scholarly journals Immunomodulation Induced During Interferon-α Therapy Impairs the Anti-HBV Immune Response Through CD24+CD38hi B Cells

2020 ◽  
Vol 11 ◽  
Author(s):  
Binqing Fu ◽  
Dongyao Wang ◽  
Xiaokun Shen ◽  
Chuang Guo ◽  
Yanyan Liu ◽  
...  
Keyword(s):  
B Cells ◽  
Persistent Infection ◽  
Randomised Trial ◽  
Interferon Α ◽  
Therapeutic Effects ◽  
Type I ◽  
Chronic Hbv ◽  
B Cell Subsets ◽  
And Control ◽  
Immunomodulation Effect

Type I interferon is widely used for antiviral therapy, yet has yielded disappointing results toward chronic HBV infection. Here we identify that PEG-IFNα-2b therapy toward persistent infection in humans is a double-edged sword of both immunostimulation and immunomodulation. Our studies of this randomised trial showed persistent PEG-IFNα-2b therapy induced large number of CD24+CD38hi B cells and launched a CD24+CD38hi B cells centered immunosuppressive response, including downregulating functions of T cells and NK cells. Patients with low induced CD24+CD38hi B cells have achieved an improved therapeutic effect. Specifically, using the anti-CD24 antibody to deplete CD24+CD38hi B cells without harming other B cell subsets suggest a promising strategy to improve the therapeutic effects. Our findings show that PEG-IFNα-2b therapy toward persistent infection constitutes an immunomodulation effect, and strategies to identifying the molecular basis for the antiviral versus immunomodulatory effects of PEG-IFNα-2b to selectively manipulate these opposing activities provide an opportunity to ameliorate anti-virus immunity and control viral infection.

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

Rheumatology ◽  
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.

scholarly journals Elevated STAT1 expression but not phosphorylation in lupus B cells correlates with disease activity and increased plasmablast susceptibility

Rheumatology ◽  
2020 ◽  
Vol 59 (11) ◽  
pp. 3435-3442 ◽  
Author(s):  
Arman Aue ◽  
Franziska Szelinski ◽  
Sarah Y Weißenberg ◽  
Annika Wiedemann ◽  
Thomas Rose ◽  
...  
Keyword(s):  
B Cells ◽  
Disease Activity ◽  
B Cell ◽  
Mononuclear Cells ◽  
Janus Kinase ◽  
T Cell Subsets ◽  
Type I ◽  
Type I Ifn ◽  
Peripheral Blood Mononuclear ◽  
B Cell Subsets

Abstract Objectives SLE is characterized by two pathogenic key signatures, type I IFN and B-cell abnormalities. 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). JAK-STAT inhibition is an attractive therapeutic possibility for SLE. 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 with 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), seven primary Sjögren’s (pSS) and 22 SLE patients was analysed by flow cytometry. STAT1 and STAT3 expression and phosphorylation in PBMCs (peripheral blood mononuclear cells) 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. STAT1 activation in plasmablasts was IFNα dependent while monocytes exhibited dependence on IFNγ. Conclusion Enhanced expression of STAT1 by B-cell candidates as a 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 a promise to block STAT1 expression and control plasmablast induction in SLE.

scholarly journals Identification of T- and B-Cell Subsets That Expand in the Central and Peripheral Lymphoid Organs during the Establishment of Nut Allergy in an Adjuvant-Free Mouse Model

ISRN Allergy ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Babu Gonipeta ◽  
David Duriancik ◽  
EunJung Kim ◽  
Elizabeth Gardner ◽  
Venu Gangur
Keyword(s):  
B Cells ◽  
Mouse Model ◽  
B Cell ◽  
Significant Proportion ◽  
T Cell Subsets ◽  
Cell Phenotype ◽  
Mesenteric Lymph ◽  
B Cell Subsets ◽  
And Control ◽  
Early Establishment

Nut allergies are potentially fatal and rarely outgrown for reasons that are not well understood. Phenotype of T- and B-cell subsets that expand during the early stages of nut allergy is largely unknown. Here we studied this problem using a novel mouse model of nut allergy. Mice were rendered hazelnut allergic by a transdermal sensitization/oral elicitation protocol. Using flow cytometry, the T- and B-cell phenotype in the bone marrow (BM), spleen, and the mesenteric lymph node (MLN) of allergic and control mice was analyzed. Nut allergic mice exhibited an expansion of CD4+ CD62L− T cells in BM and spleen; a similar trend was noted in the MLN. There was expansion of CD80+ B cells in BM and spleen and MLN and CD62L− cells in BM and spleen. Interestingly, among CD80+ B cells, significant proportion was CD73− particularly in the MLN. These data demonstrate that during the early establishment of hazelnut allergy there is (i) expansion of CD4+CD62L− T-cell subsets in both the BM and the periphery, (ii) expansion of CD80+ and CD62L− B-cell subsets in BM and the periphery, and (iii) a significant downregulation of CD73 on a subset of B cells in MLN.

