TLRs and interferons: a central paradigm in autoimmunity

Kono, Dwight H.; Baccalà, Roberto; Theofilopoulos, Argyrios N.

doi:10.1016/j.coi.2013.10.006

Cited by 50 publications

(34 citation statements)

References 81 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The requirement for endosomal TLR signaling in systemic autoimmunity is well established in models of lupus and is consistent with the genetics and pathogenesis of human SLE (4). Notably, mice with nonfunctional UNC93B1 ( Unc93b1 3d/3d , 3d ), which regulates trafficking of TLRs from the endoplasmic reticulum (ER) to endolysosomes, do not respond to ligands of endolysosomal TLR3, TLR7, and TLR9 (36) and consequently 3d lupus-prone B6- Fas lpr and BXSB mice fail to develop severe disease (37).…”

Section: Introductionsupporting

confidence: 64%

“…They are critical mediators of both innate and adaptive immune responses, and are required for the eradication of certain viral and bacterial infections (2, 3). It is therefore not surprising that type I IFNs play a significant role in autoimmunity (4–6). Indeed, lupus and other autoimmune diseases may occur following type I IFN treatment for cancer, hepatitis, and other disorders (7).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Induction of Systemic Autoimmunity by a Xenobiotic Requires Endosomal TLR Trafficking and Signaling from the Late Endosome and Endolysosome but Not Type I IFN

Pollard

Escalante

Huang

et al. 2017

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Type I IFN and nucleic acid-sensing TLRs are both strongly implicated in the pathogenesis of lupus with most patients expressing IFN-induced genes in peripheral blood cells and with TLRs promoting type I IFNs and autoreactive B cells. About a third of SLE patients, however, lack the IFN signature suggesting the possibility of type I IFN-independent mechanisms. Here, we examined the role of type I IFN and TLR trafficking and signaling in a xenobiotic systemic autoimmunity induced by mercury (HgIA). Strikingly, autoAb production in HgIA was not dependent on the type I IFN receptor even in NZB mice that require type I IFN signaling for spontaneous disease, but was dependent on the endosomal TLR transporter UNC93B1 and the endosomal proton transporter, SLC15A4. HgIA also required the AP-3 complex, which transports TLRs from the early endosome to the late endolysosomal compartments. Examination of TLR signaling pathways implicated the canonical NF-κB pathway and the proinflammatory cytokine IL-6 in autoantibody production, but not IRF7. These findings identify HgIA as a novel type I IFN-independent model of systemic autoimmunity and implicate TLR-mediated NF-κB proinflammatory signaling from the late endocytic pathway compartments in autoAb generation.

show abstract

Section: Introductionsupporting

confidence: 64%

Section: Introductionmentioning

confidence: 99%

Induction of Systemic Autoimmunity by a Xenobiotic Requires Endosomal TLR Trafficking and Signaling from the Late Endosome and Endolysosome but Not Type I IFN

Pollard

Escalante

Huang

et al. 2017

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…While new information regarding TLR-independent pathways driving IFN-I production suggests mechanisms that might act early in the pre-autoimmune phase of lupus, activation of endosomal TLRs, particularly TLR7, remains a highly significant pathway for amplification of the IFN-I response and lupus disease once autoantibodies have been produced [47]. It is well established that immune complexes carrying potentially stimulatory nucleic acids and their associated proteins access the endosomal compartments after binding the Fc receptor FCGR2A, and TLR7 activation is closely associated with presence of autoantibody specificities targeting RNA-associated proteins in lupus patients [48].…”

Section: Mechanisms Of Induction and Amplification Of Ifn-imentioning

confidence: 99%

Advances in understanding the role of type I interferons in systemic lupus erythematosus

Crow

2014

Current Opinion in Rheumatology

100

View full text Add to dashboard Cite

Purpose of Review Advances in understanding the genetic and molecular basis of innate immune system activation and function have supported the hypothesis that type I interferons (IFN-I), essential mediators of anti-viral host defense, are central contributors to the pathogenesis of systemic lupus erythematosus (SLE). This review addresses recent data that support the rationale for therapeutic targeting of the IFN-I pathway in SLE. Recent Findings New insights into mechanisms of cell-intrinsic innate immune system activation, driven by endogenous virus-like nucleic acids and potentially modified by environmental stressors, provide a model for induction of IFN-I that may precede clinically apparent autoimmunity in patients with lupus. Further amplification of IFN-α production, induced by nucleic acid-containing immune complexes that activate endosomal Toll-like receptors, augments and sustains immune system activation, autoimmunity and tissue damage. Summary As demonstrated in murine studies of persistent virus infection accompanied by sustained production of IFN-I, blockade of the IFN-I pathway may reverse the immune dysregulation and tissue damage that are essential features of the immunopathogenesis of SLE. Recent research progress has identified numerous therapeutic targets, and specific candidate therapeutics relevant to the IFN-I pathway are under investigation.

show abstract

“…A type I interferon (IFN-α, β, ω, τ, IFN-I) molecular signature is found in patients with systemic lupus erythematosus (SLE), a heterogeneous systemic disease with autoantibodies to nuclear antigens (ANA) and double-stranded DNA (dsDNA) (Ronnblom and Pascual, 2008, Kono et al, 2013, Lipsky, 2001). An IFN-I-stimulated gene (ISG) profile is significantly correlated with the levels of anti-dsDNA antibody and disease severity.…”

Section: Introductionmentioning

confidence: 99%

Neutrophils Regulate Humoral Autoimmunity by Restricting Interferon-γ Production via the Generation of Reactive Oxygen Species

Huang¹,

Li²,

Dorta‐Estremera³

et al. 2015

Cell Reports

View full text Add to dashboard Cite

Summary Here we examine the mechanism by which plasmacytoid dendritic cells (pDCs) and type I interferons promote humoral autoimmunity. In an amyloid-induced experimental autoimmune model, neutrophil depletion enhanced anti-nuclear antibody development, which correlated with heightened IFN-γ production by natural killer (NK) cells. IFN-α/β produced by pDCs activated NK cells via IL-15 induction. Neutrophils released reactive oxygen species (ROS), which negatively modulated the levels of IL-15 thereby inhibiting IFN-γ production. Mice deficient in NADPH oxidase 2 produced increased amounts of IFN-γ and developed augmented titers of autoantibodies. Both pDC-IFN-α/β pathway and IFN-γ were indispensable in stimulating humoral autoimmunity. Male NZB/W F1 mice expressed higher levels of superoxide than their female lupus-prone siblings, and depletion of neutrophils resulted in spontaneous NK cell and autoimmune B cell activation. Our findings suggest a regulatory role for neutrophils in vivo and highlight the importance of an NK-IFN-γ axis downstream of pDC-IFN-α/β pathway in systemic autoimmunity.

show abstract

TLRs and interferons: a central paradigm in autoimmunity

Cited by 50 publications

References 81 publications

Induction of Systemic Autoimmunity by a Xenobiotic Requires Endosomal TLR Trafficking and Signaling from the Late Endosome and Endolysosome but Not Type I IFN

Induction of Systemic Autoimmunity by a Xenobiotic Requires Endosomal TLR Trafficking and Signaling from the Late Endosome and Endolysosome but Not Type I IFN

Advances in understanding the role of type I interferons in systemic lupus erythematosus

Neutrophils Regulate Humoral Autoimmunity by Restricting Interferon-γ Production via the Generation of Reactive Oxygen Species

Contact Info

Product

Resources

About