scholarly journals Selectins impair regulatory T cell function and contribute to systemic lupus erythematosus pathogenesis

2021 ◽  
Vol 13 (600) ◽  
pp. eabi4994
Author(s):  
Marc Scherlinger ◽  
Vivien Guillotin ◽  
Isabelle Douchet ◽  
Pierre Vacher ◽  
Andréa Boizard-Moracchini ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Transforming Growth Factor ◽  
Cell Function ◽  
Transforming Growth Factor Β ◽  
Systemic Autoimmune Disease ◽  
Systemic Lupus ◽  
Autoantibody Production ◽  
Systemic Lupus Erythematosus Pathogenesis ◽  
Dsdna Antibody

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a loss of tolerance toward self-nucleic acids, autoantibody production, interferon expression and signaling, and a defect in the regulatory T (Treg) cell compartment. In this work, we identified that platelets from patients with active SLE preferentially interacted with Treg cells via the P-selectin/P-selectin glycoprotein ligand-1 (PSGL-1) axis. Selectin interaction with PSGL-1 blocked the regulatory and suppressive properties of Treg cells and particularly follicular Treg cells by triggering Syk phosphorylation and an increase in intracytosolic calcium. Mechanistically, P-selectin engagement on Treg cells induced a down-regulation of the transforming growth factor–β axis, altering the phenotype of Treg cells and limiting their immunosuppressive responses. In patients with SLE, we found an up-regulation of P- and E-selectin both on microparticles and in their soluble forms that correlated with disease activity. Last, blocking P-selectin in a mouse model of SLE improved cardinal features of the disease, such as anti-dsDNA antibody concentrations and kidney pathology. Overall, our results identify a P-selectin–dependent pathway that is active in patients with SLE and validate it as a potential therapeutic avenue.

Systemic lupus erythematosus

2018 ◽  
Author(s):  
Chee-Seng Yee
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Immune System ◽  
Lupus Erythematosus ◽  
Cell Function ◽  
Adaptive Immune System ◽  
Unknown Etiology ◽  
Inflammatory Disorder ◽  
Systemic Lupus ◽  
Autoantibody Production ◽  
Cellular Apoptosis

Systemic lupus erythematosus is a chronic multisystem autoimmune inflammatory disorder of unknown etiology. Numerous abnormalities within the innate and adaptive immune system have been described. The hallmark of this disease is B-cell hyperactivity resulting in autoantibody production, abnormal T-cell function, impaired clearance of immune complexes (resulting in their deposition in tissues), complement activation, and defective cellular apoptosis. However, these abnormalities of the immune system are not uniform across patients or within the same patient at different stages of the disease, resulting in heterogeneity in its presentation and progress.

A novel role of peptidyl-prolyl isomerase-1 as inducer of IL-6 expression in systemic lupus erythematosus

2015 ◽  
Vol 3 (2) ◽  
pp. 139-152
Author(s):  
Michael R Takeno ◽  
Jacob B Gunn
Keyword(s):  
Systemic Lupus Erythematosus ◽  
T Cell Activation ◽  
Lupus Erythematosus ◽  
Molecular Mechanisms ◽  
Clinical Manifestations ◽  
Systemic Autoimmune Disease ◽  
Systemic Lupus ◽  
Autoantibody Production ◽  
Stat3 Phosphorylation ◽  
Pin1 Inhibitor

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with various clinical manifestations affecting different tissues. Pro-inflammatory cytokines, such as interleukin 1β, IL-6 and IFN-g are associated with the SLE progression; however, the precise molecular mechanisms that in occurs improper cytokines production in SLE remain unknown. Autoantibody production and renal disease were evaluated in NZB/W F1 mice treated with a specific Pin1 inhibitor, Juglone. Inhibition of Pin1 activity significantly suppressed the IL-6 expression in NZB/W F1 mice and developed milder renal lesions than the lesions developing in non Juglone-treated mice. We further found that Pin1 inhibitor treatment suppresses B-cell differentiation and T-cell activation in NZB/W F1 lupus mice. Finally, stat3 phosphorylation was decreased in T cells from Pin1inhibitor-treated mice at 40 weeks of age as compared to that from the saline and isotype control mAb treatment groups. This is the first study to demonstrate that Pin1 plays critical roles in SLE development. Pin1 inhibition to the appropriate level might provide a novel therapeutic strategy target for future SLE therapies.