scholarly journals The Multiple Functions of B Cells in Chronic HBV Infection

2020 ◽  
Vol 11 ◽  
Author(s):  
Ying Cai ◽  
Wenwei Yin
Keyword(s):  
Immune Response ◽  
Chronic Hepatitis ◽  
B Cells ◽  
Hepatitis B ◽  
B Cell ◽  
Hbv Infection ◽  
Chronic Hbv Infection ◽  
Multiple Functions ◽  
Chronic Hbv ◽  
B Cell Subsets

Chronic hepatitis B virus (HBV) infection is one of the main causes of liver diseases, of which the natural history and clinical outcomes are associated with the role of B cells. As humoral immune cells, B cells play a critical role in the process of anti-HBV antibody production. In addition, some studies have also characterized other B cell subsets involved in antigen presentation and regulating the immune response beyond antibody secretion. However, not all B cell subsets play a positive role in the immune response to chronic HBV infection, and various B cell subsets jointly mediate persistent HBV infection, tolerance, and liver damage. Thus, we further sought to elucidate the multiple functions of B cells to gain novel insight into the understanding of chronic hepatitis B (CHB) pathogenesis. We also reviewed the current immunotherapies targeting B cells to explore novel therapeutic interventions for the treatment of chronic HBV infection.

scholarly journals The Expression of TLR-9, CD86, and CD95 Phenotypes in Circulating B Cells of Patients with Chronic Viral Hepatitis B or C before and after Antiviral Therapy

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Ping-wei Zhao ◽  
Liang Ma ◽  
Hui-fan Ji ◽  
Lei Yu ◽  
Jun-yan Feng ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Viral Hepatitis ◽  
Differential Expression ◽  
Significant Negative Correlation ◽  
Chronic Viral Hepatitis ◽  
Healthy Controls ◽  
Before And After ◽  
Chronic Hbv ◽  
B Cell Subsets

Aims. This study aimed to assess the differential expression of specific B cell subtypes in patients with chronic viral hepatitis.Methods. The frequencies of differential expression of specific B cell subtypes in patients with chronic viral hepatitis and healthy controls were assessed by flow cytometry using monoclonal antibodies specific for CD38, CD27, CD86, CD95, TLR-9, and IgD. The effect of adefovir treatment on B cell subsets in HBV patients was determined. The values of clinical parameters in the patients were also measured.Results. The frequency of CD86+ B cells was not significantly different in chronic HBV patients but was higher in HCV patients compared with that in healthy controls. CD95 and IgD levels were lower in HBV and HCV patients than in healthy controls. A significant negative correlation occurred between the proportion of CD95+ B cells and HBV DNA viral load. The frequency of TLR-9 on the B cells in HBV and HCV patients was higher compared with that of healthy controls. After treatment with adefovir, the frequency of CD95 and IgD expressed on B cells was increased in HBV patients.Conclusions. Activated B cells and exhausted B cells homeostasis were commonly disturbed in HBV and HCV patients.

scholarly journals Interferon α Enhances B Cell Activation Associated With FOXM1 Induction: Potential Novel Therapeutic Strategy for Targeting the Plasmablasts of Systemic Lupus Erythematosus

2021 ◽  
Vol 11 ◽  
Author(s):  
Kanae Akita ◽  
Ken Yasaka ◽  
Tsuyoshi Shirai ◽  
Tomonori Ishii ◽  
Hideo Harigae ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Cell Activation ◽  
Type I ◽  
Healthy Controls ◽  
B Cell Activation ◽  
Systemic Lupus ◽  
B Cell Subsets ◽  
Novel Therapeutic

Systemic lupus erythematosus (SLE) is an autoimmune disease. It is characterized by the production of various pathogenic autoantibodies and is suggested to be triggered by increased type I interferon (IFN) signature. Previous studies have identified increased plasmablasts in the peripheral blood of SLE patients. The biological characteristics of SLE plasmablasts remain unknown, and few treatments that target SLE plasmablasts have been applied despite the unique cellular properties of plasmablasts compared with other B cell subsets and plasma cells. We conducted microarray analysis of naïve and memory B cells and plasmablasts (CD38+CD43+ B cells) that were freshly isolated from healthy controls and active SLE (n = 4, each) to clarify the unique biological properties of SLE plasmablasts. The results revealed that all B cell subsets of SLE expressed more type I IFN-stimulated genes. In addition, SLE plasmablasts upregulated the expression of cell cycle-related genes associated with higher FOXM1 and FOXM1-regulated gene expression levels than that in healthy controls. This suggests that a causative relationship exists between type I IFN priming and enhanced proliferative capacity through FOXM1. The effects of pretreatment of IFNα on B cell activation and FOXM1 inhibitor FDI-6 on B cell proliferation and survival were investigated. Pretreatment with IFNα promoted B cell activation after stimulation with anti-IgG/IgM antibody. Flow cytometry revealed that pretreatment with IFNα preferentially enhanced the Atk and p38 pathways after triggering B cell receptors. FDI-6 inhibited cell division and induced apoptosis in activated B cells. These effects were pronounced in activated B cells pretreated with interferon α. This study can provide better understanding of the pathogenic mechanism of interferon-stimulated genes on SLE B cells and an insight into the development of novel therapeutic strategies.

