Gr1+ Cells Suppress T-Dependent Antibody Responses in (NZB × NZW)F1 Male Mice through Inhibition of T Follicular Helper Cells and Germinal Center Formation

Der, Evan; Dimo, Joana; Trigunaite, Abhishek; Jones, Justin; Jørgensen, Trine N.

doi:10.4049/jimmunol.1302479

Cited by 23 publications

(22 citation statements)

References 47 publications

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“…Similar to our study, a plasticity in neutrophil function was suggested by the loss of the suppressive phenotype in neutrophils from older mice (16). This same group also described Gr-1+ cell inhibition of Tfh differentiation in vitro and correspondingly increased Tfh with in vivo depletion of Gr-1+ cells, although the specificity of these findings to a neutrophil population is undetermined (46). In other studies, co-culture of neutrophils with T cells impaired Treg differentiation and promoted Th17 differentiation (17), leaving an open question as to whether neutrophils are predominantly immunosuppressive.…”

Section: Discussionmentioning

confidence: 97%

Neutrophils Slow Disease Progression in Murine Lupus via Modulation of Autoreactive Germinal Centers

Bird

Chang

Barnard

et al. 2017

The Journal of Immunology

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Neutrophils are well characterized as mediators of peripheral tissue damage in lupus, but it remains unclear whether they influence loss of self-tolerance in the adaptive immune compartment. Lupus neutrophils produce elevated levels of factors known to fuel autoantibody production, including interleukin-6 and B cell survival factors, but also reactive oxygen intermediates, which can suppress lymphocyte proliferation. In order to assess whether neutrophils directly influence the progression of auto-reactivity in secondary lymphoid organs (SLO), we characterized the localization and cell-cell contacts of splenic neutrophils at several stages in the progression of disease in the NZB/W murine model of lupus. Neutrophils accumulate in SLO over the course of lupus progression, preferentially localizing near T lymphocytes early in disease and B cells with advanced disease. RNA sequencing reveals that the splenic neutrophil transcriptional program changes significantly over the course of disease, with neutrophil expression of anti-inflammatory mediators peaking during early- and mid-stage disease, and evidence of neutrophil activation with advanced disease. To assess whether neutrophils exert predominantly protective or deleterious effects on loss of B cell self-tolerance in vivo, we depleted neutrophils at different stages of disease. Neutrophil depletion early in lupus resulted in a striking acceleration in the onset of renal disease, SLO germinal center formation, and auto-reactive plasma cell production. In contrast, neutrophil depletion with more advanced disease did not alter SLE progression. These results demonstrate a surprising temporal and context dependent role for neutrophils in restraining auto-reactive B cell activation in lupus.

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Section: Discussionmentioning

confidence: 97%

Neutrophils Slow Disease Progression in Murine Lupus via Modulation of Autoreactive Germinal Centers

Bird

Chang

Barnard

et al. 2017

The Journal of Immunology

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“…In young <9 week old lupusprone male, as well as female, (NZB x NZW)F1 mice, Ly6G + Gr1 high CD11b + and Ly 6 C high Gr1 low CD11b + neutrophils were found to be immunosuppressive towards B and T cells, respectively. As female mice aged, however, the cells lost their immunosuppressive capability both in vitro and in vivo [13,28]. A similar loss of function was also observed in males, albeit not until much later in life.…”

Section: Anti-inflammatory Properties Of Neutrophils In Lupusmentioning

confidence: 71%

“…In addition to the temporal difference in immunosuppression between male and female-derived Nregs, our studies also showed that Ly6G + Gr1 high CD11b + and Ly6C high Gr1 low CD11b + neutrophils not only targeted different lymphoid cell populations in vitro, but also utilized different immunosuppressive mechanisms [13,28]. For example, female Gr1 high CD11b + cells depended on cell-cell contact and utilized ROS/NO as their mechanism of inhibition in B cell differentiation assays, while male cells exerted their suppressive capacity via an unknown secreted, soluble factor ([28] and unpublished results).…”

Section: Anti-inflammatory Properties Of Neutrophils In Lupusmentioning

confidence: 84%

“…We recently reported the presence and function of populations of regulatory Ly6G + Gr1 high CD11b + and Ly6C high Gr1 low CD11b + neutrophils in the (NZB x NZW)F1 mouse model of SLE [13,28]. Since, lupus presents with an overwhelming female bias, we hypothesized that such regulatory neutrophils could be a mechanism preventing disease in otherwise genetically predisposed males.…”

