THU0293 B-cell responses to type I interferon define disease activity in SLE and can be measured by cell surface tetherin (CD317)

Germinal centers (GCs) are induced microanatomical structures wherein B cells undergo affinity maturation to improve the quality of the antibody response. Although GCs are crucial to appropriate humoral responses to infectious challenges and vaccines, many questions remain about the molecular signals driving B cell participation in GC responses. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is an important mediator of type I interferon and proinflammatory cytokine responses during infection and cellular stress. Recent studies have reported important roles for STING in B cell responses, including an impact on GC B cells and downstream antibody responses, which could have great consequences for vaccine design and understanding STING-associated interferonopathies. GCs are also involved in untoward reactions to autoantigens in a plethora of autoimmune disorders, and it is generally thought that these responses coopt the mechanisms used in foreign antigen-directed GCs. Here, we set out to investigate the importance of the cGAS-STING pathway in autoreactive B cell responses. In a direct competition scenario in a murine mixed bone marrow chimera model of autoreactive GCs, we find that B cell intrinsic deficiency of cGAS, STING, or the type I interferon receptor IFNAR, does not impair GC participation, whereas Toll-like receptor (TLR)-7 deficiency mediates a near-complete block. Our findings suggest that physiological B cell responses are strictly sustained by signals linked to BCR-mediated endocytosis. This wiring of B cell signals may enable appropriate antibody responses, while at the same time restricting aberrant antibody responses during infections and in autoimmune or autoinflammatory settings.

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Plasmacytoid Dendritic Cells and Type I Interferon Promote Extrafollicular B Cell Responses to Extracellular Self-DNA

Immunity ◽

10.1016/j.immuni.2020.04.015 ◽

2020 ◽

Vol 52 (6) ◽

pp. 1022-1038.e7 ◽

Cited By ~ 3

Author(s):

Chetna Soni ◽

Oriana A. Perez ◽

William N. Voss ◽

Joseph N. Pucella ◽

Lee Serpas ◽

...

Keyword(s):

Dendritic Cells ◽

B Cell ◽

Type I Interferon ◽

Plasmacytoid Dendritic Cells ◽

Type I ◽

Cell Responses ◽

B Cell Responses

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Type I interferon suppresses virus-specific B cell responses by modulating CD8 + T cell differentiation

Science Immunology ◽

10.1126/sciimmunol.aah3565 ◽

2016 ◽

Vol 1 (4) ◽

Cited By ~ 5

Author(s):

E. Ashley Moseman ◽

Tuoqi Wu ◽

Juan Carlos de la Torre ◽

Pamela L. Schwartzberg ◽

Dorian B. McGavern

Keyword(s):

Cell Differentiation ◽

T Cell ◽

B Cell ◽

Type I Interferon ◽

Cd8 T Cell ◽

T Cell Differentiation ◽

Type I ◽

Cell Responses ◽

B Cell Responses

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Type 1 interferon supports B cell responses to polysaccharide antigens but is not required for MPL/TDCM adjuvant effects on innate B cells

10.1101/2021.10.30.466603 ◽

2021 ◽

Author(s):

Ariel Spurrier ◽

Jamie Jennings-Gee ◽

Karen Haas

Keyword(s):

B Cells ◽

B Cell ◽

Cell Activation ◽

Lipid A ◽

Type I ◽

Type I Ifn ◽

Cell Responses ◽

Monophosphoryl Lipid A ◽

B Cell Responses ◽

Adjuvant Effects

We previously described monophosphoryl lipid A (MPL) and synthetic cord factor, trehalose-6,6-dicorynomycolate (TDCM) significantly increases antibody (Ab) responses to T cell independent type 2 antigens (TI-2 Ags) in a manner dependent on B cell-intrinsic TLR4 expression as well as MyD88 and TRIF adapter proteins. Given the requirement for TRIF in optimal MPL/TDCM adjuvant effects and the capacity of MPL to drive type I IFN production, we aimed to investigate the extent to which adjuvant effects on TI-2 Ab responses depend on type I IFN receptor (IFNAR) signaling. We found IFNAR-/- mice had impaired early TI-2 Ag-induced B cell activation and expansion and that B cell-intrinsic type I IFN signaling on B cells was essential for normal antibody responses to TI-2 Ags, including haptenated Ficoll and the pneumococcal vaccine, Pneumovax23. However, MPL/TDCM significantly increased TI-2 IgM and IgG responses in IFNAR-/- mice. MPL/TDCM enhanced TI-2 Ab production primarily by activating innate B cells (B-1b and splenic CD23- B cells) as opposed to CD23+ enriched follicular B cells. In summary, our study highlights an important role for type I IFN in supporting early B cell responses to TI-2 Ags through B cell-expressed IFNAR, but nonetheless demonstrates an MPL/TDCM adjuvant significantly increases TI-2 Ab responses independently of type I IFN signaling and does so by predominantly supporting increased polysaccharide-specific Ab production by innate B cell populations.