A novel role of peptidyl-prolyl isomerase-1 as inducer of IL-6 expression in systemic lupus erythematosus

2015 ◽  
Vol 3 (2) ◽  
pp. 439-450
Author(s):  
Michael R Takeno ◽  
Jacob B Gunn ◽  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
T Cell Activation ◽  
Lupus Erythematosus ◽  
Molecular Mechanisms ◽  
Clinical Manifestations ◽  
Systemic Autoimmune Disease ◽  
Systemic Lupus ◽  
Autoantibody Production ◽  
Stat3 Phosphorylation ◽  
Pin1 Inhibitor

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with various clinical manifestations affecting different tissues. Pro-inflammatory cytokines, such as interleukin 1β, IL-6 and IFN-g are associated with the SLE progression; however, the precise molecular mechanisms that in occurs improper cytokines production in SLE remain unknown. Autoantibody production and renal disease were evaluated in NZB/W F1 mice treated with a specific Pin1 inhibitor, Juglone. Inhibition of Pin1 activity significantly suppressed the IL-6 expression in NZB/W F1 mice and developed milder renal lesions than the lesions developing in non Juglone-treated mice. We further found that Pin1 inhibitor treatment suppresses B-cell differentiation and T-cell activation in NZB/W F1 lupus mice. Finally, stat3 phosphorylation was decreased in T cells from Pin1inhibitor-treated mice at 40 weeks of age as compared to that from the saline and isotype control mAb treatment groups. This is the first study to demonstrate that Pin1 plays critical roles in SLE development. Pin1 inhibition to the appropriate level might provide a novel therapeutic strategy target for future SLE therapies.

The Circulating Cell-free microRNA Profile in Systemic Sclerosis Is Distinct from Both Healthy Controls and Systemic Lupus Erythematosus

2014 ◽  
Vol 42 (2) ◽  
pp. 214-221 ◽  
Author(s):  
Samantha O. Steen ◽  
Line V. Iversen ◽  
Anting Liu Carlsen ◽  
Mark Burton ◽  
Christoffer T. Nielsen ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Systemic Sclerosis ◽  
Expression Profile ◽  
Lupus Erythematosus ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Stepwise Logistic Regression ◽  
Circulating Microrna ◽  
Healthy Controls ◽  
Systemic Lupus

Objective.To evaluate the expression profile of cell-free circulating microRNA (miRNA) in systemic sclerosis (SSc), healthy controls (HC), and systemic lupus erythematosus (SLE).Methods.Total RNA was purified from plasma and 45 different, mature miRNA were measured using quantitative PCR assays after reverse transcription. Samples (n = 189) were from patients with SSc (n = 120), SLE (n = 29), and from HC (n = 40). Expression data were clustered by principal components analysis, and diagnostically specific miRNA profiles were developed by leave-one-out cross-validation. Diagnostic probability scores were derived from stepwise logistic regression.Results.Thirty-seven miRNA specificities were consistently detected and 26 of these were unaffected by SSc sample age and present in more than two-thirds of SSc samples. SSc cases showed a distinct expression profile with 14/26 miRNA significantly decreased (false discovery rate < 0.05) and 5/26 increased compared with HC. A 21-miRNA classifier gave optimum accuracy (80%) for discriminating SSc from both HC and SLE. The discrimination between HC and SSc (95% accuracy) was strongly driven by miRNA of the 17∼92 cluster and by miR-16, -223, and -638, while SLE and SSc differed mainly in the expression of miR-142-3p, -150, -223, and -638. Except for a weak correlation between anti-Scl-70 and miR-638 (p = 0.048), there were no correlations with other patient variables.Conclusion.Circulating miRNA profiles are characteristic for SSc compared with both HC and SLE cases. Some of the predicted targets of the differentially regulated miRNA are of relevance for transforming growth factor-β signaling and fibrosis, but need to be validated in independent studies.

