Balance between Regulatory T and Th17 Cells in Systemic Lupus Erythematosus: The Old and the New

Alunno, Alessia; Bartoloni, Elena; Bistoni, Onelia; Nocentini, Giuseppe; Ronchetti, Simona; Caterbi, Sara; Valentini, Valentina; Riccardi, Carlo; Gerli, Roberto

doi:10.1155/2012/823085

Cited by 130 publications

(90 citation statements)

References 69 publications

(65 reference statements)

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“…It is reported that IFN-I significantly lowers the threshold of T and B cell activation [8], prolongs the survival of activated T cells and promotes memory T cell development [50]. Additionally, IFN-I suppresses regulatory T cell (T reg ) functions and increases Th17 differentiation, which will result in an expansion of autoreactive T cells [51,52]. With regard to B cells, IFN-I induces the production of B lymphocyte stimulator (BLyS), supporting B cell activation and differentiation through the B cell receptor, as well as facilitating Ig class-switching to generate potentially pathogenic autoantibodies [53,54].…”

Section: Role Of Dsdna In Antibody Productionmentioning

confidence: 99%

Self-dsDNA in the pathogenesis of systemic lupus erythematosus

Bai

Tong

Liu

et al. 2017

Clinical and Experimental Immunology

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SummarySystemic lupus erythematosus (SLE) is a systemic and poly-aetiological autoimmune disease characterized by the production of antibodies to autologous double-stranded DNA (dsDNA) which serve as diagnostic and prognostic markers. The defective clearance of apoptotic material, together with neutrophil extracellular traps (NETs), provides abundant chromatin or self-dsDNA to trigger the production of anti-dsDNA antibodies, although the mechanisms remain to be elucidated. In SLE patients, the immune complex (IC) of dsDNA and its autoantibodies trigger the robust type I interferon (IFN-I) production through intracellular DNA sensors, which drives the adaptive immune system to break down self-tolerance. In this review, we will discuss the potential resources of self-dsDNA, the mechanisms of self-dsDNA-mediated inflammation through various DNA sensors and its functions in SLE pathogenesis.

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Section: Role Of Dsdna In Antibody Productionmentioning

confidence: 99%

Self-dsDNA in the pathogenesis of systemic lupus erythematosus

Bai

Tong

Liu

et al. 2017

Clinical and Experimental Immunology

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“…The impact of Th17/regulatory T (Treg) immune imbalances (i.e., elevated Th17 response, depressed Treg function) is critical to the pathogenesis of SLE [4][5][6][7], just like other autoimmune diseases [8]. Interleukin (IL)-17A, IL-17F, and IL-22 production by Th17 cells promotes the autoimmune response [9].…”

Section: Introductionmentioning

confidence: 99%

Chloroquine Autophagic Inhibition Rebalances Th17/Treg-Mediated Immunity and Ameliorates Systemic Lupus Erythematosus

An¹,

Chen²,

Wang³

et al. 2017

Cell Physiol Biochem

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Background: Imbalanced cellular immunity is critical to the pathogenesis of systemic lupus erythematosus (SLE). Recently, autophagy has emerged as a key homeostatic mechanism in T lymphocytes. This study was conducted to explore the impact of autophagy on the Th17/ regulatory T (Treg) immune imbalance in SLE. Methods: Peripheral Th17 and Treg cells from newly diagnosed patients with SLE and healthy controls were detected by flow cytometry. Additionally, the effects of chloroquine (CQ) autophagic inhibition on the Th17/Treg immune response were investigated in vitro. In addition, hydroxychloroquine (HCQ) treatment of the Th17/Treg immune response and the disease progression of lupus MRL/lpr mice were studied in vivo. Results: Compared with healthy controls, both peripheral Th17 and Treg cells of patients with SLE exhibited activated autophagy, resulting in a heightened Th17 proinflammatory response and diminished Treg immunosuppression. Furthermore, in vitro experiments indicated that CQ autophagic inhibition effectively rebalanced the Th17/Treg immune responses in patients with SLE. In vivo studies of MRL/lpr mice similarly confirmed that HCQ treatment decisively inhibited the autophagy of Th17/Treg cellular subsets, restoring the immune balance, lowering the serum levels of inflammatory cytokines and autoantibodies, and improving renal histopathology. Conclusion: Activated autophagy contributed to the Th17/Treg immune imbalance in SLE, and chloroquine autophagic inhibition rebalanced Th17/ Treg-mediated immunity and ameliorated SLE.N. An, Y. Chen and C. Wang contributed equally to this work.

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“…This widely accepted theory about the pathology of MS was based on data from experiments with EAE, the animal model of MS. SLE is an autoimmune disorder characterized by chronic inflammation that can affect virtually any organ and the presence of autoantibodies directed mostly against nuclear antigens (7). Patients with SLE or lupus-prone mice exhibit an imbalance between Th17 cells and Tregs (13), which can partly be explained by deficient IL-2 production, as IL-2 is necessary for the maintenance of Tregs and inhibition of Th17 differentiation (14)(15)(16)(17). Low numbers of Tregs, along with high numbers of Th17 cells, could contribute to organ damage in SLE triggered by immune complexes, autoantibodies, inflammatory cytokines, and activated T cells.…”

Section: Introductionmentioning

confidence: 99%

CaMK4-dependent activation of AKT/mTOR and CREM-α underlies autoimmunity-associated Th17 imbalance

Koga¹,

Hedrich²,

Mizui³

et al. 2014

J. Clin. Invest.

187

162

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Tissue inflammation in several autoimmune diseases, including SLE and MS, has been linked to an imbalance of IL-17-producing Th (Th17) cells and Tregs; however, the factors that promote Th17-driven autoimmunity are unclear. Here, we present evidence that the calcium/calmodulin-dependent protein kinase IV (CaMK4) is increased and required during Th17 cell differentiation. Isolation of naive T cells from a murine model of lupus revealed increased levels of CaMK4 following stimulation with Th17-inducing cytokines but not following Treg, Th1, or Th2 induction. Furthermore, naive T cells from mice lacking CaMK4 did not produce IL-17. Genetic or pharmacologic inhibition of CaMK4 decreased the frequency of IL-17-producing T cells and ameliorated EAE and lupus-like disease in murine models. Inhibition of CaMK4 reduced Il17 transcription through decreased activation of the cAMP response element modulator α (CREM-α) and reduced activation of the AKT/mTOR pathway, which is known to enhance Th17 differentiation. Importantly, silencing CaMK4 in T cells from patients with SLE and healthy individuals inhibited Th17 differentiation through reduction of IL17A and IL17F mRNA. Collectively, our results suggest that CaMK4 inhibition has potential as a therapeutic strategy for Th17-driven autoimmune diseases.

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Balance between Regulatory T and Th17 Cells in Systemic Lupus Erythematosus: The Old and the New

Cited by 130 publications

References 69 publications

Self-dsDNA in the pathogenesis of systemic lupus erythematosus

Self-dsDNA in the pathogenesis of systemic lupus erythematosus

Chloroquine Autophagic Inhibition Rebalances Th17/Treg-Mediated Immunity and Ameliorates Systemic Lupus Erythematosus

CaMK4-dependent activation of AKT/mTOR and CREM-α underlies autoimmunity-associated Th17 imbalance

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