scholarly journals Naive and Effector B-cell Subtypes are Increased in Chronic Rhinosinusitis with Polyps

2018 ◽  
Vol 32 (1) ◽  
pp. 3-6 ◽  
Author(s):  
Dijana Miljkovic ◽  
Alkis Psaltis ◽  
Peter-John Wormald ◽  
Sarah Vreugde
Keyword(s):  
B Cells ◽  
B Cell ◽  
Chronic Rhinosinusitis ◽  
Peripheral Blood ◽  
Nasal Polyposis ◽  
Potential Role ◽  
Memory B Cells ◽  
Live Cells ◽  
B Cell Subsets ◽  
And Control

Background Recent studies demonstrated that B cells and their chemoattractants are elevated in the nasal mucosa of patients with chronic rhinosinusitis (CRS) with nasal polyposis (CRSwNP). However, the presence of naive B cells and of plasmablasts and memory B-cell subsets in the mucosa and periphery of the same patient with CRS is yet to be characterized. Objective Here we sought to quantify naive, plasmablasts, and memory B cells in mucosal tissue and peripheral blood of patients with CRSwNP, patients with CRS without nasal polyps (CRSsNP), and control patients. Methods Polyps, mucosa, and peripheral blood samples were prospectively collected from the patients with CRS and from the non-CRS controls. We used flow cytometry to distinguish among naive, plasmablast, and memory B cells in sinus tissue and peripheral blood. Results A total of 45 patients were recruited for the study. The patients with CRSwNP had significantly increased mucosal B-cell numbers versus the controls (3.39 ± 4.05% versus 0.39 ± 1.05% of live cells; p < 0.01, Kruskal-Wallis test), which included naive B cells (0.61 ± 0.94 versus 0.11 ± 0.24% of live cells; p < 0.03, Kruskal-Wallis test), plasmablasts (0.06 ± 0.26 versus 0.00 ± 0.00% e cells; p < 0.055, Kruskal-Wallis test), and memory B cells (0.62 ± 1.26 versus 0.05 ± 0.15% of live cells; p < 0.02, Kruskal-Wallis test). Conclusion Our study identified increased frequencies of different B-cell subtypes in the mucosa of patients with CRSwNP but not in the peripheral blood. We also found that patients with CRSwNP had significantly increased B-cell subtypes compared with the patients with CRSsNP and the controls. These results implied a potential role for mucosal B cells in the ongoing inflammation in patients with CRSwNP.

Lymphoproliferative disorders (LPD) involving lungs: T and B cell subsets within pulmonary infiltrates and in peripheral blood

1984 ◽  
Vol 42 ◽  
pp. 700-701
Author(s):  
Irene Stachura ◽  
Milton H. Dalbow ◽  
Michael J. Niemiec ◽  
Matias Pardo ◽  
Gurmukh Singh ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Lymphoproliferative Disorders ◽  
Mixed Population ◽  
Lymphoid Cells ◽  
Lymphomatoid Granulomatosis ◽  
Cell Type ◽  
Cell Surface Antigens ◽  
Pulmonary Infiltrates ◽  
B Cell Subsets

Lymphoid cells were analyzed within pulmonary infiltrates of six patients with lymphoproliferative disorders involving lungs by immunofluorescence and immunoperoxidase techniques utilizing monoclonal antibodies to cell surface antigens T11 (total T), T4 (inducer/helper T), T8 (cytotoxic/suppressor T) and B1 (B cells) and the antisera against heavy (G,A,M) and light (kappa, lambda) immunoglobulin chains. Three patients had pseudolymphoma, two patients had lymphoma and one patient had lymphomatoid granulomatosis.A mixed population of cells was present in tissue infiltrates from the three patients with pseudolymphoma, IgM-kappa producing cells constituted the main B cell type in one patient. In two patients with lymphoma pattern the infiltrates were composed exclusively of T4+ cells and IgG-lambda B cells predominated slightly in the patient with lymphomatoid granulomatosis.

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