in systemic lupus erythematosus patients

Arthritis Research & Therapy ◽

10.1186/s13075-021-02557-0 ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

Kittikorn Wangriatisak ◽

Chokchai Thanadetsuntorn ◽

Thamonwan Krittayapoositpot ◽

Chaniya Leepiyasakulchai ◽

Thanitta Suangtamai ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

B Cells ◽

Disease Activity ◽

B Cell ◽

Lupus Erythematosus ◽

Systemic Lupus ◽

Autoreactive B Cells ◽

Dsdna Antibody ◽

Cell Subpopulations ◽

B Cell Subsets

Abstract Background Autoreactive B cells are well recognized as key participants in the pathogenesis of systemic lupus erythematosus (SLE). However, elucidating the particular subset of B cells in producing anti-dsDNA antibodies is limited due to their B cell heterogeneity. This study aimed to identify peripheral B cell subpopulations that display autoreactivity to DNA and contribute to lupus pathogenesis. Methods Flow cytometry was used to detect total B cell subsets (n = 20) and DNA autoreactive B cells (n = 15) in SLE patients’ peripheral blood. Clinical disease activities were assessed in SLE patients using modified SLEDAI-2 K and used for correlation analyses with expanded B cell subsets and DNA autoreactive B cells. Results The increases of circulating double negative 2 (DN2) and activated naïve (aNAV) B cells were significantly observed in SLE patients. Expanded B cell subsets and DNA autoreactive B cells represented a high proportion of aNAV B cells with overexpression of CD69 and CD86. The frequencies of aNAV B cells in total B cell populations were significantly correlated with modified SLEDAI-2 K scores. Further analysis showed that expansion of aNAV DNA autoreactive B cells was more related to disease activity and serum anti-dsDNA antibody levels than to total aNAV B cells. Conclusion Our study demonstrated an expansion of aNAV B cells in SLE patients. The association between the frequency of aNAV B cells and disease activity patients suggested that these expanded B cells may play a role in SLE pathogenesis.

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Multiple Functions of B Cells in the Pathogenesis of Systemic Lupus Erythematosus

International Journal of Molecular Sciences ◽

10.3390/ijms20236021 ◽

2019 ◽

Vol 20 (23) ◽

pp. 6021 ◽

Cited By ~ 3

Author(s):

Kongyang Ma ◽

Wenhan Du ◽

Xiaohui Wang ◽

Shiwen Yuan ◽

Xiaoyan Cai ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

B Cells ◽

B Cell ◽

Lupus Erythematosus ◽

Therapeutic Interventions ◽

Systemic Lupus ◽

Autoantibody Production ◽

Regulatory B Cell ◽

Functional Features ◽

B Cell Subsets

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by excessive autoantibody production and multi-organ involvement. Although the etiology of SLE still remains unclear, recent studies have characterized several pathogenic B cell subsets and regulatory B cell subsets involved in the pathogenesis of SLE. Among pathogenic B cell subsets, age-associated B cells (ABCs) are a newly identified subset of autoreactive B cells with T-bet-dependent transcriptional programs and unique functional features in SLE. Accumulation of T-bet+ CD11c+ ABCs has been observed in SLE patients and lupus mouse models. In addition, innate-like B cells with the autoreactive B cell receptor (BCR) expression and long-lived plasma cells with persistent autoantibody production contribute to the development of SLE. Moreover, several regulatory B cell subsets with immune suppressive functions have been identified, while the impaired inhibitory effects of regulatory B cells have been indicated in SLE. Thus, further elucidation on the functional features of B cell subsets will provide new insights in understanding lupus pathogenesis and lead to novel therapeutic interventions in the treatment of SLE.

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Proportions of B-cell subsets are altered in incomplete systemic lupus erythematosus and correlate with interferon score and IgG levels

Rheumatology ◽

10.1093/rheumatology/keaa114 ◽

2020 ◽

Vol 59 (9) ◽

pp. 2616-2624

Author(s):

Svenja Henning ◽

Wietske M Lambers ◽

Berber Doornbos-van der Meer ◽

Wayel H Abdulahad ◽

Frans G M Kroese ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Lupus Erythematosus ◽