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Different B-cell responses to human T-cell lymphotropic virus type I (HTLV-I) envelope synthetic peptides in HTLV-I-infected individuals

Journal of Clinical Immunology ◽

10.1007/bf00918682 ◽

1991 ◽

Vol 11 (3) ◽

pp. 143-151 ◽

Cited By ~ 8

Author(s):

Hiroaki Ida ◽

Akihiko Kurata ◽

Katsumi Eguchi ◽

Atsushi Kawakami ◽

Kiyoshi Migita ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Virus Type ◽

Synthetic Peptides ◽

Type I ◽

Cell Responses ◽

Human T Cell ◽

B Cell Responses

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B cell tetherin: a flow-cytometric cell-specific assay for response to Type-I interferon predicts clinical features and flares in SLE

10.1101/554352 ◽

2019 ◽

Author(s):

Yasser M. El-Sherbiny ◽

Md. Yuzaiful Md. Yusof ◽

Antonios Psarras ◽

Elizabeth M. A. Hensor ◽

Kumba Z. Kabba ◽

...

Keyword(s):

Cell Surface ◽

B Cell ◽

Validation Cohort ◽

Type I Interferon ◽

Type I ◽

Flow Cytometric Assay ◽

Discovery Cohort ◽

Memory B Cell ◽

Flow Cytometric

ABSTRACTObjectiveType I interferon (IFN-I) responses are broadly associated with autoimmune disease including SLE. Given the cardinal role of autoantibodies in SLE, we investigated whether a B lineage cell-specific IFN assay might correlate with SLE activity.MethodsB cells and PBMCs were stimulated with IFN-I and IFN-II. Gene expression was scrutinised for pathway-related membrane protein expression. A flow-cytometric assay for tetherin (CD317), an IFN-induced protein ubiquitously expressed on leucocytes, was validated in vitro then clinically against SLE diagnosis, plasmablast expansion, and BILAG-2004 score in a discovery cohort (156 SLE; 30 RA; 22 healthy controls). A second longitudinal validation cohort of 80 patients was also evaluated for SLE flare prediction.ResultsIn vitro, a close cell-specific and dose-responsive relationship between IFN-I responsive genes and cell surface tetherin in all immune subsets existed. Tetherin expression was selectively responsive to the IFN-I compared to IFN-II and -III. In the discovery cohort memory B-cell tetherin was best associated with diagnosis (SLE/HC: effect size=0.11, p=0.003;SLE/RA: effect size=0.17, p<0.001); plasmablast numbers in rituximab-treated patients (Rho=0.38, p=0.047) and BILAG-2004. Association were equivalent or stronger than interferon score or monocyte tetherin. The validation cohort confirmed this relationship with memory B-cell tetherin predictive of future clinical flares (Hazard Ratio=2.29 (1.01–4.64), p=0.022).ConclusionMemory B cell surface tetherin, a reflection of cell-specific IFN response in a convenient flow cytometric assay, was associated with SLE diagnosis, disease activity and predicted flares better than other cell subsets or whole blood assays in independent validation cohorts.

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Context-dependent miR-21 regulation of TLR7-mediated autoimmune and foreign antigen driven antibody-forming cell and germinal center responses

10.1101/2021.03.12.435182 ◽

2021 ◽

Author(s):

Stephanie L. Schell ◽

Kristen N. Bricker ◽

Adam J. Fike ◽

Sathi Babu Chodisetti ◽

Phillip P. Domeier ◽

...

Keyword(s):

B Cell ◽

Lupus Erythematosus ◽

Germinal Center ◽

Target Genes ◽

Type I ◽

List Type ◽

Foreign Antigen ◽

Cell Responses ◽

Context Dependent ◽

B Cell Responses

AbstractMicroRNAs (miRNAs) are involved in healthy B cell responses and the loss of tolerance in systemic lupus erythematosus (SLE), though the role of many miRNAs remains poorly understood. Dampening miR-21 activity was previously shown to reduce splenomegaly and blood urea nitrogen levels in SLE-prone mice, but the detailed cellular responses and mechanism of action remains unexplored. Herein, using the TLR7 agonist imiquimod-induced SLE model, we observed that loss of miR-21 in Sle1b mice prevented the formation of plasma cells and autoantibody forming cells (AFC), without a significant effect on the magnitude of the germinal center (GC) response. We further observed reduced dendritic cell and monocyte numbers in the spleens of miR-21 deficient Sle1b (Sle1b.miR-21KO) mice that were associated with reduced interferon, proinflammatory cytokines, and effector CD4+ T cell responses. RNAseq analysis on B cells from Sle1b.miR-21KO mice revealed reduced activation and response to interferon and cytokine and target array analysis revealed modulation of numerous miR-21 target genes in response to TLR7 activation and type I interferon stimulation. Our findings in the B6.Sle1b.Yaa spontaneous model recapitulated the miR-21 role in TLR7-induced responses with an additional role in autoimmune GC and Tfh responses. Finally, immunization with T-dependent antigen revealed a role for miR-21 in foreign antigen driven GC and Ab, but not AFC responses. Our data suggest a potential multifaceted, context-dependent role for miR-21 in autoimmune and foreign antigen driven AFC and GC responses. Further study is warranted to delineate the cell-intrinsic requirements and mechanisms of miR-21 during infection and SLE development.Key PointsmiR-21 has context dependent effects on AFC and GC responsesmiR-21 promotes TLR7-driven autoimmunity with activation of multiple B cell pathwaysmiR-21 is required for optimal B cell responses to T-dependent foreign antigen

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