Endosomal Toll‐like receptors in clinically overt and silent autoimmunity

Clancy, Robert M.; Markham, Androo J.; Buyon, Jill P.

doi:10.1111/imr.12383

Cited by 38 publications

(30 citation statements)

References 60 publications

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“…A subset of SLE patients treated with HCQ also showed low levels of the IFN genes, although differences with the non-HCQ group were not statistically significant in the small sample tested. The lack of effect of HCQ on expression of Type I IFN-inducible genes in some SLE patients is consistent with the concept proposed elsewhere that once the immune response is amplified, which would be anticipated in SLE more than in ILE, it becomes difficult to arrest the abnormalities [29]. The finding of clinical benefit and decreased expression of the Type I IFN signature is also consistent with other reports showing a correlation between disease activity in SLE patients and circulating IFN-a levels [30].…”

Section: Discussionsupporting

confidence: 87%

Clinical and Immunologic Profiles in Incomplete Lupus Erythematosus and Improvement with Hydroxychloroquine Treatment

Olsen

McAloose

Carter

et al. 2016

Autoimmune Diseases

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Objective. The study goals were to evaluate performance of SLE classification criteria, to define patients with incomplete lupus erythematosus (ILE), and to probe for features in these patients that might be useful as indicators of disease status and hydroxychloroquine response. Methods. Patients with ILE (N = 70) and SLE (N = 32) defined by the 1997 American College of Rheumatology criteria were reclassified using the 2012 Systemic Lupus International Collaborating Clinics criteria. Disease activity, patient reported outcomes, and levels of Type I interferon- (IFN-) inducible genes, autoantibodies, and cytokines were measured. Subgroups treated with hydroxychloroquine (HCQ) were compared to patients not on this drug. Results. The classification sets were correlated (R2 = 0.87). ILE patients were older (P = 0.0043) with lower disease activity scores (P < 0.001) and greater dissatisfaction with health status (P = 0.034) than SLE patients. ILE was associated with lower levels of macrophage-derived cytokines and levels of expressed Type I IFN-inducible genes. Treatment of ILE with HCQ was associated with better self-reported health status scores and lower expression levels of Type I IFN-inducible genes than ILE patients not on HCQ. Conclusion. The 2012 SLICC SLE classification criteria will be useful to define ILE in trials. Patients with ILE have better health status and immune profiles when treated with HCQ.

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Section: Discussionsupporting

confidence: 87%

Clinical and Immunologic Profiles in Incomplete Lupus Erythematosus and Improvement with Hydroxychloroquine Treatment

Olsen

McAloose

Carter

et al. 2016

Autoimmune Diseases

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“…Although the cellular sources of dysregulated soluble mediators in preclinical SLE remain unknown and are the subject of future study, our data suggest that restoring homeostasis within the IL-5, IL-6, and IFN pathways might be effective interventions prior to SLE classification. Of interest, hydroxychloroquine has been shown to activation of TLR7 pathways [74], pathogenic in SLE [74], as well as decrease production of IL-6 and IFN-γ in several small patient cohorts and in vitro studies [75-78]. A mainstay of treatment in SLE [79], hydroxychloroquine has already been shown to delay SLE onset and slow the accrual of autoantibodies in patients approaching SLE classification [4].…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of innate and adaptive serum mediators precedes systemic lupus erythematosus classification and improves prognostic accuracy of autoantibodies

Munroe

Guthridge

et al. 2016

Journal of Autoimmunity

144

130

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Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a poorly understood preclinical stage of immune dysregulation and symptom accrual. Accumulation of antinuclear autoantibody (ANA) specificities is a hallmark of impending clinical disease. Yet, many ANA-positive individuals remain healthy, suggesting that additional immune dysregulation underlies SLE pathogenesis. Indeed, we have recently demonstrated that interferon (IFN) pathways are dysregulated in preclinical SLE. To determine if other forms of immune dysregulation contribute to preclinical SLE pathogenesis, we measured SLE-associated autoantibodies and soluble mediators in samples from 84 individuals collected prior to SLE classification (average timespan = 5.98 years), compared to unaffected, healthy control samples matched by race, gender, age (± 5 years), and time of sample procurement. We found that multiple soluble mediators, including interleukin (IL)-5, IL-6, and IFN-γ, were significantly elevated in cases compared to controls more than 3.5 years pre-classification, prior to or concurrent with autoantibody positivity. Additional mediators, including innate cytokines, IFN-associated chemokines, and soluble tumor necrosis factor (TNF) superfamily mediators increased longitudinally in cases approaching SLE classification, but not in controls. In particular, levels of B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL) were comparable in cases and controls until less than 10 months pre-classification. Over the entire pre-classification period, random forest models incorporating ANA and anti-Ro/SSA positivity with levels of IL-5, IL-6, and the IFN-γ-induced chemokine, MIG, distinguished future SLE patients with 92% (± 1.8%) accuracy, compared to 78% accuracy utilizing ANA positivity alone. These data suggest that immune dysregulation involving multiple pathways contributes to SLE pathogenesis. Importantly, distinct immunological profiles are predictive for individuals who will develop clinical SLE and may be useful for delineating early pathogenesis, discovering therapeutic targets, and designing prevention trials.

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“…MyD88, which results in production of type I interferons and other cytokines [70]. In autoinflammatory disorders such as SLE, the persistent stimulation with endogenous DNA is thought to cause a continuous activation of the pathway, resulting in a dysregulated production of pro-inflammatory cytokines [71,72].…”

Section: Tlr9 Blockadementioning

confidence: 99%

Reappraisal of Antimalarials in Interferonopathies: New Perspectives for Old Drugs

Piscianz

Cuzzoni

Sharma

et al. 2018

CMC

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The story of antimalarials as antinflammatory drugs dates back few centuries. Chinin, the extract of the Cinchona bark, has been exploited since the 18th century for its antimalarial and antifebrile properties. Later, during the Second World War, the broad use of antimalarials allowed arguing their antirheumatic effect on soldiers. Since then, these drugs have been broadly used to treat Systemic Lupus Erythematosus, but, only recently, the molecular mechanisms of action have been partly clarified.The inhibitory action on vacuole function and trafficking has been considered for decades the main mechanism of the action of antimalarials, affecting the activation of phagocytes and dendritic cells. In addition, chloroquine is also as a potent inhibitor of autophagy, providing another possible explanation of its antinflammatory action. However, much attention has been recently devoted to the action of antimalarials on the so-called cGAS-STING pathway deputed to the sensing of nucleic acid and to the production of type 1 interferons. This pathway is a fundamental mechanism for host defence, since it is able to detect microbial DNA and RNA and induce the immune response that will lead to the production of interferons. Of note, genetic defects in disposal of nucleic acids lead to inappropriate activation of the cGAS-STING pathway and inflammation. These disorders, named type I interferonopathies, represent a valuable model to study the antinflammatory potential of antimalarials.We will discuss possible development of antimalarials to improve the treatment of type I interferonopathies and, likely multifactorial disorders characterised by interferon inflammation, such as systemic lupus erythematosus.

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Endosomal Toll‐like receptors in clinically overt and silent autoimmunity

Cited by 38 publications

References 60 publications

Clinical and Immunologic Profiles in Incomplete Lupus Erythematosus and Improvement with Hydroxychloroquine Treatment

Clinical and Immunologic Profiles in Incomplete Lupus Erythematosus and Improvement with Hydroxychloroquine Treatment

Dysregulation of innate and adaptive serum mediators precedes systemic lupus erythematosus classification and improves prognostic accuracy of autoantibodies

Reappraisal of Antimalarials in Interferonopathies: New Perspectives for Old Drugs

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