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

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.

scholarly journals The expansion of activated naive DNA autoreactive B Cells and its association with disease activity in Systemic Lupus Erythematosus patients

2021 ◽  
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 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-2K 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-2K 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. Thus, aNAV B cells may provide a candidate biomarker for monitoring disease activity in these patients.

scholarly journals OP0005 ELEVATED STAT1 EXPRESSION BUT NOT PHOSPHORYLATION IN LUPUS B CELLS CORRELATES WITH DISEASE ACTIVITY AND INCREASED PLASMABLAST SUSCEPTIBILITY

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 4-5
Author(s):  
A. Aue ◽  
F. Szelinski ◽  
S. Weißenberg ◽  
A. Wiedemann ◽  
T. Rose ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cells ◽  
Autoimmune Diseases ◽  
Disease Activity ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Type I ◽  
Type I Ifn ◽  
Systemic Lupus ◽  
B Cell Subsets

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

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

2019 ◽  
Vol 20 (23) ◽  
pp. 6021 ◽  
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.

scholarly journals Activated memory B cell subsets correlate with disease activity in systemic lupus erythematosus: Delineation by expression of CD27, IgD, and CD95

2008 ◽  
Vol 58 (6) ◽  
pp. 1762-1773 ◽  
Author(s):  
Annett M. Jacobi ◽  
Karin Reiter ◽  
Meggan Mackay ◽  
Cynthia Aranow ◽  
Falk Hiepe ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Systemic Lupus ◽  
Memory B Cell ◽  
B Cell Subsets

scholarly journals Phenotyping of P105-Negative B Cell Subsets in Patients with Systemic Lupus Erythematosus

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Syuichi Koarada ◽  
Yoshifumi Tada ◽  
Rie Suematsu ◽  
Sachiko Soejima ◽  
Hisako Inoue ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Flow Cytometry ◽  
B Cells ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Normal Subjects ◽  
Systemic Lupus ◽  
Phenotypic Analysis ◽  
B Cell Subsets

This study aimed to investigate phenotype of RP105(−) B cell subsets in patients with systemic lupus erythematosus (SLE). Flow cytometry was used for phenotyping RP105-negaive B cell subsets. Based on CD19, RP105, and CD138 expression, RP105(−) B cells consist of at least 5 subsets of late B cells, including CD19(+)RP105(int), CD19(+) RP105(−), CD19(low) RP105(−) CD138(−), CD19(low) RP105(−)CD138(int), and CD19(low) RP105(−) CD138(++) B cells. Especially, CD19(+)RP105(int) and CD19(low) RP105(−)CD138(int) B cells are significantly larger than other RP105(−) B cell subsets in SLE. By comparison of RP105(−) B cell subsets between patients with SLE and normal subjects, these subsets were detectable even in normal subjects, but the percentages of RP105(−) B cell subsets were significantly larger in SLE. The phenotypic analysis of RP105(−) B cell subsets suggests dysregulation of later B cell subsets in SLE and may provide new insights into understanding regulation of B cells in human SLE.

scholarly journals Increased Proportion of CD226+ B Cells Is Associated With the Disease Activity and Prognosis of Systemic Lupus Erythematosus

2021 ◽  
Vol 12 ◽  
Author(s):  
Miki Nakano ◽  
Masahiro Ayano ◽  
Kazuo Kushimoto ◽  
Shotaro Kawano ◽  
Kazuhiko Higashioka ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cells ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Activity Index ◽  
Renal Involvement ◽  
Laboratory Data ◽  
Clinical Manifestations ◽  
Systemic Lupus ◽  
Dsdna Antibody

BackgroundCD226, an activating receptor expressed on the surface of natural killer (NK) cells and T cells, is also seen on B cells and CD226 polymorphism is associated with systemic lupus erythematosus (SLE). Because the specific roles of CD226+ B cells in SLE are still unknown, we investigated the association of CD226+ B cells with SLE.MethodsWe measured CD226 expression on B cells and its subsets using flow cytometry in 48 SLE patients and 24 healthy controls (HCs). We assessed the relationships between CD226+ B cells and SLE Disease Activity Index 2000 (SLEDAI-2K), clinical manifestations, laboratory data, and prognosis after 12 months.ResultsThe proportions of CD226+ cells in whole B cells and all its subsets were significantly higher in SLE patients than HCs. In SLE patients, the proportions of CD226+ B cells and CD226+ switched-memory (SM) B cells were significantly correlated with SLEDAI-2K scores and anti-dsDNA antibody titers, and negatively correlated with serum complement levels. Moreover, basal percentages of CD226+ B cells and CD226+ SM B cells were low in patients who were in Lupus Low Disease Activity State after 12 months. In patients with renal involvement, the proportion of CD226+ B cells increased. Additionally, the proportion of CD226+ B cells was higher in patients who were not in complete renal remission after 12 months.ConclusionsIncreased proportion of CD226+ B cells was associated with disease activity and prognosis of SLE. CD226+ B cells may be a useful biomarker for the management of SLE.

scholarly journals THU0221 EVIDENCE FOR A PATHOGENIC ROLE OF EXTRA-FOLLICULAR, IL-10 PRODUCING CCR6+B-HELPER T-CELLS IN SYSTEMIC LUPUS ERYTHEMATOSUS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 337-337
Author(s):  
M. Gerosa ◽  
F. Facciotti ◽  
P. Larghi ◽  
R. Bosotti ◽  
C. Vasco ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
T Cells ◽  
B Cells ◽  
Disease Activity ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Helper T Cells ◽  
Systemic Lupus ◽  
Pathogenic Role