Cell Subset ◽

Cross Sectional Study ◽

Type I ◽

Healthy Controls ◽

Sectional Study ◽

Cross Sectional ◽

B Cell Subsets

Abstract Objectives Incomplete SLE (iSLE) patients display symptoms typical for SLE but have insufficient criteria to fulfil the diagnosis. Biomarkers are needed to identify iSLE patients that will progress to SLE. IFN type I activation, B-cell-activating factor (BAFF) and B-cell subset distortions play an important role in the pathogenesis of SLE. The aim of this cross-sectional study was to investigate whether B-cell subsets are altered in iSLE patients, and whether these alterations correlate with IFN scores and BAFF levels. Methods iSLE patients (n = 34), SLE patients (n = 41) with quiescent disease (SLEDAI ≤4) and healthy controls (n = 22) were included. Proportions of B-cell subsets were measured with flow cytometry, IFN scores with RT-PCR and BAFF levels with ELISA. Results Proportions of age-associated B-cells were elevated in iSLE patients compared with healthy controls and correlated with IgG levels. In iSLE patients, IFN scores and BAFF levels were significantly increased compared with healthy controls. Also, IFN scores correlated with proportions of switched memory B-cells, plasma cells and IgG levels, and correlated negatively with complement levels in iSLE patients. Conclusion In this cross-sectional study, distortions in B-cell subsets were observed in iSLE patients and were correlated with IFN scores and IgG levels. Since these factors play an important role in the pathogenesis of SLE, iSLE patients with these distortions, high IFN scores, and high levels of IgG and BAFF may be at risk for progression to SLE.

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CHANGES IN B-CELL SUBSETS DO NOT ACCOUNT FOR DECREASED COMPLEMENT RECEPTOR 2 LEVELS IN HUMAN SYSTEMIC LUPUS ERYTHEMATOSUS.

Journal of Investigative Medicine ◽

10.1097/00042871-200701010-00282 ◽

2007 ◽

Vol 55 (1) ◽

pp. S121

Author(s):

D. W. Pearson ◽

S. A. Boackle

Keyword(s):

Systemic Lupus Erythematosus ◽

B Cell ◽

Lupus Erythematosus ◽

Complement Receptor ◽

Human Systemic Lupus Erythematosus ◽

Systemic Lupus ◽

Complement Receptor 2 ◽

B Cell Subsets

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Sample stability and variability of B-cell subsets in blood from healthy subjects and patients with systemic lupus erythematosus

Cytometry Part B Clinical Cytometry ◽

10.1002/cyto.b.20482 ◽

2009 ◽

Vol 9999B ◽

pp. NA-NA ◽

Cited By ~ 1

Author(s):

Shelley Sims Belouski ◽

Daniel Wallace ◽

Michael Weisman ◽

Mariko Ishimori ◽

Lisa Hendricks ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

B Cell ◽

Lupus Erythematosus ◽

Healthy Subjects ◽

Systemic Lupus ◽

Sample Stability ◽

B Cell Subsets

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MicroRNA Profiling of B Cell Subsets from Systemic Lupus Erythematosus Patients Reveals Promising Novel Biomarkers

International Journal of Molecular Sciences ◽

10.3390/ijms160816953 ◽

2015 ◽

Vol 16 (8) ◽

pp. 16953-16965 ◽

Cited By ~ 21

Author(s):

Isabelle Duroux-Richard ◽

Jimena Cuenca ◽

Clara Ponsolles ◽

Alejandro Badilla Piñeiro ◽

Fernando Gonzalez ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

B Cell ◽

Lupus Erythematosus ◽

Systemic Lupus ◽

Microrna Profiling ◽

Novel Biomarkers ◽

B Cell Subsets

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Inactive disease in lupus patients is linked to autoantibodies to type-I interferons that normalize blood IFNα and B cell subsets

10.1101/2021.04.07.21255049 ◽

2021 ◽

Author(s):

Madhvi Menon ◽

Hannah F. Bradford ◽

Liis Haljasmagi ◽

Martti Vanker ◽

Pärt Peterson ◽

...

Keyword(s):

B Cell ◽

Lupus Erythematosus ◽

Type I Interferons ◽

Inactive Disease ◽

Type I ◽

B Cell Differentiation ◽

Novel Therapy ◽

Signalling Molecules ◽

B Cell Subsets

AbstractSystemic Lupus Erythematosus (SLE) is characterized by a prominent increase in expression of type-I interferon (IFN)-regulated genes in 50-75% of patients. Here we investigate the presence of autoantibodies (auto-Abs) against type I IFN in SLE patients and their possible role in controlling disease severity. We report that out of 491 SLE patients, 66 had detectable anti-IFNα-auto-Abs. The presence of neutralizing anti-IFNα-auto-Abs correlates with lower levels of circulating IFNα protein, inhibition of IFN down-stream signalling molecules and gene signatures and with an inactive global disease score. Previously reported B cell frequency abnormalities, found to be involved in SLE pathogenesis, including increased levels of immature, double negative and plasmablast B cell populations were partially normalized in patients with neutralising anti-IFNα-auto-Abs compared to other patient groups. We also show that sera from SLE patients with neutralising anti-IFNα-auto-Abs biases in vitro B cell differentiation towards classical memory phenotype, while sera from patients without anti-IFNα-Abs drives plasmablasts differentiation. Our findings support a role for neutralising anti-IFNα-auto-Abs in controlling SLE pathogenesis and highlight their potential efficacy as novel therapy.

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