Neutrophils and interferon-α-producing cells: who produces interferon in lupus?

Decker, Patrice

doi:10.1186/ar3345

Cited by 20 publications

(16 citation statements)

References 22 publications

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“…Our data indicate that the development of lupus in 564Igi mice more closely resembles the pathogenesis of severe lupus in patients than chemically induced lupus . Further, our data, together with other reports collectively suggest that neutrophils and monocytes are major contributors of IFN‐I and the subsequent development of SLE. A plausible mechanism for the initiation of the SLE would be a viral infection activating TLR7 (and TLR8) inducing IFN‐I, activation‐induced cytidine deaminase upregulation, and CSR of Ig genes coding for autoreactive autoantibodies that form ICs capable of inducing expansion of granulocytes and monocytes via FcγRs resulting in IFN‐I production.…”

Section: Discussionsupporting

confidence: 81%

Expression of an anti‐RNA autoantibody in a mouse model of SLE increases neutrophil and monocyte numbers as well as IFN‐I expression

et al. 2013

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SUMMARY Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of anti-nucleic acid autoantibodies, high levels of circulating type I interferon (IFN-I), and an IFN-I-dependent elevated expression of activating FcγR. Increases in neutrophils and monocytes are often observed in clinical SLE, but how these contribute to autoantibody and IFN-I production is poorly understood. We are analyzing SLE pathogenesis in 564Igi mice, an SLE-model strain carrying gene-targeted heavy and light chain antibody genes encoding an anti-RNA autoantibody in a C57BL/6 background. Similar to human SLE patients, 564Igi mice produce anti-RNA autoantibodies and expanded neutrophil and monocyte populations. These myeloid cells produce IFN-I and exhibit increased FcγRIV expression induced via an IFN-I autocrine loop. A direct effect of IFN-I on 564Igi bone marrow B cells and neutrophils is supported by their up-regulation of “IFN-I signature genes”. In addition, 564Igi developing B cells show up-regulated TLR7 resulting in IgG2a/2b class switch recombination and autoantibody production. Our results indicate that the production of anti-RNA autoantibody is sufficient to induce an increase of bone marrow, blood and spleen IFN-I-producing neutrophils, and suggest a mechanism by which autoantibody and IFN-I contribute to SLE by activating B lymphocytes, neutrophils and monocyte effector cells in vivo.

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Section: Discussionsupporting

confidence: 81%

Expression of an anti‐RNA autoantibody in a mouse model of SLE increases neutrophil and monocyte numbers as well as IFN‐I expression

et al. 2013

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“…Second, both T1-IFNs and IL-17-induced G-CSF prime PMN for NETosis (250, 290). In accord, circulating PMN of SLE patients are also the main cells expressing the transcriptional T1-IFN signature and release more NETs than PMN from healthy individuals (250, 253, 288, 289, 291, 292). Thirdly, T1-IFNs stimulate BAFF production, which is essential for T1-IFN-mediated pathogenic effects in mouse SLE (261, 262, 293).…”

Section: T1-ifns the Th17 Response And Their Interactions In Autoimmmentioning

confidence: 90%

“…However, increasing evidence suggests a more prominent contribution of IL-17 and PMN to T1-IFN-mediated disease in SLE. First, besides being major inducers of IFN-α production by pDC upon NETosis, PMN also appear to be a significant source of IFN-α themselves (288, 289). This was related to their sheer numbers, as circulating pDC were 27 times more efficient in secreting IFN-α, but PMN were 100 times more frequent (289).…”

Section: T1-ifns the Th17 Response And Their Interactions In Autoimmmentioning

confidence: 99%

Interactions between Type 1 Interferons and the Th17 Response in Tuberculosis: Lessons Learned from Autoimmune Diseases

et al. 2017

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The classical paradigm of tuberculosis (TB) immunity, with a central protective role for Th1 responses and IFN-γ-stimulated cellular responses, has been challenged by unsatisfactory results of vaccine strategies aimed at enhancing Th1 immunity. Moreover, preclinical TB models have shown that increasing IFN-γ responses in the lungs is more damaging to the host than to the pathogen. Type 1 interferon signaling and altered Th17 responses have also been associated with active TB, but their functional roles in TB pathogenesis remain to be established. These two host responses have been studied in more detail in autoimmune diseases (AID) and show functional interactions that are of potential interest in TB immunity. In this review, we first identify the role of type 1 interferons and Th17 immunity in TB, followed by an overview of interactions between these responses observed in systemic AID. We discuss (i) the effects of GM-CSF-secreting Th17.1 cells and type 1 interferons on CCR2+ monocytes; (ii) convergence of IL-17 and type 1 interferon signaling on stimulating B-cell activating factor production and the central role of neutrophils in this process; and (iii) synergy between IL-17 and type 1 interferons in the generation and function of tertiary lymphoid structures and the associated follicular helper T-cell responses. Evaluation of these autoimmune-related pathways in TB pathogenesis provides a new perspective on recent developments in TB research.

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“…This interest in type I IFNs initiated a plethora of clinical trials with therapeutic targets directed at IFNα and type I IFN receptor, which have more recently been redirected toward those expressing the IFN signature . Neutrophils have generated interest for their role in the production of type I IFNs and for their proinflammatory and antiinflammatory functions in SLE . Moreover, there is a burgeoning number of reports showing that they play an integral role in disease pathogenesis.…”

Section: Traditional Concepts Of Sle Immunopathogenesismentioning

confidence: 99%

Low‐Density Neutrophils in Systemic Lupus Erythematosus

Tay

Celhar

Fairhurst

2020

Arthritis & Rheumatology

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Patients with systemic lupus erythematosus ( SLE ) display increased numbers of immature neutrophils in the blood, but the exact role of these immature neutrophils is unclear. Neutrophils that sediment within the peripheral blood mononuclear cell fraction after density centrifugation of blood are generally defined as low‐density neutrophils ( LDN s). Far beyond antimicrobial functions, LDN s are emerging as decision‐shapers during innate and adaptive immune responses. Traditionally, neutrophils have been viewed as a homogeneous population. However, the various LDN populations identified in SLE to date are heterogeneously composed of mixed populations of activated mature neutrophils and immature neutrophils at various stages of differentiation. Controversy also surrounds the role of LDN s in SLE in terms of whether they are proinflammatory or polymorphonuclear myeloid‐derived suppressor cells. It is clear that LDN s in SLE can secrete increased levels of type I interferon ( IFN ) and that they contribute to the cycle of inflammation and tissue damage. They readily form neutrophil extracellular traps, exposing modified autoantigens and oxidized mitochondrial DNA , which contribute to autoantibody production and type I IFN signaling, respectively. Importantly, the ability of LDN s in SLE to perform canonical neutrophil functions is polarized, based on mature CD 10+ and immature CD 10− neutrophils. Although this field is still relatively new, multiomic approaches have advanced our understanding of the diverse origins, phenotype, and function of LDN s in SLE . This review updates the literature on the origin and nature of LDN s, their distinctive features, and their biologic roles in the immunopathogenesis and end‐organ damage in SLE .

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Neutrophils and interferon-α-producing cells: who produces interferon in lupus?

Cited by 20 publications

References 22 publications

Expression of an anti‐RNA autoantibody in a mouse model of SLE increases neutrophil and monocyte numbers as well as IFN‐I expression

Expression of an anti‐RNA autoantibody in a mouse model of SLE increases neutrophil and monocyte numbers as well as IFN‐I expression

Interactions between Type 1 Interferons and the Th17 Response in Tuberculosis: Lessons Learned from Autoimmune Diseases

Low‐Density Neutrophils in Systemic Lupus Erythematosus

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