Background:IL-10 plays a key role in systemic lupus erythematosus (SLE) pathogenesis, promoting B-cell response. IL10 is mainly secreted by regulatory T-cells, but follicular helper T-cells (TFH), also produce it. We previously identified a subset of CCR6+IL-7R+T-cells in human tonsils providing IL-10-dependent B-cell help. These CCR6+T-cells were able to produce IL-10, inducing IgG production.Objectives:to investigate a possible role of CD4+CCR6+IL7R+T-cells in SLE pathogenesis.Methods:37 patients fulfilling the ACR criteria for SLE have been included. Disease activity was assessed by 2k-SLEDAI. PBMC were analyzed by flow cytometry, using specific lineage markers. CCR6+IL7R+T-cells purified from total PBMC of SLE patients or healthy donors (HD) were co-cultured with autologous CD20+B-cells. IL-10, Il-17, total IgG and anti-dsDNA antibodies titers in patients serum and culture supernatants were assessed by ELISA. Embedded sections of lymph nodes from 8 SLE patients were analyzed by immunofluorescence (IF).Results:IL10 levels were significantly higher in SLE patients (Fig 1A). CD4+CCR6+IL7R+T-cells were significantly increased in SLE, in particular in those with higher disease activity and higher IL10 levels. CD4+CCR6+IL7R+T-cells levels associated with anti-dsDNA positivity. CCR6+IL7R+T-cells of SLE patients induced production of IgG and anti-dsDNA IgG (in anti-dsDNA + patients) from autologous B-cells, providing spontaneous help for autoantibody productionex vivo(Fig 1B-C). The IF study of lymph nodes of SLE patients showed that IL-10-producing CCR6+T-cells were highly abundant and co-localized with B-cells at follicle margins.Fig 1Conclusion:our study revealed a novel population of extra-follicular B-helper T-cells, which produce IL-10 and could play a prominent pathogenic role in SLE. Further studies will clarify if this potentially pathogenic cell population might represent a possible future therapeutic target.References:[1]Facciotti F. J Allergy Clin Immunol. 2016; Geginat J. Semin Immunol. 2019; Tsokos GC. Nat Rev Rheumatol. 2019Tab 1:SLE patients characteristics(n=37)DemographicsFemale/Male, n37/5Age, years, median (IQR)44 (38-49)Disease duration, years, median (IQR)19 (11-26)Lab testsANA86%*anti-dsDNA (%)46% medium/high titre41%Disease activity and clinical manifestations SLEDAI-2K, median (min-max)3.5 (0-24) Moderate/high activity19%Ongoing therapyPrednisone dose mg/day, median (IQR)7,5 mg (2,5 – 20)hydroxychloroquine78%Immunosuppressants87%Fig 2Disclosure of Interests: :Maria Gerosa: None declared, Federica Facciotti: None declared, Paola Larghi: None declared, Roberto Bosotti: None declared, Chiara Vasco: None declared, Nicola Gagliani: None declared, Chiara Cordiglieri: None declared, Elsa Rottoli: None declared, Alessandra Emiliana Penatti: None declared, Lorenza Maria Argolini: None declared, Bhavna Karnani: None declared, Yasushi Kobayashi: None declared, Mauro Bombaci: None declared, Jan Piet Van Hamburg: None declared, Roberta Gualtierotti: None declared, Stefano Gatti: None declared, Sara Torretta: None declared, Lorenzo Pignataro: None declared, Sander W. Tas: None declared, Roberto Caporali Consultant of: AbbVie; Gilead Sciences, Inc.; Lilly; Merck Sharp & Dohme; Celgene; Bristol-Myers Squibb; Pfizer; UCB, Speakers bureau: Abbvie; Bristol-Myers Squibb; Celgene; Lilly; Gilead Sciences, Inc; MSD; Pfizer; Roche; UCB, Sergio Abrignani: None declared, Massimiliano Pagani: None declared, Fabio Grassi: None declared, Pier Luigi Meroni: None declared, Richard Flavell: None declared, Jens Geginat: None declared

scholarly journals Aberrant expression of PD-1 on B cells and its association with the clinical parameters of systemic lupus erythematosus

2020 ◽  
Author(s):  
Yang Lu ◽  
Qingqing Zhu ◽  
Yun Li ◽  
Qiyi Wang ◽  
Chao Jiang ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cells ◽  
B Cell ◽  
T Cell Activation ◽  
Lupus Erythematosus ◽  
Expression Patterns ◽  
Healthy Controls ◽  
Systemic Lupus ◽  
Aberrant Expression ◽  
Cell Subpopulations

Abstract Background: Programmed death 1 (PD-1) is an immunoregulatory receptor that inhibits T cell activation and proliferation upon binding to its cognate ligand (PD-L1). However, the role of the PD-1/PD-L1 axis in B cell function, especially in inflammatory and autoimmune disorders, is less clear. The aim of this study was to analyze the PD-1 expression patterns on multiple B cell subpopulations isolated from systemic lupus erythematosus (SLE) patients, and determine their clinical relevance. Results: The frequency of B cells increased significantly in patients with active SLE compared with healthy controls and patients with inactive SLE. In particular, the frequencies of the IgD CD27 and IgD CD27high (plasmablast cells) subpopulations were significantly higher in the patients compared to healthy individuals. Interestingly, the patients with active SLE harbored an increased proportion of the PD-1+ B cells, which correlated significantly with the disease severity (SLEDAI scores), incidence of lupus nephritis, and the circulating levels of autoantibodies and complement factors. Furthermore, the primary PD-1+ B cells isolated from the peripheral blood of SLE patients proliferated faster and secreted more anti-dsDNA antibodies and immunoglobulins in vitro compared to the PD-1+/- B cells from healthy controls. Conclusions: PD-1 is overexpressed on all B cell subpopulations of SLE patients and associated with disease progression.

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