scholarly journals When systemic lupus erythematosus affects vision: a rare presentation of this condition

2020 ◽  
Vol 13 (1) ◽  
pp. e229382
Author(s):  
Tiago Gama Ramires ◽  
Luísa Vieira ◽  
Nuno Riso ◽  
Maria Francisca Moraes-Fontes
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Systemic Lupus ◽  
Blurred Vision ◽  
Rare Presentation ◽  
Complement Components ◽  
Oral Ulcers ◽  
Dsdna Antibody ◽  
Rare Manifestation ◽  
Retinal Vascular Tortuosity

A 23-year-old woman with fever, oral ulcers, arthalgias and weight loss of 2-week duration suddenly developed blurred vision, with reduced visual acuity, cotton wool exudates and retinal vascular tortuosity. Laboratory testing revealed anaemia, lymphopaenia, positive antinuclear antibody and high anti-dsDNA antibody titre with low complement components. There was no evidence of infection, clinching the diagnosis of lupus retinopathy. Steroid therapy alone was highly effective and was also accompanied by a normalisation of haemoglobin and lymphocyte counts, after which azathioprine was added. Hydroxychloroquine was introduced after resolution of retinal changes. Immunosuppressive therapy was progressively tapered over the course of 12 months and then discontinued, and the patient remains in remission 48 months after the initial presentation. Our patient exemplifies a very rare manifestation of systemic lupus erythematosus. We emphasise the importance of its early detection and complexity of treatment in order to reduce visual morbidity.

scholarly journals The expansion of activated naive DNA autoreactive B cells and its association with disease activity in systemic lupus erythematosus patients

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Kittikorn Wangriatisak ◽  
Chokchai Thanadetsuntorn ◽  
Thamonwan Krittayapoositpot ◽  
Chaniya Leepiyasakulchai ◽  
Thanitta Suangtamai ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cells ◽  
Disease Activity ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Systemic Lupus ◽  
Autoreactive B Cells ◽  
Dsdna Antibody ◽  
Cell Subpopulations ◽  
B Cell Subsets

Abstract Background Autoreactive B cells are well recognized as key participants in the pathogenesis of systemic lupus erythematosus (SLE). However, elucidating the particular subset of B cells in producing anti-dsDNA antibodies is limited due to their B cell heterogeneity. This study aimed to identify peripheral B cell subpopulations that display autoreactivity to DNA and contribute to lupus pathogenesis. Methods Flow cytometry was used to detect total B cell subsets (n = 20) and DNA autoreactive B cells (n = 15) in SLE patients’ peripheral blood. Clinical disease activities were assessed in SLE patients using modified SLEDAI-2 K and used for correlation analyses with expanded B cell subsets and DNA autoreactive B cells. Results The increases of circulating double negative 2 (DN2) and activated naïve (aNAV) B cells were significantly observed in SLE patients. Expanded B cell subsets and DNA autoreactive B cells represented a high proportion of aNAV B cells with overexpression of CD69 and CD86. The frequencies of aNAV B cells in total B cell populations were significantly correlated with modified SLEDAI-2 K scores. Further analysis showed that expansion of aNAV DNA autoreactive B cells was more related to disease activity and serum anti-dsDNA antibody levels than to total aNAV B cells. Conclusion Our study demonstrated an expansion of aNAV B cells in SLE patients. The association between the frequency of aNAV B cells and disease activity patients suggested that these expanded B cells may play a role in SLE pathogenesis.

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