T cell signaling abnormalities contribute to aberrant immune cell function and autoimmunity

Moulton, Vaishali R.; Tsokos, George C.

doi:10.1172/jci78087

Cited by 196 publications

(154 citation statements)

References 107 publications

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“…Thus, the early elevation of IFN-γ, followed by significant increases in BLyS and APRIL when within one year of disease classification when SLE is imminent, supports the model that simultaneous dysregulation of T helper, regulatory, IFN-related, and TNF-related pathways may unleash an inflammatory cycle that erodes immune tolerance to a point where clinical disease is inevitable [18]. Such alterations are likely due to abnormalities in receptor-mediated proximal and distal signaling pathways [68], many of which are current targets for novel therapeutic approaches to dampen inflammation and target organ damage in SLE [69]. Additional, future studies will be required to determine if dysregulation of signaling pathways that leads to aberrant cellular activation and secretion of inflammatory mediators is due to genetic [23, 70], epigenetic [71], and/or environmental triggers, such as vitamin D deficiency [51] and/or immune dysregulation caused by latent Epstein-Barr viral infection [72, 73].…”

Section: Discussionmentioning

confidence: 76%

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

143

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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Section: Discussionmentioning

confidence: 76%

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

143

130

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“…It is a key cytokine involved in the pathogenesis of autoimmune diseases including SLE [10, 33, 34]. Increased number of Th17 cells as well as high serum levels of IL-17 has been demonstrated in SLE patients [35–37].…”

Section: Il-17 In Slementioning

confidence: 99%

T cells and IL-17 in lupus nephritis

Koga

Ichinose

Tsokos

2017

Clinical Immunology

Self Cite

104

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Systemic lupus erythematosus (SLE) is a complicated autoimmune disorder characterized by autoantibodies production, immune complex formation, and immune dysregulation, resulting in damage of multiple organs including the kidney. Lupus nephritis (LN) is the most common severe manifestation of SLE involving the majority of patients. Even though there are a number of reports indicating that interleukin-17 (IL-17) and Th17 cells play important roles in the pathogenesis of LN, the precise molecular mechanisms underline the development of LN have not been totally elucidated. In this review, we briefly summarize general characteristics of T and IL-17 cells in SLE. In addition, we discuss in detail T cell signaling pathways which control IL-17 production in patients with LN and in glomerulonephritis in lupus-prone mice. A better understanding of signaling and gene regulation defects in LN will lead to the identification of novel therapeutic targets and predictive biomarkers for diagnosis and prognosis of this disease.

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“…Teff cells contribute to the immune response by producing pro-inflammatory cytokines, whereas Treg cells suppress immunity and inflammation. Overactive Teff cells and pro-inflammatory cytokine production have been implicated in the pathogenesis of systemic lupus erythematosus (SLE) (1). Studies in SLE patients and murine models of lupus have shown increased frequencies of Th1 and Th17 cells, as well as enhanced level of IFNγ and IL-17 (2–4).…”

Section: Introductionmentioning

confidence: 99%

Glucose Oxidation Is Critical for CD4+ T Cell Activation in a Mouse Model of Systemic Lupus Erythematosus

Yin

Choi

et al. 2016

The Journal of Immunology

140

132

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We have previously shown that CD4+ T cells from B6.Sle1.Sle2.Sle3 (TC) lupus mice and patients present a high cellular metabolism, and a treatment combining 2-deoxyglucose (2DG), which inhibits glucose metabolism, and metformin, which inhibits oxygen consumption, normalized lupus T cell functions in vitro and reverted disease in mice. We obtained similar results with B6.lpr mice, another model of lupus, and showed that a continuous treatment is required to maintain the beneficial effect of metabolic inhibitors. Further, we investigated the relative roles of glucose oxidation and pyruvate reduction into lactate in this process.. Treatments of TC mice with either 2DG or metformin were sufficient to prevent autoimmune activation, while their combination was necessary to reverse the process. Treatment of TC mice with dichloroacetate (DCA), an inhibitor of lactate production, failed to effectively prevent or reverse autoimmune pathology. In vitro, CD4+ T cell activation upregulated the expression of genes that favor oxidative phosphorylation. Blocking glucose oxidation inhibited both IFNγ and IL-17 production, which could not be achieved by blocking pyruvate reduction. Overall, our data shows that targeting glucose oxidation is required to prevent or reverse lupus development in mice, which cannot be achieved by simply targeting the pyruvate-lactate conversion.

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T cell signaling abnormalities contribute to aberrant immune cell function and autoimmunity

Abstract: R e v i e w S e R i e S : A u t o i m m u n i t y2 2 2 1

Cited by 196 publications

References 107 publications

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

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

T cells and IL-17 in lupus nephritis

Glucose Oxidation Is Critical for CD4+ T Cell Activation in a Mouse Model of Systemic Lupus Erythematosus

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