Section: Anti-inflammatory Properties Of Neutrophils In Lupusmentioning

confidence: 99%

“…While the functions of these effector mechanisms are detrimental to pathogens, these enzymes may also harm the host resulting in tissue damage and necrosis. More recent evidence suggests that neutrophils can also function as antigen presenting cells [5,6], as a source of autoantigen and type I interferon (IFNα) in autoimmunity [7][8][9][10], or even as negative regulators of T and B cell responses during systemic inflammation [11][12][13][14]. In this review we discuss evidence from human and mouse studies supporting a key role for pro-and antiinflammatory neutrophils in lupus pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Pro- and Anti-inflammatory Neutrophils in Lupus

Der¹,

Trigunaite²,

Khan³

et al. 2014

J Clin Cell Immunol

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A hallmark of SLE is the presence of elevated levels of circulating anti-nuclear autoantibodies specific towards chromatin, histones or dsDNA. Understanding the regulation of antibody production is therefore of utmost importance in understanding lupus pathogenesis. Spearheaded by the identification of accumulating immunosuppressive neutrophils in cancer patients, the nature and function of neutrophils have expanded from a uniform pro-inflammatory cell population to a heterogeneous population of cells with pro-inflammatory or immunosuppressive capacities. While much is known about pro-inflammatory neutrophils and the likely pathogenic function of such cells in lupus, a potential role for immunosuppressive neutrophils in protecting genetically predisposed individuals has only recently emerged. For example, SLE-derived neutrophils spontaneously produce type I interferons (IFNα), strongly associated with disease development, release chromatin-containing neutrophil extracellular traps (NETs), potentially functioning as a source of nuclear auto-antigen, and may activate B cells in a T cell independent fashion. In contrast, levels and functions of regulatory neutrophils (Nregs) involved in T celldependent B cell differentiation and germinal center reactions, are dysregulated in female lupus-prone mice during disease development. Here we review data supporting a role for both pro-and anti-inflammatory neutrophils in lupus.

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Elimination of Granulocytic Myeloid‐Derived Suppressor Cells in Lupus‐Prone Mice Linked to Reactive Oxygen Species–Dependent Extracellular Trap Formation

Vlachou

Mintzas

Glymenaki

et al. 2016

Arthritis & Rheumatology

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Objective. Emerging evidence supports a crucial role of myeloid-derived suppressor cells (MDSCs) in the regulation of autoimmune diseases. However, their role in systemic lupus erythematosus (SLE) remains unknown. This study sought to address the role of MDSCs in the pathogenesis of SLE.Methods. MDSCs from (NZB 3 NZW)F1 lupusprone mice were assessed for phenotype by flow cytometry, and the function of MDSCs was analyzed by in vitro T cell proliferation assay and real-time quantitative polymerase chain reaction. Extracellular trap (ET) formation was evaluated by immunofluorescence and confocal microscopy. The production of reactive oxygen species (ROS) by Ly-6G1 cells was determined by fluorescenceactivated cell sorting analysis.Results. Expansion of MDSCs was impaired and the function of MDSCs was defective in the lymphoid organs of (NZB 3 NZW)F1 lupus-prone mice with established disease, in which involvement of predominantly the granulocytic MDSC (G-MDSC) cell subset was observed. More specifically, the results showed that increased elimination of G-MDSCs, driven by the inflammatory milieu of lupus, could be attributed to ET formation, and that cytokines, such as interferon-a (IFNa), IFNg, and interleukin-6, play a role in this process. Induction of ET release by G-MDSCs was mediated by the production of ROS, since inhibition of ROS generation significantly reduced ET release.Conclusion. Collectively, the results of this study reveal that elimination of a crucial regulatory immune cell subset is a feature of the SLE microenvironment. These findings provide new insights into the pathogenetic mechanisms of the disease.Although the incidence of autoimmune diseases is individually rare, these diseases affect ;5% of the population in Western countries. Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease, characterized by involvement of multiple organs (1). The development of SLE and its progression have been attributed to the interplay between innate immune components and self-reactive B and T lymphocytes and their products (2). Despite major advancements in elucidating the pathways underlying the effector phases of

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Gr1+ Cells Suppress T-Dependent Antibody Responses in (NZB × NZW)F1 Male Mice through Inhibition of T Follicular Helper Cells and Germinal Center Formation

Cited by 23 publications

References 47 publications

Neutrophils Slow Disease Progression in Murine Lupus via Modulation of Autoreactive Germinal Centers

Neutrophils Slow Disease Progression in Murine Lupus via Modulation of Autoreactive Germinal Centers

Pro- and Anti-inflammatory Neutrophils in Lupus

Elimination of Granulocytic Myeloid‐Derived Suppressor Cells in Lupus‐Prone Mice Linked to Reactive Oxygen Species–Dependent Extracellular Trap Formation

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